bluuebunny/crossref_metadata_2025 huggingface dataset:
Observation Impact during the North Atlantic TReC—2003
Authors: Langland Rolf H.
Published: August 2005

An adjoint-based method is used to calculate the impact of observation data on a measure of short-range forecast error in the Navy Operational Global Atmospheric Prediction System (NOGAPS) during November and December 2003. The evaluated observations include all regular satellite and in situ data assimilated in the Naval Research Laboratory (NRL) Atmospheric Variational Data Assimilation System (NAVDAS) at 1800 UTC, and also targeted dropsonde profiles provided by the North Atlantic Observing-System Research and Predictability Experiment (THORPEX) Regional Campaign (NA-TReC) field program. Commerical aircraft observations account for 46% of the total forecast error reduction by observations in the NA-TReC domain, which includes the North Atlantic and adjacent regions of North America and Europe. Targeted dropsonde data have high impact per observation, but the impact of all dropsonde data is less than 2% of the total during the 2-month study period. Eight of 12 targeted dropsonde cases reduce forecast error. The percent of total impact for other observations assimilated at 1800 UTC in the NA-TReC domain is as follows: Advanced Microwave Sounding Unit-A (AMSU-A) radiances (16%), satellite winds (14%), land surface data (9%), radiosondes (8%), and ship-surface data (5%). If observations over the entire global domain are evaluated, the largest impact of data provided at 1800 UTC during November and December 2003 is provided by AMSU-A radiance data (48% of total).
Stratospheric Polar Cap Mean Height and Temperature as Extended-Range Weather Predictors
Authors: Siegmund Peter
Published: August 2005

The skill of stratospheric and tropospheric predictors in predicting near-surface quantities at the extended range (∼10 days–2 months) has been investigated, using 40 yr of reanalysis data from the European Centre for Medium-Range Weather Forecasts. The predictors are 1) the geopotential height (Z) at various levels, 2) the difference between Z and the 1000-hPa geopotential [Z − Z(1000)], and 3) the temperature at various levels. The predictors are averages over the area north of 65°N. The predictands are Z(1000) averaged over the same area and geographical fields of several near-surface quantities. The predictive skill has been investigated for different lead times between predictor and predictand and different averaging periods of the predictor and the predictand.

The results show that the predictive skill of Z in the troposphere is mainly due to the predictive skill of sea level pressure, whereas the predictive skill of Z in the stratosphere is mainly due to the predictive skill of stratospheric temperature. The predictive skill is largest in the end of December, for the predictor Z at 50 hPa and the temperature between 250 and 50 hPa. The temperature also has significant predictive skill in the upper stratosphere in the summer. In winter, for lead times larger than 5 days the stratospheric Z is a better predictor of the daily Z(1000) than Z(1000) itself. Whereas the predictive skill of the stratospheric Z is largest for zero lead time, the predictive skill of the stratospheric Z − Z(1000) and temperature are largest for lead times of about 10 days, evidencing the finite propagation time of geopotential anomalies from the stratosphere to the surface. The skill of the stratospheric height and temperature in predicting the wintertime monthly mean field of Z(1000) is mainly limited to the region north of 60°N. The stratospheric predictive skill for the monthly mean fields of the zonal wind at 850 hPa and the near-surface temperature is particularly large around 60°N. The correlation pattern of the near-surface temperature field and the stratospheric temperature is qualitatively similar to the corresponding pattern for the Arctic Oscillation index, except at middle latitudes over Eurasia and over the subtropical Pacific.
Sensitivity of Tropical Cyclone Rainbands to Ice-Phase Microphysics
Authors: Franklin Charmaine N. , Holland Greg J. , May Peter T.
Published: August 2005

