bluuebunny/crossref_metadata_2025 huggingface dataset:
Motivations, Obstacles, and Resources: The Adoption Of The General-Purpose Local Option Sales Tax in Georgia Counties
Authors: Zhao Zhirong
Published: October 2005

Local governments in Georgia have been authorized since the 1970s to levy a 1 percent general-purpose Local Option Sales Tax (LOST), which is earmarked for property tax relief. Using data during 1975 to 2002, this study examines the adoption of the LOST through a discrete-time event history analysis. The dependent variable is the probability that an eligible county will adopt it in a particular year. This probability is negatively related to the obstacles prohibiting the innovation and positively related to (1) the motivations to innovate and (2) the resources for overcoming the obstacles. The findings suggest that the motivations are higher in counties with higher property tax millage rates and the potential of sales tax exportation; the obstacles include high existing sales tax rates and severe tax competition; and the major resource for overcoming these obstacles is the adoption of the LOST in other Georgia counties.
Is the Mesolithic–Neolithic Subsistence Dichotomy Real? New Stable Isotope Evidence from the Danube Gorges
Authors: Borić Dušan , Grupe Gisela , Peters Joris , Mikić Živko
Published: October 2005

The article presents new results of stable isotope analyses made on animal and human bones from the Mesolithic–early Neolithic sites of Lepenski Vir and Vlasac in the Danube Gorges of the Balkans. It reconstructs the food web for the region during these periods on the basis of stable isotope analyses of mammal and fish species found at Vlasac. These results are compared to measurements made on human burials from the two sites. In the light of these new results, the article also discusses interpretations provided by previous isotopic studies of this material. It concludes that great care is required in the interpretation of stable isotope results due to inherent methodological complexities of this type of analysis, and suggests that it is also necessary to integrate stable isotope results with information based on the examination of faunal remains and the archaeological context of analysed burials when making inferences about palaeodietary patterns.
Identity, Gender, Religion and Economy: New Isotope and Radiocarbon Evidence for Marine Resource Intensification in Early Historic Orkney, Scotland, UK
Authors: Barrett James H. , Richards Michael P.
Published: October 2005

Stable isotope measurements and radiocarbon dates on 54 burials from northern Scotland document trends in marine protein consumption from the late Iron Age to the end of the Middle Ages. They illuminate how local environmental and cultural contingencies interrelated with a pan-European trend towards more intensive fishing around the end of the first millennium AD. Little use was made of marine foods in late Iron Age Orkney despite its maritime setting. Significant fish consumption appeared in the Viking Age (ninth to eleventh centuries AD), first in the case of some men buried with grave-goods of Scandinavian style but soon among both sexes in ‘Christian’ burials. There was then a peak in marine protein consumption from approximately the eleventh to the fourteenth centuries AD, particularly among men, after which the importance of fish-eating returned to Viking Age levels. The causes of these developments probably entailed a complex relationship between ethnicity, gender, Christian fasting practices, population growth, long-range fish trade and environmental change.
Deep-Sea Fishing in the European Mesolithic: Fact or Fantasy?
Authors: Pickard Catriona , Bonsall Clive
Published: October 2005

Some previous authors have argued for the practice of offshore, deep-water fishing in the European Mesolithic. In this article, various lines of evidence are brought to bear on this question: the kinds of fishing gear employed, the evidence relating to the use of boats and navigation, site location, ethnographic data, and fish biology and behaviour. It is concluded that the existence of deep-sea fisheries cannot be demonstrated on the basis of the available data. However, around much of Europe Mesolithic shorelines now lie below sea level and the study highlights the need for underwater archaeological investigation of submerged landscapes.
Narwhals or Unicorns? Exotic Animals as Material Culture in Medieval Europe
Authors: Pluskowski Aleksander
Published: October 2005

Animals from distant lands fired the imaginations of people living in Europe throughout the Middle Ages. This is attested by a considerable wealth of iconographic and written material which has been explored from many perspectives, providing valuable insights into medieval western conceptualizations of the fringes of the known world and the otherness of exotica. However, the physical remains of non-indigenous species – both those recovered from archaeological contexts and extant in private collections – have generally been examined in isolation and rarely incorporated into a broader framework exploring the reception and utility of exotica. This article offers a new perspective on the topic by focusing on the zoological identity of non-indigenous animal body parts as ‘material culture’.
Detention of asylum seekers in the US, UK, France, Germany, and Italy
Authors: Welch Michael , Schuster Liza
Published: October 2005

Although criminologists in the US and Europe continue to explore issues of immigration, race, and ethnicity in the context of crime, they have yet to examine the detention of asylum seekers. Still, this is a social phenomenon that requires serious consideration since in many instances such policies and practices violate international standards for the protection of refugees. This work takes a critical look at the detention of persons fleeing persecution by situating it an expanding culture of control stoked by the criminology of the other. The article offers evidence of a steady increase in the reliance on detention of asylum seekers in the US, UK, France, Germany, and Italy. Indications of a conservative shift in criminological thought affecting crime—and asylum—policy are addressed alongside concerns for human rights in a post-September 11 world.
Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets
Authors: Pandey Dharmendra , Goyal Pankaj , Bamburg James R. , Siess Wolfgang
Published: October 2005

