bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chondrotoxicity of Low pH, Epinephrine, and Preservatives Found in Local Anesthetics Containing Epinephrine
Authors: Dragoo Jason L. , Korotkova Tatiana , Kim Hyeon Joo , Jagadish Anubhav 
Published: March 2010

Background: Recent clinical and basic science investigations have revealed the chondrotoxicity of local anesthetics, especially those containing epinephrine, administered via an intra-articular pain pump. However, the exact mechanism of toxicity is unknown. This study evaluates the chondrotoxicity of low pH, epinephrine, and preservatives found in commonly used local anesthetics. Hypothesis: The chondrotoxicity of local anesthetics containing epinephrine is due to low pH, epinephrine, or the preservative sodium metabisulfite. Study Design: Controlled laboratory study. Methods: Human chondrocytes were harvested and cultured in a custom bioreactor designed to simulate metabolism of medication. Pain pumps were used to infuse one of the following medications into the culture system: control media; media titrated to pH 4.5, 5.0, 5.5, 6.0, 6.5; media with 1:100000 or 1:200000 epinephrine only; media with 0.5 mg/mL of sodium metabisulfite preservative; media with 0.5 mg/mL of methylparaben preservative, 0.25% bupivacaine, 0.25% bupivacaine with epinephrine, 1% lidocaine, and 1% lidocaine with epinephrine. Cultures were perfused for 24 hours and then were stained with live/dead cell viability assay. The chondrocytes were then examined by fluorescence microscopy and counted, and the percentage of cell death was calculated. Results: Cultures containing media titrated to pH 4.5 and 5.0 and local anesthetics containing epinephrine (pH 4.0-5.5) had high cell death rates compared with controls at all time points ( P < .001), while cultures containing 1:100000 and 1:200000 epinephrine alone had no increased death rate. Also, 0.5 mg/mL sodium metabisulfite preservative had a significant effect on cell death ( P < .034); however, the preservative methylparaben had no effect ( P > .05). The percentage of cell death was not significant for 1% lidocaine (12.5%; P > .943) and 0.25% bupivacaine (16.5%; P > .609). Conclusion: The marked chondrotoxicity of local anesthetics containing epinephrine appears to be a combined effect of low pH, as these medications are titrated to pH 4.0 to 5.5 for product stability, and the preservative sodium metabisulfite. Extreme caution should be exercised when using intra-articular pain pumps with local anesthetics containing epinephrine. Clinical Relevance: Understanding the causes of chondrotoxicity using local anesthetics containing epinephrine is critical to decrease complications associated with this class of medications.
Supporting persons with Down syndrome and advanced dementia
Authors: McCarron Mary , McCallion Philip , Fahey-McCarthy Elizabeth , Connaire Kevin , Dunn-Lane Jean 
Published: March 2010

Aim: To understand staff perceptions of critical issues in caring for persons with intellectual disability (ID) and advanced dementia. Background: There has been growing interest in addressing resource, training, and service redesign issues including an increase in collaborative practices in response to the growing incidence of dementia among persons with ID. Most recently this has included consideration of the specific issues in advanced dementia. Method: Thirteen focus group interviews were held involving staff in six ID services and one specialist palliative care provider in Ireland. A qualitative descriptive approach was taken to analysis. Results: Staff identified three key themes: (1) readiness to respond to end of life needs, (2) the fear of swallowing difficulties, and (3) environmental concerns and ageing in place. Discussion: Four underlying issues that emerged in this study offer clues to solutions: (a) differences in staff preparation associated with settings, (b) lack of understanding and lack of collaboration with palliative care services, (c) uncertainties about the ability to transfer existing palliative care models to persons with ID and dementia and (d) the need to develop training on end stage dementia and related care approaches.
Structural Health Monitoring, In-service Experience, Benefit and Way Ahead
Authors: Stolz Christian , Neumair Manfred 
Published: March 2010

The structural health monitoring (SHM) is an important requirement to handle military aircraft safety. In contrast with civil aircraft, the missions, configurations and environments are changing frequently and therefore also the load spectra, which lead to a various life consumption. To ensure the structural integrity of the airframe and structural systems by SHM systems the following four functions are essential: Event and fatigue monitoring, including remaining life assessment and damage detection monitoring. This is the basis for an economic and safety in-service operation of a flying weapon system. This article shows the way from a simple monitoring system to a state-of-the-art support system based on examples from the German Air Force (GAF). From a military aircraft manufacturer’s point of view, the pro and contra of these systems based on in-service experience of various aircraft types are listed. Referring to this experience the benefit of the modernization of SHM-System will be presented and the requirements on a modern SHM-System especially for the ground support system and the logistic and in addition for new monitoring areas will be worked out. The approach for hot spot monitoring for damage detection is explained. A special view will be given on the possible integration of modern damage detection methods in existing and new SHM-Systems. Furthermore the combination of damage detection system and existing usage monitoring systems opens the way for enhanced monitoring systems.
Safety and efficacy of weekly 5-fluorouracil/ folinic acid/oxaliplatin/irinotecan in the first-line treatment of gastrointestinal cancer
Authors: Peinert Stefan , Grothe Wilfried , Stein Alexander , Müller Lutz P. , Ruessel Joern , Voigt Wieland , Schmoll Hans-Joachim , Arnold Dirk 
Published: March 2010