A high-resolution tropical cyclone model with explicit cloud microphysics has been used to investigate the dynamics and energetics of tropical cyclone rainbands. As a first step, the model rainbands have been qualitatively compared with observed rainband characteristics. The model-generated rainbands show many of the mesoscale and convective-scale features of observed tropical cyclone rainbands. Sensitivity studies of numerically simulated tropical cyclone convection to ice-phase microphysical parameters showed that the model was most sensitive to changes in the graupel fall speed parameters. Increasing the fall speeds saw graupel being confined to the convective regions and producing higher rain rates in the inner core of the storm. A greater region of stratiform precipitation was produced when the efficiency for the collection of snow and cloud ice by graupel was reduced and when the mean size of graupel was reduced. Both of these simulations resulted in a higher concentration of snow being transported into the stratiform region. Although the precipitation structure changed across the simulations, the surface rainfall rate and the fundamental dynamical variables showed little sensitivity to the parameter variations.
Bricolages religieux ou transactions symboliques? Quelques éléments à partir de la recomposition des croyances relatives a l’après-mort dans un Occident déchristianisé
Authors: Hiernaux Jean-Pierre
Published: August 2005

English

In a context in which many subjects cannot be pinned down within classic religious frameworks, and subsequently engage in certain recompositions of meaning—can these be reduced to a set of connotations, unhappily rendered banal by the application of the label, “bricolage”? Is it not rather the case that we are faced with evidence of symbolic transactions of greater importance, and which rather exceed the limit of the narrow description “religious bricolage”?

French

Dans un contexte ou` nombre de sujets échappent aux encadrements religieux classiques, les recompositions de sens qu'ils engagent peuvent-elles se réduire à des connotations défavorablement banalisées du mot "bricolage"? Ne serions-nous pas plutôt devant des transactions symboliques aux convergences et implications plus profondes et qui débordent cette autre limite qu'annonce le composé restrictif "bricolages religieux";?
Bricolage vaut-il dissémination? Quelques réflexions sur l’opérationnalité sociologique d’une métaphore problématique
Authors: Hervieu-Léger Danièle
Published: August 2005

English

The author develops a reflection on the significance acquired by the notion of "bricolage" (tinkering) - applied in this instance to individual belief systems - in the contemporary sociology of religion and religious "modernity";. The author does not go along with a certain atomization of belief in general, increasingly associated with "high modernity";, and linked to a supposed absence of pre-constraints on bricolage. Instead, she puts forward the idea of the existence of specific and real constraints on bricolage in contemporary Western societies. The topics of health care, science and the afterlife are considered workshops for this style of bricolage, and are explored as sources of illustration for these hypotheses.

French

Láuteure développe une réflexion sur la place prise par la notion de "bricolage"- appliquée aux croyances des individus- dans la sociologie contemporaine de la modernité religieuse. Contre une atomisation du champ du croire en haute modernité, liée à l'absence de pré-contrainte au bricolage, il sera avancé l'existence de contraintes spécifiques mais bien réelles du bricolage contemporain dans les sociétés occidentales. Laboratoire de ces bricolages, les champs de la santé, la science et de l'après-mort seront explorés pour illuster ces hypothèses.
Russia and the Russians
Authors: Sakowicz Iwona
Published: August 2005

This paper examines the portrait of Russia and the Russians presented in the columns of the major London newspapers during the rule of Alexander II (1855-81), when Russia was undergoing profound political and social change. It argues that despite the development of economic and political ties between the two countries the British press mainly presented a distorted picture of Russia. The brief visits of overseas correspondents, not speaking the language of the country, and looking mostly for cultural differences, failed to change the negative picture formed during the first half of the nineteenth century. Russia was still perceived as a semi-barbaric and despotic country and this image was conveyed in thousands of copies of the printed daily newspapers circulating all over Britain.
The secret city
Authors: Cross Anthony
Published: August 2005