Cofilin is a regulator of actin filament dynamics. We studied whether during platelet activation Rho kinase stimulates LIM kinase (LIMK) leading to subsequent phosphorylation and inactivation of cofilin. Platelet shape change and aggregation/secretion were induced by low and high concentrations of thrombin, respectively. We found that during these platelet responses Rho kinase activation was responsible for mediating rapid Thr508 phosphorylation and activation of LIMK-1 and for the F-actin increase during shape change and, in part, during secretion. Surprisingly, during shape change cofilin phosphorylation was unaltered, and during aggregation/secretion cofilin was first rapidly dephosphorylated by an okadaic acid–insensitive phosphatase and then slowly rephosphorylated by LIMK-1. LIMK-1 phosphorylation and cofilin dephosphorylation and rephosphorylation during aggregation were independent of integrin αIIbβ3 engagement. Cofilin phosphorylation did not regulate cofilin association with F-actin and was unrelated to the F-actin increase in thrombin-activated platelets. Our study identifies LIMK-1 as being activated by Rho kinase in thrombin-stimulated platelets. Two counteracting pathways, a cofilin phosphatase and LIMK-1, are activated during platelet aggregation/secretion regulating cofilin phosphorylation sequentially and independently of integrin αIIbβ3 engagement. Rho kinase–mediated F-actin increase during platelet shape change and secretion involves a mechanism other than LIMK-1–mediated cofilin phosphorylation, raising the possibility of another LIMK substrate regulating platelet actin assembly.
Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function
Authors: Williams Cassin Kimmel , Li Ji-Liang , Murga Matilde , Harris Adrian L. , Tosato Giovanna
Published: October 2005

Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The γ-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overerexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.
Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells
Authors: Kawamura Kazuko , Kadowaki Norimitsu , Kitawaki Toshio , Uchiyama Takashi
Published: October 2005

Immune responses to pathogens need to be maintained within appropriate levels to minimize tissue damage, whereas such controlled immunity may allow persistent infection of certain types of pathogens. Interleukin 10 (IL-10) plays an important role in such immune regulation. We previously showed that HSV-stimulated human plasmacytoid dendritic cells (pDCs) induced naive CD4+ T cells to differentiate into interferon γ (IFN-γ)/IL-10–producing T cells. Here we show that HSV-stimulated pDCs induce allogeneic naive CD4+ T cells to differentiate into cytotoxic regulatory T cells that poorly proliferate on restimulation and inhibit proliferation of coexisting naive CD4+ T cells. IL-3–stimulated pDCs or myeloid DCs did not induce such regulatory T cells. Both IFN-α and IL-10 were responsible for the induction of anergic and regulatory properties. High percentages of CD4+ T cells cocultured with HSV-stimulated pDCs, and to a lesser extent those cocultured with IL-3–stimulated pDCs, expressed granzyme B and perforin in an IL-10–dependent manner. CD4+ T cells cocultured with HSV-stimulated pDCs accordingly exhibited cytotoxic activity. The finding that virus-stimulated pDCs are capable of inducing CD4+ cytotoxic regulatory T cells suggests that this DC subset may play an important role in suppressing excessive inflammatory responses and also in inducing persistent viral infection.
SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity
Authors: Yilmaz Ömer H. , Kiel Mark J. , Morrison Sean J.
Published: October 2005

Recent advances have increased the purity of hematopoietic stem cells (HSCs) isolated from young mouse bone marrow. However, little attention has been paid to the purity of HSCs from other contexts. Although Thy-1lowSca-1+Lineage-c-kit+ cells from young bone marrow are highly enriched for HSCs (1 in 5 cells gives long-term multilineage reconstitution after transplantation into irradiated mice), the same population from old, reconstituted, or cytokine-mobilized mice engrafts much less efficiently (1 in 78 to 1 in 185 cells gives long-term multilineage reconstitution). To test whether we could increase the purity of HSCs isolated from these contexts, we examined the SLAM family markers CD150 and CD48. All detectable HSCs from old, reconstituted, and cyclophosphamide/G-CSF-mobilized mice were CD150+CD48-, just as in normal young bone marrow. Thy-1lowSca-1+Lineage-c-kit+ cells from old, reconstituted, or mobilized mice included mainly CD48+ and/or CD150- cells that lacked reconstituting ability. CD150+CD48-Sca-1+Lineage-c-kit+ cells from old, reconstituted, or mobilized mice were much more highly enriched for HSCs, with 1 in 3 to 1 in 7 cells giving long-term multilineage reconstitution. SLAM family receptor expression is conserved among HSCs from diverse contexts, and HSCs from old, reconstituted, and mobilized mice engraft relatively efficiently after transplantation when contaminating cells are eliminated.
Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation
Authors: Goriely Stanislas , Molle Céline , Nguyen Muriel , Albarani Valentina , Haddou Najate Ouled , Lin Rongtuan , De Wit Dominique , Flamand Véronique , Willems Fabienne , Goldman Michel
Published: October 2005