Background: Standard chemotherapy for patients with metastatic colorectal cancer (mCRC) or gastric cancer (GC) consists of two-drug, usually fluoropyrimidine-based, combinations, with or without the addition of biological agents. Studies of triple-drug regimens combining 5-fluorouracil (5-FU)/folinic acid (FA) with both oxaliplatin and irinotecan have shown promising efficacy in studies of patients with mCRC or GC. However, improved efficacy has often been achieved at the expense of high rates of grade 3 or 4 toxicities such as neutropenia and diarrhoea, occasionally even resulting in toxic deaths. Objective/Methods: We performed a phase II study of previously untreated patients with mCRC or GC to assess the safety and efficacy of our 5-fluorouracil/folinic acid/oxaliplatin/irinotecan (FUFOXIRI) regimen with weekly administration of irinotecan 70 mg/m 2, oxaliplatin 50 mg/m2, FA 500 mg/m2 and 5-FU 2000 mg/m2 on days 1, 8, 15 and 22, repeated from day 36. Results: A total of 22 patients were enrolled, 11 each with mCRC and GC receiving a median of four cycles per patient. The FUFOXIRI regimen was generally well tolerated with no toxic deaths, neutropenic fever or grade 4 toxicities. Most common grade 3 side effects were diarrhoea and neutropenia each affecting 24% of patients. Dose reductions due to toxicity were performed in 48% of all and 60% of patients having received at least two cycles of FUFOXIRI. The overall response rate was 46% (all partial responses), 55% and 36% for patients with mCRC and GC, respectively. Median progression-free survival for all patients, mCRC and GC patients was 9.5, 10.0 and 8.0 months, respectively. The median overall survival for all patients was 16.5, 18.0 and 15.0 months for patients with mCRC and GC, respectively. Conclusion: These data show excellent tolerance and efficacy of the FUFOXIRI regimen in both mCRC and GC. Therefore, FUFOXIRI is a promising backbone for future studies incorporating biologic ‘targeted’ agents for the treatment of gastrointestinal cancers.
CpG-ODN 2006 and human parvovirus B19 genome consensus sequences selectively inhibit growth and development of erythroid progenitor cells
Authors: Guo Yong-Mei , Ishii Keiko , Hirokawa Makoto , Tagawa Hiroyuki , Ohyagi Hideaki , Michishita Yoshihiro , Ubukawa Kumi , Yamashita Junsuke , Ohteki Toshiaki , Onai Nobuyuki , Kawakami Kazuyoshi , Xiao Weiguo , Sawada Kenichi 
Published: March 2010

AbstractRecent studies have shown that anemia is commonly observed after exposure to pathogens or pathogen-derived products, which are recognized via Toll-like receptor 9 (TLR9). In the current study, we demonstrate that CpG oligodeoxynucleotide-2006, a TLR9 ligand with phosphodiester (PO; 2006-PO) but not with the phosphorothioate backbone, selectively inhibits the erythroid growth derived from human CD34+ cells. The 2006-PO was internalized by the erythroid progenitors within 30 minutes; however, expression of TLR9 mRNA was not detected in these cells. The 2006-PO directly inhibited burst-forming unit-erythroid growth, resulted in the accumulation of cells in S and G2/M phases, and increased cell size and frequency of apoptotic cells. These features were similar to those observed in erythroid progenitors infected with human parvovirus B19 that causes pure red cell aplasia. The consensus sequence of 2006-PO was defined as 5′-GTTTTGT-3′, which was located in the P6-promoter region of B19 and inhibited erythroid growth in a sequence-specific manner and down-regulated expression of erythropoietin receptor (EPOR) mRNA and EPOR. B19 genome extracted from serum also inhibited erythroid growth and down-regulated expression of EPOR on glycophorin A+ cells. These results provide a possible insight into our understanding of the mechanisms of human parvovirus B19-mediated inhibition of erythropoiesis.
Long-term study of indolent adult T-cell leukemia-lymphoma
Authors: Takasaki Yumi , Iwanaga Masako , Imaizumi Yoshitaka , Tawara Masayuki , Joh Tatsuro , Kohno Tomoko , Yamada Yasuaki , Kamihira Shimeru , Ikeda Schuichi , Miyazaki Yasushi , Tomonaga Masao , Tsukasaki Kunihiro 
Published: March 2010