Hugh Walpole, among the most popular and prolific of English authors in the first four decades of the twentieth century, is now largely forgotten and unread. There are, however, many aspects of his life and work that retain considerable interest and invite re-visiting. This article is essentially devoted to the period of some three years between September 1914 and November 1917 that brought Walpole his firsthand knowledge of a Russia torn by war and revolution and provided the material for two of his more important novels. The first part of the article looks at Walpole’s knowledge of Russian literature and at his activities in Russia as a journalist, then as a serving officer with the Russian Red Cross and, finally, as the Head of British Propaganda in Petrograd. The second section examines, firstly, The Dark Forest (1916), a novel arising from Walpole’s experiences at the Carpathian front, and then The Secret City (1919), his contribution to the ‘Petersburg myth’.
Factors Influencing the Initiation and Duration of Breastfeeding Among Low-Income Women Followed by the Canada Prenatal Nutrition Program in 4 Regions of Quebec
Authors: Simard Isabel , O’Brien Huguette Turgeon , Beaudoin André , Turcotte Daniel , Damant Dominique , Ferland Suzanne , Marcotte Marie-Josée , Jauvin Nathalie , Champoux Lyne
Published: August 2005

The factors that influence the actual initiation and duration of breastfeeding were studied among low-income women followed by the Canada Prenatal Nutrition Program (CPNP). A group of 196 pregnant women were selected at random from a sample of 6223 pregnant women who registered with the CPNP. Two 24-hour recalls and information regarding lifestyle habits, peer support, and infant-feeding practices were obtained between 26 and 34 weeks of gestation and 21 days and 6 months after birth. Women who received a university education (completed or not completed) versus women with [.lessequal] high school education (odds ratio [OR], 8.40; 95% confidence interval [CI], 1.02-69.50), women born outside Canada (OR,8.81; 95% CI, 3.34-23.19), and women of low birth weight infants (OR, 0.39; 95% CI, 0.16-0.96) were more likely to initiate breastfeeding. Late introduction of solid foods ( P = .004), nonsmoking ( P = .005), multiparity ( P = .012), and a higher level of education ( P = .049) were positively associated with the duration of breastfeeding among initiators. Understanding factors associated with initiation and duration of breastfeeding among low-income women is critical to better target breastfeeding promotion.
Country of Origin and Race/Ethnicity: Impact on Breastfeeding Intentions
Authors: Bonuck Karen A. , Freeman Kathy , Trombley Michelle
Published: August 2005

This article reports on breastfeeding intentions of Hispanic and black women by country of origin (continental US born or foreign born) in a low-income population that has experienced demographic shifts. Data were derived from prenatal interviews with 382 women from 2 community clinics. Primary outcome measures were intentions to formula feed, breastfeed, or formula and breastfeed. Foreign-born women were significantly more likely to intend to only breastfeed (42% vs 24% for continental US born, P < .05). In multivariate analyses, country of origin and having breastfed a previous child were the only significant predictors of breastfeeding intention. In contrast to previous work, black (non-Hispanic) and Hispanic women’s breastfeeding plans were similar. This finding coincides with dramatic increases in the numbers of blacks from West Indian countries—where breastfeeding is the norm—in the study locale.
The Democratic Peace is What States Make of It: A Constructivist Analysis of the US-Indian ‘Near-Miss’ in the 1971 South Asian Crisis
Authors: Widmaier Wesley W.
Published: August 2005

In 1971, the United States and India — the world’s two largest democracies — almost went to war in a ‘near-miss’ at odds with the hypothesis that democracies do not fight one another. In this article, I reformulate the democratic peace hypothesis by subsuming it under a broadened constructivist analysis, one that recognizes that institutional qualities do not ‘speak for themselves’ but rather that struggles over the meaning of democracy can engender conflict. I then argue that differences regarding the meaning of democracy shaped post-World War II US perceptions of the South Asian distribution of power, explaining shifts from periods of Democratic friendship to Republican enmity toward India, with the latter most clearly manifested in the 1971 crisis. I conclude by emphasizing the merit of a constructivist theory of democratic interactions in explaining cooperation and conflict.
Can a Cancer Program–Sponsored Spiritual Event Meet With Acceptance From Patients and Other Attendees?
Authors: Dann Nancy J. , Higby Donald J. , Mertens Wilson C.
Published: August 2005