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by dendritic cells (DCs) in response to Toll-like receptor (TLR) ligation. While the mechanisms regulating IL-12p40 chain gene expression are well characterized, molecular events involved in IL-12p35 chain gene activation remain to be clarified. Since IL-12p35 mRNA was induced in human DCs activated through TLR3 or TLR4 but not TLR2, we investigated the potential role of interferon regulatory factor 3 (IRF-3) in IL-12p35 gene transactivation. First, a binding site for IRF-3 named interferon-stimulated response element-1 (ISRE-1) was identified in the human IL-12p35 promoter region between nucleotides -251 and -240. The ISRE-1 site was required for IL-12p35 gene activation in RAW 264.7 cells stimulated by lipopolysaccharide (LPS) or PolyI:C. Ectopic expression of IRF-3 was found to up-regulate IL-12p35 gene activation in the same system. Furthermore, chromatin immunoprecipitation (ChIP) studies demonstrated that IRF-3 is recruited to ISRE-1 site in TLR4- or TLR3-stimulated human DCs. Finally, experiments on DCs from IRF-3-deficient mice established that TLR4-induced IL-12p35 mRNA and IL-12p70 synthesis are impaired in absence of IRF-3. We conclude that IRF-3 binds to a critical cis-acting element in the IL-12p35 gene promoter and thereby represents a key factor for the induction of IL-12p70 synthesis in DCs.
Respiratory epithelial cells require Toll-like receptor 4 for induction of Human β-defensin 2 by Lipopolysaccharide
Authors: MacRedmond Ruth , Greene Catherine , Taggart Clifford C , McElvaney Noel , O'Neill Shane
Published: October 2005

Background

The respiratory epithelium is a major portal of entry for pathogens and employs innate defense mechanisms to prevent colonization and infection. Induced expression of human β-defensin 2 (HBD2) represents a direct response by the epithelium to potential infection. Here we provide evidence for the critical role of Toll-like receptor 4 (TLR4) in lipopolysaccharide (LPS)-induced HBD2 expression by human A549 epithelial cells.

Methods

Using RTPCR, fluorescence microscopy, ELISA and luciferase reporter gene assays we quantified interleukin-8, TLR4 and HBD2 expression in unstimulated or agonist-treated A549 and/or HEK293 cells. We also assessed the effect of over expressing wild type and/or mutant TLR4, MyD88 and/or Mal transgenes on LPS-induced HBD2 expression in these cells.

Results

We demonstrate that A549 cells express TLR4 on their surface and respond directly toPseudomonasLPS with increased HBD2 gene and protein expression. These effects are blocked by a TLR4 neutralizing antibody or functionally inactive TLR4, MyD88 and/or Mal transgenes. We further implicate TLR4 in LPS-induced HBD2 production by demonstrating HBD2 expression in LPS non-responsive HEK293 cells transfected with a TLR4 expression plasmid.

Conclusion

This data defines an additional role for TLR4 in the host defense in the lung.
The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-α2β and Ribavirin
Authors: Tran Huy A , Jones Tracey L , Batey Robert G
Published: October 2005

Background

The study aims to assess the pattern of thyroid response to combination Interferon-α2β (IFN-α) and Ribavirin (RBV) anti-viral therapy in an Australian hepatitis C cohort. These include the prevalence of thyroid dysfunction (TD) including hyperthyroidism and hypothyroidism and their possible predictors, the common overall pattern of thyroid function tests whilst receiving therapy and TD outcomes, and the correlation with HCV status outcome.

Methods

A retrospective analysis of all medical records was performed to assess thyroid function in Hepatitis C Virus (HCV) patients who were treated at the Hunter Area hepatitis C treatment center between 1995 and March 2004. The centre is part of the John Hunter hospital, a major tertiary referral centre in New South Wales, Australia.

Results

There were 272 cases available for review. The prevalence of TD is 6.7 percent and is made up predominantly of females (80 percent). There were 3 (1.1 percent) cases of hyperthyroidism with 2 (67 percent) females. Thirteen out of fifteen (80 percent) cases of hypothyroidism were females with the overall prevalence of 5.5 percent. The majority of hypothyroid patients still required Thyroxine supplement at the end of follow up.

Conclusion

Ninety three percent of HCV treated patients have intact thyroid function at the end of treatment. The predominant TD is hypothyroidism. The predominant pattern of thyrotoxicosis (TTX) is that of thyroiditis although the number is small. Graves' like disease was not observed. People with pre-existing thyroid auto-antibodies should be closely monitored for thyroid dysfunction, particularly hypothyroidism.
A trial of somatic gene targeting in vivo with an adenovirus vector
Authors: Ino Asami , Naito Yasuhiro , Mizuguchi Hiroyuki , Handa Naofumi , Hayakawa Takao , Kobayashi Ichizo
Published: October 2005

Background

Gene targeting in vivo provides a potentially powerful method for gene analysis and gene therapy. In order to sensitively detect and accurately measure designed sequence changes, we have used a transgenic mouse system, MutaMouse, which has been developed for detection of mutation in vivo. It carries bacteriophage lambda genome with lacZ
+ gene, whose change to lacZ-negative allele is detected after in vitro packaging into bacteriophage particles. We have also demonstrated that gene transfer with a replication-defective adenovirus vector can achieve efficient and accurate gene targeting in vitro.