Abstract
The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.
The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma
Authors: Spagnuolo Paul A. , Hu Jiayi , Hurren Rose , Wang Xiaoming , Gronda Marcela , Sukhai Mahadeo A. , Di Meo Ashley , Boss Jonathan , Ashali Iman , Beheshti Zavareh Reza , Fine Noah , Simpson Craig D. , Sharmeen Sumaiya , Rottapel Rob , Schimmer Aaron D. 
Published: March 2010

AbstractOn-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we conducted chemical screens and identified the antihelmintic flubendazole. Flubendazole induced cell death in leukemia and myeloma cell lines and primary patient samples at nanomolar concentrations. Moreover, it delayed tumor growth in leukemia and myeloma xenografts without evidence of toxicity. Mechanistically, flubendazole inhibited tubulin polymerization by binding tubulin at a site distinct from vinblastine. In addition, cells resistant to vinblastine because of overexpression of P-glycoprotein remained fully sensitive to flubendazole, indicating that flubendazole can overcome some forms of vinblastine resistance. Given the different mechanisms of action, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. Flubendazole synergized with vinblastine to reduce the viability of OCI-AML2 cells. In addition, combinations of flubendazole with vinblastine or vincristine in a leukemia xenograft model delayed tumor growth more than either drug alone. Therefore, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma.
Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin
Authors: Starr Marlene E. , Ueda Junji , Takahashi Hitoshi , Weiler Hartmut , Esmon Charles T. , Evers B. Mark , Saito Hiroshi 
Published: March 2010

AbstractThe protein C (PC) pathway is an important anticoagulant mechanism that prevents thrombosis during the systemic inflammatory response. Thrombomodulin (TM), an endothelial cell membrane receptor, accelerates the conversion of PC to activated protein C (APC), which leads to the down-regulation of thrombin production and fibrin formation. Induction of acute endotoxemia in young and aged mice with a low dose of bacterial endotoxin lipopolysaccharide (LPS, 2.5 mg/kg) caused a high mortality rate in aged (80%) but not young (0%) mice. After injection with this dose of LPS, fibrin formation was significantly elevated only in aged mice, plasma APC levels were increased only in young mice, and TM expression was profoundly depressed in the aged. The increased thrombosis, suppressed APC level, and decreased TM expression were not observed in young mice receiving a higher dose of LPS (20 mg/kg), which resulted in a mortality rate (78%) equivalent to that seen in aged mice with the low-dose LPS. Mutant mice with reduced TM showed significantly less plasma APC and increased fibrin formation compared with wild-type mice after LPS. These results demonstrate that PC pathway activation is suppressed with aging and is partly responsible for age-associated thrombosis and high mortality during endotoxemia.
Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor
Authors: Zhu Donghui , Wang Yaoming , Singh Itender , Bell Robert D. , Deane Rashid , Zhong Zhihui , Sagare Abhay , Winkler Ethan A. , Zlokovic Berislav V. 
Published: March 2010

AbstractThe anticoagulant factor protein S (PS) has direct cellular activities. Lack of PS in mice causes lethal coagulopathy, ischemic/thrombotic injuries, vascular dysgenesis, and blood-brain barrier (BBB) disruption with intracerebral hemorrhages. Thus, we hypothesized that PS maintains and/or enhances the BBB integrity. Using a BBB model with human brain endothelial cells, we show PS inhibits time- and dose-dependently (half maximal effective concentration [EC50] = 27 ± 3 nM) oxygen/glucose deprivation-induced BBB breakdown, as demonstrated by measurements of the transmonolayer electrical resistance, permeability of endothelial monolayers to dextran (40 kDa), and rearrangement of F-actin toward the cortical cytoskeletal ring. Using Tyro-3, Axl, and Mer (TAM) receptor, tyrosine kinase silencing through RNA interference, specific N-terminus–blocking antibodies, Tyro3 phosphorylation, and Tyro3-, Axl- and Mer-deficient mouse brain endothelial cells, we show that Tyro3 mediates PS vasculoprotection. After Tyro3 ligation, PS activated sphingosine 1-phosphate receptor (S1P1), resulting in Rac1-dependent BBB protection. Using 2-photon in vivo imaging, we show that PS blocks postischemic BBB disruption in Tyro3+/+, Axl−/−, and Mer−/− mice, but not in Tyro3−/− mice or Tyro3+/+ mice receiving low-dose W146, a S1P1-specific antagonist. Our findings indicate that PS protects the BBB integrity via Tyro3 and S1P1, suggesting potentially novel treatments for neurovascular dysfunction resulting from hypoxic/ischemic BBB damage.
Complexity of cis-regulatory organization of six3aduring forebrain and eye development in zebrafish
Authors: Chao Chung-Hao , Wang Horng-Dar , Yuh Chiou-Hwa 
Published: March 2010

Abstract

Background
Six3a belongs to the SIX family of homeodomain proteins and is expressed in the most anterior neural plate at the beginning of neurogenesis in various species. Though the function of Six3a as a crucial regulator of eye and forebrain development has been thoroughly investigated, the transcriptional regulation of six3a is not well understood.