Background: While many cancer patients derive strength from spiritual or religious faith, concern often remains regarding how different patient subgroups and other community members might react to faith-based services when sponsored by a secular health care organization. Methods:“A Sacred Gathering for Those Touched by Cancer” was presented in 2 Catholic and 2 Protestant churches. The service included key themes (surrendering fear, peace, hope, community support, and God's love) reinforced by Scripture, music, ritual, and prayer. Patients, clergy, and staff participated. Questionnaires evaluating attendee characteristics, emotional response to the service, and satisfaction with service components were distributed. Results:Attendees (women: 80%; Catholic: 71%; half older than 50 years) returned 450 questionnaires. Most found the service very (83%) or somewhat (14%) helpful. Multivariate regression of perceptions indicated (1) the opinion that the service was helpful was associated with the perception that the service made the respondent feel hopeful ( P< .0001), that respondents found inspirational messages important ( P= .058), and that the respondent was a current patient ( P= .018) and (2) an angry response reported by respondents was associated with current patient status ( P= .0044). Men tended to feel less loved by God ( P= .012) and people ( P= .034) and less hopeful ( P= .057) than women did. Men liked music less ( P= .048), liked Scripture and prayers concerning community less ( P= .040), and found prayer ( P= .0035) less important. However, men felt the gatherings were as helpful as women did. Past patients felt less sadness than did others ( P = .0084). Increased perceived helpfulness of the service was associated in a multivariate analysis with current patient status, feeling hopeful as a result of the service, increased appreciation of the service’s inspirational message, and the perception that the service was not too long. Conclusions: While almost all attendees found the service somewhat or very helpful, distinct preferences and reactions to the service were noted for gender, patient status, and religious affiliation. This evaluation will help tailor future events to better meet the spiritual needs of cancer patients and their loved ones.
Chinese Herbal Medicine and Chemotherapy in the Treatment of Hepatocellular Carcinoma: A Meta-analysis of Randomized Controlled Trials
Authors: Shu Xiaojuan , McCulloch Michael , Xiao Hang , Broffman Michael , Gao Jin
Published: August 2005

Background: Hepatocellular carcinoma (HCC), one of the most common malignancies worldwide, is highly resistant to standard therapy. It is unclear whether chemotherapy, arterial embolization, or arterial chemoembolization improve survival advantage enough to justify their high toxicity. Treatment with Chinese herbal medicine has been explored, combining herbs that stimulate host immune response with those that have cytotoxic activity against HCC cells. The authors sought to evaluate the effectiveness of Chinese herbal medicine combined with chemotherapy. The hypothesis was that Chinese herbal medicine added to chemotherapy for the treatment of HCC would improve survival and tumor response, when compared to treatment with chemotherapy alone. Methods:The authors searched the databases TCMLARS, PubMed, and EMBASE as well as the bibliographies of studies identified in the systematic search for potentially relevant titles or abstracts of studies in any language. They retained those that (1) treated only HCC patients, (2) were described as randomized or reported that there was no statistical difference between treatment groups, (3) gave patients either Chinese herbal medicine therapy combined with chemotherapy in the treatment group or chemotherapy alone in the control group, and (4) provided data on the number of enrolled subjects and responders and nonresponders for tumor response and survival. The authors used random effects meta-analysis to combine data. Results:Twenty-six studies representing 2079 patients met the inclusion criteria. Chinese herbal medicine combined with chemotherapy, compared to chemotherapy alone, improved survival at 12 months (relative risk [RR], 1.55; 95% confidence interval [CI], 1.39-1.72; P< .000), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P< .000), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P< .000). Tumor response increased (RR, 1.39; 95% CI, 1.24-1.56; P< .000). Conclusions:These findings provide promising evidence that combining Chinese herbal medicine with chemotherapy may benefit patients with HCC. Because of the low quality of these studies, these findings should be confirmed through conducting high-quality, rigorously controlled trials.
Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor β genotype of donor
Authors: Lin Ming-Tseh , Storer Barry , Martin Paul J. , Tseng Li-Hui , Grogan Bryan , Chen Pei-Jer , Zhao Lue P. , Hansen John A.
Published: August 2005