Methods

An 8 kb long DNA corresponding to the bacteriophage lambda transgene with one of two lacZ-negative single-base-pair-substitution mutant allele was inserted into a replication-defective adenovirus vector. This recombinant adenovirus was injected to the transgenic mice via tail-vein. Twenty-four hours later, genomic DNA was extracted from the liver tissue and the lambda::lacZ were recovered by in vitro packaging. The lacZ-negative phage was detected as a plaque former on agar with phenyl-beta-D-galactoside.

Results

The mutant frequency of the lacZ-negative recombinant adenovirus injected mice was at the same level with the control mouse (~1/10000). Our further restriction analysis did not detect any designed recombinant.

Conclusion

The frequency of gene targeting in the mouse liver by these recombinant adenoviruses was shown to be less than 1/20000 in our assay. However, these results will aid the development of a sensitive, reliable and PCR-independent assay for gene targeting in vivo mediated by virus vectors and other means.
Macrophage and Mast-Cell Invasion of Tumor Cell Islets Confers a Marked Survival Advantage in Non–Small-Cell Lung Cancer
Authors: Welsh Tomas J. , Green Ruth H. , Richardson Donna , Waller David A. , O'Byrne Kenneth J. , Bradding Peter
Published: October 2005

Purpose

The role played by the innate immune system in determining survival from non–small-cell lung cancer (NSCLC) is unclear. The aim of this study was to investigate the prognostic significance of macrophage and mast-cell infiltration in NSCLC.

Methods

We used immunohistochemistry to identify tryptase+ mast cells and CD68+ macrophages in the tumor stroma and tumor islets in 175 patients with surgically resected NSCLC.

Results

Macrophages were detected in both the tumor stroma and islets in all patients. Mast cells were detected in the stroma and islets in 99.4% and 68.5% of patients, respectively. Using multivariate Cox proportional hazards analysis, increasing tumor islet macrophage density (P < .001) and tumor islet/stromal macrophage ratio (P < .001) emerged as favorable independent prognostic indicators. In contrast, increasing stromal macrophage density was an independent predictor of reduced survival (P = .001). The presence of tumor islet mast cells (P = .018) and increasing islet/stromal mast-cell ratio (P = .032) were also favorable independent prognostic indicators. Macrophage islet density showed the strongest effect: 5-year survival was 52.9% in patients with an islet macrophage density greater than the median versus 7.7% when less than the median (P < .0001). In the same groups, respectively, median survival was 2,244 versus 334 days (P < .0001). Patients with a high islet macrophage density but incomplete resection survived markedly longer than patients with a low islet macrophage density but complete resection.

Conclusion

The tumor islet CD68+ macrophage density is a powerful independent predictor of survival from surgically resected NSCLC. The biologic explanation for this and its implications for the use of adjunctive treatment requires further study.
Non–Small-Cell Lung Cancer Vaccine Therapy: A Concise Review
Authors: O'Mahony Deirdre , Kummar Shivaani , Gutierrez Martin E.
Published: October 2005

Lung cancer is the leading cause of cancer deaths in the United States and throughout the world; globally, there are more than 1.1 million deaths each year. Treatment modalities currently employed are significantly limited; 50% of patients experience disease recurrence after surgery, and less than a quarter of patients respond to systemic chemotherapy. These statistics have fueled the search for a safer, more effective treatment modality. Despite significant advances in our understanding of the molecular basis of cancer immunology, many obstacles remain. However, encouraging clinical results in patients immunized with autologous tumor cell vaccines expressing granulocyte macrophage colony-stimulating factor strongly advocate further investigation of immunotherapy in non–small-cell lung cancer (NSCLC). Further studies are needed to demonstrate whether these novel therapies can potentially complement or even replace current therapeutic approaches. We present a review of the various vaccine-based strategies employed to target and treat NSCLC.
Not Working 3 Years After Breast Cancer: Predictors in a Population-Based Study
Authors: Drolet Mélanie , Maunsell Elizabeth , Brisson Jacques , Brisson Chantal , Mâsse Benoît , Deschênes Luc
Published: October 2005

Purpose

Little is known about factors increasing likelihood of not working among breast cancer survivors compared with women in the general population.

Patients and Methods

A population-based retrospective cohort study was conducted in Quebec, Canada, based on the consecutive series of working women aged younger than 60 years when first treated for breast cancer (identified through the Quebec Tumor Registry), and on a group of randomly selected similar women, living in Quebec, who were working at the time of survivors' diagnoses, but who were without cancer (identified through provincial health care files). Data came from a telephone interview, 3 years after diagnosis for 646 survivors (73% of those eligible) or during a similar period for 890 comparison women (51%).

Results

Slightly more survivors were not working 3 years after diagnosis compared with women never diagnosed with cancer (21% and 15%, respectively). Older age (for survivors and comparison women, relative risk [RR] = 4.62, P < .0001 and RR = 4.98, P < .0001, respectively) and union membership (RR = 1.88, P = .0003 and RR = 1.40, P = .06, respectively) increased the likelihood of not working at the end of follow-up. In addition, income less than $20,000 compared with ≥ $50,000 was associated with not working only among survivors (RR = 3.18; P = .0008). Adjuvant treatments did not predict work cessation, but any new cancer event during follow-up did (RR = 2.14; P < .0001).