Results
To elucidate the transcriptional regulation of six3a, we performed an in vivo reporter assay. Alignment of the 21-kb region surrounding the zebrafish six3a gene with the analogous region from different species identified several conserved non-coding modules. Transgenesis in zebrafish identified two enhancer elements and one suppressor. The D module drives the GFP reporter in the forebrain and eyes at an early stage, while the A module is responsible for the later expression. The A module also works as a repressor suppressing ectopic expression from the D module. Mutational analysis further minimized the A module to four highly conserved elements and the D module to three elements. Using electrophoresis mobility shift assays, we also provided evidence for the presence of DNA-binding proteins in embryonic nuclear extracts. The transcription factors that may occupy those highly conserved elements were also predicted.

Conclusion
This study provides a comprehensive view of six3a transcription regulation during brain and eye development and offers an opportunity to establish the gene regulatory networks underlying neurogenesis in zebrafish.
The Mediterranean Sea as a barrier to gene flow: evidence from variation in and around the F7 and F12 genomic regions
Authors: Athanasiadis Georgios , González-Pérez Emili , Esteban Esther , Dugoujon Jean-Michel , Stoneking Mark , Moral Pedro 
Published: March 2010

Abstract

Background
The Mediterranean has a long history of interactions among different peoples. In this study, we investigate the genetic relationships among thirteen population samples from the broader Mediterranean region together with three other groups from the Ivory Coast and Bolivia with a particular focus on the genetic structure between North Africa and South Europe. Analyses were carried out on a diverse set of neutral and functional polymorphisms located in and around the coagulation factor VII and XII genomic regions (F7 and F12).

Results
Principal component analysis revealed a significant clustering of the Mediterranean samples into North African and South European groups consistent with the results from the hierarchical AMOVA, which showed a low but significant differentiation between groups from the two shores. For the same range of geographic distances, populations from each side of the Mediterranean were found to differ genetically more than populations within the same side. To further investigate this differentiation, we carried out haplotype analyses, which provided partial evidence that sub-Saharan gene flow was higher towards North Africa than South Europe.

Conclusions
As there is no consensus between the two genomic regions regarding gene flow through the Sahara, it is hard to reach a solid conclusion about its role in the differentiation between the two Mediterranean shores and more data are necessary to reach a definite conclusion. However our data suggest that the Mediterranean Sea was at least partially a barrier to gene flow between the two shores.
Escherichia coli infection induces distinct local and systemic transcriptome responses in the mammary gland
Authors: Mitterhuemer Simone , Petzl Wolfram , Krebs Stefan , Mehne Daniel , Klanner Andrea , Wolf Eckhard , Zerbe Holm , Blum Helmut 
Published: March 2010

AbstractBackgroundColiform bacteria are the most common etiologic agents in severe mastitis of cows.Escherichia coliinfections are mostly restricted to a single udder quarter whereas neighboring quarters stay clinically inapparent, implicating the presence of a systemic defense reaction. To address its underlying mechanism, we performed a transcriptome study of mammary tissue from udder quarters inoculated withE. coli(6 h and 24 h post infection), from neighboring quarters of the same animals, and from untreated control animals.ResultsAfter 6 h 13 probe sets of differentially expressed genes (DEG) were detected in infected quarters versus control animals. Eighteen hours later 2154 and 476 DEG were found in infected and in neighboring quarters vs. control animals. Cluster analysis revealed DEG found only in infected quarters (local response) and DEG detected in both infected and neighboring quarters (systemic response). The first group includes genes mainly involved in immune response and inflammation, while the systemic reaction comprises antigen processing and presentation, cytokines, protein degradation and apoptosis. Enhanced expression of antimicrobial genes (S100A8,S100A9,S100A12,CXCL2,GNLY), acute phase genes (LBP,SAA3,CP,BF, C6,C4BPA,IF), and indicators of oxidative stress (GPX3,MT1A,MT2A,SOD2) point to an active defense reaction in infected and neighboring healthy quarters. Its early onset is indicated by increased transcription ofNFIL3at 6 h. NFIL3 is a predicted regulator of many genes of the systemic response at 24 h. The significance of our transcriptome study was evidenced by some recent findings with candidate gene based approaches.ConclusionsThe discovery and holistic analysis of an extensive systemic reaction in the mammary gland significantly expands the knowledge of host-pathogen interactions in mastitis which may be relevant for the development of novel therapies and for genetic selection towards mastitis resistance.