Conclusion

Although reassuring that adjuvant treatments did not appear to play a role in survivors' not working, other aspects of the cancer experience might nonetheless have influenced the decision to reduce work effort after breast cancer.
Fatigue and Relating Factors in High-Risk Breast Cancer Patients Treated With Adjuvant Standard or High-Dose Chemotherapy: A Longitudinal Study
Authors: Nieboer Peter , Buijs Ciska , Rodenhuis Sjoerd , Seynaeve Caroline , Beex Louk V.A.M. , van der Wall Elsken , Richel Dick J. , Nooij Marianne A. , Voest Emile E. , Hupperets Pierre , Mulder Nanno H. , van der Graaf Winette T.A. , TenVergert Els M. , van Tinteren Harm , de Vries Elisabeth G.E.
Published: October 2005

Purpose

Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients.

Patients and Methods

Eight hundred eighty-five patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score ≤ 46 defined as fatigue), poor mental health using mental health scale (score ≤ 56 defined as poor mental health) both of Short-Form 36, muscle and joint pain with Rotterdam Symptom Checklist, and Hb levels were assessed before and 1, 2, and 3 years after chemotherapy.

Results

Fatigue was reported in 20% of 430 assessable patients (202 standard-dose, 228 high-dose) with at least a 3-year follow-up, without change over time or difference between treatment arms. Mean Hb levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. Linear mixed effect models showed that the higher the Hb level (P = .0006) and mental health score (P < .0001), the less fatigue was experienced. Joint (P < .0001) and muscle pain (P = .0283) were associated with more fatigue.

Conclusion

In 3 years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy. Fatigue did not change over time. The strongest fatigue predictor was poor mental health.
Discriminant analysis as a tool to identify compounds with potential as transdermal enhancers
Authors: Pugh W J , Wong R , Falson F , Michniak B B , Moss G P
Published: October 2005

Structure-activity relationships were sought for 73 enhancers of hydrocortisone permeation from propylene glycol across hairless mouse skin. Enhancers had chain lengths (CC) from 0 to 16 carbon atoms, 1 to 8 H-bonding atoms (HB), molecular weight 60 to 450, log P (calculated) −1.7 to 9.7 and log S (calculated) −7.8 to 0.7. These predictive properties were chosen because of their ready availability. Enhancement ratio (ER) was defined as hydrocortisone transferred after 24 h relative to control. Values for the ER ranged from 0.2 to 25.3. Multiple regression analysis failed to predict activity; ER values for the ‘good’ enhancers (ER>10) were underestimated. Simple guidelines suggested that high ER was associated with CC>12 and HB 2–5. This was refined by multivariate analysis to identify significant predictors. Discriminant analysis using CC, HB, and molecular weight correctly assigned 11 of the 12 ‘good’ enhancers (92%). The incorrectly assigned compound was a known, idiosyncratic Br compound. Seventeen of the 61 ‘poor’ enhancers (28%) were incorrectly assigned but four could be considered marginal (ER>8). The success of this simple approach in identifying potent enhancers suggested its potential in predicting novel enhancer activity.
Dexmedetomidine prolongs spinal anaesthesia induced by levobupivacaine 0.5% in guinea-pigs
Authors: Calasans-Maia Jorge A , Zapata-Sudo Gisele , Sudo Roberto T
Published: October 2005

Alpha-2 adrenoceptor agonists have been used in association with local anaesthetic to increase the duration of spinal anaesthesia. Intrathecal administration of clonidine prolonged motor blockade induced by local anaesthetic. Since the affinity of dexmedetomidine (DEX) to alpha-2 adrenoceptors is eight-times greater than clonidine, it is expected that DEX could be advantageous in clinical anaesthesia. We investigated the duration of motor nerve block induced by spinal injection of 0.5% levobupivacaine (LVB) associated with intrathecal or intraperitoneal administration of DEX. Seventy-two guinea-pigs were randomly divided in 12 groups, which were all treated with intrathecal injection of 50 μL of LVB. DEX was injected intrathecally with LVB in 6 groups or injected intraperitoneally after LVB in another 6 groups. Intrathecal DEX (0.1, 0.2 and 0.4 μg) increased the LVB-induced motor anaesthesia from 48 (41–66) min to 84.5 (52–91) min (P<0.05), 101.5 (83–115) min (P<0.05) and 105 (97–114) min (P<0.05), respectively. Similarly, intraperitoneal DEX (20 and 40 μg kg−1) increased the motor blockade from 48.5 (33–59) min to 88 (71–114) min (P<0.05) and 114.5 (103–156) min (P<0.05), respectively. Pre-treatment with yohimbine reduced the duration of motor block from 101.5 (83–115) to 76.5 (68–86) min (P<0.05) or from 114.5 (103–156) to 90 (83–93) min (P<0.05) when DEX was administered by the intrathecal or intraperitoneal routes. Motor block induced by spinal injection of LVB was prolonged by intrathecal and systemic administration of DEX, which was partially dependent on activation of alpha-2 adrenoceptors.
Involvement of P-glycoprotein in the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone
Authors: Pawlik A , Gawrońska-Szklarz B , Baśkiewicz-Masiuk M , Machaliński B , Safranow K
Published: October 2005

P-glycoprotein (P-gp), a product of the MDR1 gene, is an important factor in the turnover of many drugs and xenobiotics. Recent reports have suggested that P-gp can also be involved in the transport of cytokines. The aim of this study was to examine the role of P-gp in cytokine release from phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (MNCs) as well as in the release of cytokines from MNCs treated with methotrexate (MTX) and dexamethasone (DEX). The study was carried out on PHA-stimulated MNC from 10 healthy subjects. Flow cytometry was applied to measure interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ and tumour necrosis factor (TNF)-α levels in the culture supernatants. In the experiments verapamil (VER) and P-gp specific monoclonal antibodies (mAb) (clone 17F9) were used to inhibit P-gp function. P-gp inhibitors suppressed the release of IL-2, IL-4, IFN-γ and TNF-α from PHA-stimulated MNC, whereas release of IL-6 and IL-10 remained unaffected. VER and mAb significantly decreased the release of IL-2, IL-4, TNF-α and INF-γ in MNC cultures treated with MTX or DEX. The results of this study suggest that P-gp may be involved in the transmembrane transport of some cytokines. Moreover, it seems that blocking of P-gp function may influence the release of some cytokines from MNCs, displaying an additive inhibitory effect to DEX and MTX.
Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-α-induced production of pro-inflammatory cytokines and augments interleukin-10
Authors: Fukuda Tetsuko , Hisadome Masao , Komatsu Hirotsugu
Published: October 2005

N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl (Y-40138) suppresses liver injury in concanavalin A- and d-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg−1) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-α (10μg mouse−1) in BALB/c mice. TNF-α and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-γ (IFN-γ) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-α, IL-12 and IFN-γ production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-α-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-α and IL-12 production 1.5h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-α production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.
Attenuation of ciclosporin-induced nephrotoxicity by dietary supplementation of seal oil in Sprague-Dawley rats
Authors: Yang Wei , Kang Zhili , Wang Lili , Kara Mohamedtaki , Herzberg Gene R , Robb Desmond , Randell Edward , Smeda John , Xiong Jieying , Liu Hu
Published: October 2005

Fish oil, rich in omega-3 (n-3) polyunsaturated fatty acids (PUFAs), has been reported to attenuate nephrotoxicity induced by ciclosporin (cyclosporine A). Harp seal oil is a rich source of n-3 PUFAs. This study investigated the ability of dietary seal oil to reduce nephrotoxicity caused by ciclosporin. Sprague-Dawley rats were maintained on a standard diet (with sunflower oil as lipid, SFO) or a diet enriched with seal oil (with 85% seal oil and 15% sunflower oil as lipid, SO) for four weeks before and four weeks after intravenous administration of ciclosporin (15 mg kg−1 daily). Kidney function was assessed by measuring blood urea nitrogen, creatinine clearance, urinary N-acetyl-1-β-d-glucosaminidase, 6-keto-prostaglandin F1α, thromboxane B2 and malondialdehyde. Systolic blood pressure (SBP) was monitored. Ciclosporin concentrations in blood were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The fatty acid compositions of the diets and erythrocyte membranes were analysed by gas chromatography (GC). The results showed that nephrotoxicity was induced by ciclosporin in rats maintained on both SO and SFO diets. However, rats fed on SO diet endured less toxicity than those on SFO diet. The n-3 and n-6 PUFAs in the erythrocyte membrane of rats maintained on SO diet were found to be 10.79% and 11.93%, while those in rats maintained on SFO diet were found to be 1.67% and 22.71%, respectively. In conclusion, dietary supplementation of seal oil was found to reduce ciclosporin-induced nephrotoxicity in rats.
Protective effects of Polygala paniculata extract against methylmercury-induced neurotoxicity in mice
Authors: Farina Marcelo , Franco Jeferson Luis , Ribas Camila Mafalda , Meotti Flávia Carla , Dafré Alcir Luiz , Santos Adair R S , Missau Fabiana , Pizzolatti Moacir G
Published: October 2005

We have examined the possible protective effects of Polygala paniculata extract against methylmercury (MeHg)-induced neurotoxicity in adult mice. MeHg was diluted in drinking water (40 mg L−1, freely available) and the hydroalcoholic Polygala extract was diluted in a 150 mm NaCl solution and administered by gavage (100 mg kg−1 b.w., twice a day). After a two-week treatment, MeHg exposure significantly inhibited glutathione peroxidase and increased glutathione reductase activity, while the levels of thiobarbituric acid reactive substances were increased in the cerebral cortex and cerebellum. These alterations were prevented by administration of Polygala extract, except for glutathione reductase activity, which remained elevated in the cerebral cortex. Behavioural interference in the MeHg-exposed animals was evident through a marked deficit in the motor performance in the rotarod task, which was completely recovered to control levels by Polygala extract co-administration. This study has shown, for the first time, the in-vivo protective effects of Polygala extract against MeHg-induced neurotoxicity. In addition, our findings encourage studies concerning the beneficial effects of P. paniculata on neurological conditions related to excitotoxicity and oxidative stress.
Interactions between Coilin and PIASy partially link Cajal bodies to PML bodies
Authors: Sun Jun , Xu Hongzhi , Subramony S. H. , Hebert Michael D.
Published: October 2005

The eukaryotic nucleus contains a variety of dynamic structures, yet studies into the functional relationship of one type of subnuclear domain to another have been limited. For example, PML bodies and Cajal bodies associate, but the functional consequence of this association and the mediating factors are unknown. Here we report that an associated PML body/Cajal body can co-localize to an snRNA gene locus, with the Cajal body invariably situated between the PML body and the snRNA locus. Binding studies demonstrate that coilin (a Cajal body protein) directly interacts with PIASy (a PML body protein). Cell biological experiments using coilin and PIASy knockout cell lines demonstrate that interactions between coilin and PIASy account in part for the observed association of Cajal bodies with PML bodies. When the PIASy interaction region on coilin is deleted, the frequency of the association between Cajal bodies and PML bodies is reduced. These studies provide another example of coilin's role in the functional organization of the nucleus.
CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5
Authors: Dietze Eric C. , Bowie Michelle L. , Mrózek Krzysztof , Caldwell L. Elizabeth , Neal Cassandra , Marjoram Robin J. , Troch Michelle M. , Bean Gregory R. , Yokoyama Kazunari K. , Ibarra Catherine A. , Seewaldt Victoria L.
Published: October 2005

Interactions between normal mammary epithelial cells and extracellular matrix (ECM) are important for mammary gland homeostasis. Loss of interactions between ECM and normal mammary epithelial cells are thought to be an early event in mammary carcinogenesis. CREB-binding protein (CBP) is an important regulator of proliferation and apoptosis but the role of CBP in ECM signaling is poorly characterized. CBP was suppressed in basal-cytokeratin-positive HMECs (CK5/6+, CK14+, CK8–, CK18–, CK19–). Suppression of CBP resulted in loss of reconstituted ECM-mediated growth control and apoptosis and loss of laminin-5 α3-chain expression. Suppression of CBP in normal human mammary epithelial cells (HMECs) resulted in loss of CBP occupancy of the LAMA3A promoter and decreased LAMA3A promoter activity and laminin-5 α-3 chain expression. Exogenous expression of CBP in CBP-negative HMECs that have lost reconstituted ECM-mediated growth regulation and apoptosis resulted in (1) CBP occupancy of the LAMA3A promoter, (2) increased LAMA3A activity and laminin-5 α3-chain expression, and (3) enhancement of reconstituted ECM-mediated growth regulation and apoptosis. Similarly, suppression of laminin-5 α3-chain expression in HMECs resulted in loss of reconstituted ECM-mediated growth control and apoptosis. These observations suggest that loss of CBP in basal-cytokeratin-positive HMECs results in loss of reconstituted ECM-mediated growth control and apoptosis through loss of LAMA3A activity and laminin-5 α3-chain expression. Results in these studies may provide insight into early events in basal-type mammary carcinogenesis.
Hydrodynamic design and performance analysis of a centrifugal blood pump for cardiopulmonary circulation
Authors: Oh H W , Yoon E S , Park M R , Sun K , Hwang C M
Published: October 2005

This paper presents the hydrodynamic design and performance analysis method for a miniaturized centrifugal blood pump using three-dimensional computational fluid dynamics (CFD) code. In order to obtain the hydraulically high efficient configuration of a miniaturized centrifugal blood pump for cardiopulmonary circulation, well-established commercial CFD codes were incorporated considering detailed flow dynamic phenomena in the blood pump system. A prototype of centrifugal blood pump developed by the present design and analysis method has been tested in the mock circulatory system. Predicted results by the CFD code agree very well with in vitro hydraulic performance data for a centrifugal blood pump over the entire operating conditions. Preliminary in vivo animal testing has also been conducted to demonstrate the haemodynamic feasibility for use of centrifugal blood pump as a mechanical circulatory support. A miniaturized centrifugal blood pump developed by the hydraulic design optimization and performance prediction method, presented herein, shows the possibility of a good candidate for intra and extracorporeal cardiopulmonary circulation pump in the near future.
Performance comparison of an irreversible closed variable-temperature heat reservoir brayton cycle under maximum power density and maximum power conditions
Authors: Chen L , Zheng J , Sun F , Wu C
Published: October 2005

The power density is taken as an objective for performance analysis of an irreversible closed Brayton cycle coupled to variable-temperature heat reservoirs. The analytical formulas about the relationship between power density and working fluid temperature ratio (pressure ratio) are derived with the heat resistance losses in the hot- and cold-side heat exchangers, the irreversible compression and expansion losses in the compressor and turbine, and the effect of the finite thermal capacity rate of the heat reservoirs. The obtained results are compared with those results obtained by using the maximum power criterion. The influences of some design parameters, including the temperature ratio of the heat reservoirs, the effectivenesses of the heat exchangers between the working fluid and the heat reservoirs, and the efficiencies of the compressor and the turbine, on the maximum power density are provided by numerical examples, and the advantages and disadvantages of maximum power density design are analysed. The power plant design with maximum power density leads to a higher efficiency and smaller size. When the heat transfers between the working fluid and the heat reservoirs are carried out ideally and the thermal capacity rates of the heat reservoirs are infinite, the results of this article become similar to those obtained in the recent literature.
Aralast: A New α1-Protease Inhibitor for Treatment of α-Antitrypsin Deficiency
Authors: Louie Stan Gee , Sclar David Alexander , Gill Mark Anthony
Published: October 2005

OBJECTIVE

To review the epidemiology, pathogenesis, and management of patients with α-antitrypsin (AAT) deficiency syndrome and compare Aralast with Prolastin, 2 of the 3 available human plasma–derived AAT agents.

DATA SOURCES

Articles were identified using a MEDLINE (1966–September 2005) search with MESH headings that included α-antitrypsin and emphysema.

STUDY SELECTION AND DATA EXTRACTION

All papers from peer-reviewed journals on the laboratory or clinical efficacy of plasma-derived AAT (eg, Prolastin, Aralast) for patients with this autosomal recessive disorder were reviewed.

DATA SYNTHESIS

Clinical trials found that AAT augmentation prevents progression of AAT-deficient emphysema and thus its associated morbidity and mortality. Treatment with Aralast has been shown to be safe and well tolerated, with a low incidence of mild to moderate adverse events. Pharmacoeconomics studies of AAT augmentation demonstrated that the use of Aralast was cost-effective as lifelong augmentation therapy for AAT-deficient emphysema.

CONCLUSIONS

Because of its effectiveness and extra safety measure compared with Prolastin, Aralast should be recommended for formulary inclusion.
Identification of Inappropriate Drug Prescribing by Computerized, Retrospective DUR Screening in Korea
Authors: Yeom Jong Hum , Park Ji Sun , Oh Ock-Hee , Shin Hyun Taek , Oh Jung Mi
Published: October 2005

BACKGROUND

In Korea, the drug use process has changed significantly since the new pharmacy law was implemented in 2000, separating the prescribing and dispensing functions between physicians and pharmacists and mandating prospective drug use review (DUR) practice by pharmacists immediately before dispensing medications. However, a high prevalence of inappropriate prescribing has been suspected by the public, pharmacists, and health insurance managers, possibly due to suboptimal DUR practice by pharmacists.

OBJECTIVE

To assess overall patterns of drug usage and potential problems of inappropriate use in outpatient settings by analyzing prescription data that were electronically submitted to the national health insurance manager with a computerized DUR system and develop a computerized adjudication system model for drug claims.

METHODS

The national prescription drug claims data that were submitted electronically by pharmacies located in the northern part of Korea during 15 days in 2002 were retrospectively screened against the predetermined DUR standards of the selected criteria on drug dosage, duration of therapy, and drug interaction using the DUR screening system. The results of all the DUR conflicts were further validated manually by an expert panel and statistically analyzed to determine drug use patterns.

RESULTS

Of 31 994 260 drugs prescribed, 3 325 760 (10.4%) items showed a conflict with at least one of the DUR standards. The average number of drugs prescribed on each prescription was 4.07, and even more troubling was the high incidence of under-dosing, over-dosing, and contraindicated drug prescribing.

CONCLUSIONS

It is evident that inappropriate drug prescribing is very common in Korea; thus, a great deal of attention is urgently needed in the country with respect to proper prescribing and supportive interventions.
Levosimendan: A Novel Inotropic Agent for Treatment of Acute, Decompensated Heart Failure
Authors: Earl Grace L , Fitzpatrick James T
Published: October 2005

OBJECTIVE

To review the literature on a novel calcium sensitizer, levosimendan.

DATA SOURCES

Articles were identified through searches of MEDLINE (1966–June 2005), International Pharmaceutical Abstracts (1970–June 2005), and EMBASE (1992–June 2005) using the key words levosimendan, simendan, calcium sensitizer, calcium sensitiser, and congestive heart failure.

STUDY SELECTION AND DATA EXTRACTION

Clinical trials and pharmacokinetic studies evaluating the safety and efficacy of levosimendan were selected.

DATA SYNTHESIS

Levosimendan 6–24 μg/kg intravenous bolus followed by a 24-hour continuous infusion of 0.05—0.2 μg/kg/min improved cardiac output and reduced pulmonary capillary wedge pressure in a dose-dependent manner. Dose-ranging and randomized clinical trials have demonstrated improvement in symptoms and hemodynamics and short-term survival outcomes in the treatment of acute, decompensated heart failure. Clinical trials evaluating retrospective mortality data and combined endpoints (mortality, rehospitalization) have demonstrated better outcomes with levosimendan compared with dobutamine. The incidence of hypotension with levosimendan is not significantly different than with dobutamine, but there is a dose-related increase in heart rate.

CONCLUSIONS

Levosimendan is useful in moderate to severe low-output heart failure in patients who have failed to respond to diuretics and vasodilators. Based on current studies, levosimendan appears to be a safe alternative to dobutamine for treatment of acute, decompensated heart failure. Prospective clinical trials are needed to confirm the effect of levosimendan on long-term survival and its role in heart failure in the setting of myocardial infarction.