We have previously shown that the interleukin 10 (IL-10)/-592*A allele of the recipient is associated with less severe acute graft-versus-host disease (GVHD) and a lower risk of nonrelapse mortality after hematopoietic cell transplantation (HCT) from an HLA-identical sibling. In the present study, we examined variation in the IL-10 receptor β gene as a further test of the hypothesis that the IL-10 pathway regulates the risk of acute GVHD. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL10RB/c238) was genotyped in 953 HC transplant recipients and their HLA-identical sibling donors. IL-10/-592 and IL10RB/c238 genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL10RB/c238*G allele of the donor were significantly associated with a lower risk of grades III-IV acute GVHD (trend P < .001 and P = .02, respectively). The donor IL10RB/c238*G allele provided protection among patients with the IL-10/-592 A/C or A/A genotypes but not among patients with the high-risk IL-10/-592 C/C genotype. These data suggest an interaction of the patient IL-10/-592 and donor IL10RB/c238 genotypes on risk of GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.
Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells
Authors: Du Yang , Jenkins Nancy A. , Copeland Neal G.
Published: August 2005

Retroviruses can induce hematopoietic disease via insertional mutagenesis of cancer genes and provide valuable molecular tags for cancer gene discovery. Here we show that insertional mutagenesis can also identify genes that promote the immortalization of hematopoietic cells, which normally have only limited self-renewal. Transduction of mouse bone marrow cells with replication-incompetent murine stem cell virus (MSCV) expressing only neo, followed by serial passage in liquid culture containing stem cell factor (SCF) and interleukin-3 (IL-3), produced immortalized immature myeloid cell lines with neutrophil and macrophage differentiation potential in about 50% of the infected cultures. More than half of the lines have MSCV insertions at Evi1 or Prdm16. These loci encode transcription factor homologs and are validated human myeloid leukemia genes. Integrations are located in intron 1 or 2, where they promote expression of truncated proteins lacking the PRDI-BF1-RIZ1 homologous (PR) domain, similar to what is observed in human leukemias with EVI1 or PRDM16 mutations. Evi1 overexpression alone appears sufficient to immortalize immature myeloid cells and does not seem to require any other cooperating mutations. Genes identified by insertional mutagenesis by their nature could also be involved in immortalization of leukemic stem cells, and thus represent attractive drug targets for treating cancer.
Holocene climate fluctuations in the Yangtze delta of eastern China and the Neolithic response
Authors: Chen Zhongyuan , Wang Zhanghua , Schneiderman Jill , Taol Jin , Cail Yongli
Published: August 2005

Six major pollen-spore assemblage zones can be identified showing alternate warm and cool climate fluctuations on a millennial timescale. The early-Holocene optimum at c. 8000-7800 radiocarbon years BP, is marked by a large proportion of evergreen broad-leaf species in Zone I, suggesting the warmest/hottest climate setting of the Holocene. The mid-Holocene optimum ran from c. 7500 to 5000 BP (Zone III), during which many subtropical warmand wet-tolerant species represented by Castanopsis and Cyclobalanopsis glauca occurred, indicating the megathermal trend. The temperature then declined upcore in Zone IV accompanied by a high proportion of Pinus and Cupressaceae. A cooling event occurred at c. 4200 BP, as evidenced by Fagus and Potamogeton in the upper section of Zone IV. Pollen assemblages in Zones V-VI indicate a generally cooler temperature in the late Holocene with a high proportion of Gramineae, indicative of rice cultivation. Onset of the mid-Holocene optimum was associated with sediment deposition of the Holocene delta construction. This promoted the migration of Neolithic settlements onto the delta plain from highlands west of the study area. The cooling event recognized at c. 4200-4000 BP may have triggered the cultural ‘break up’ caused by the climatic transition from early warm-humid to a later cool-wet setting, and lake expansion caused by heavy precipitation.
Protein Kinase A-Dependent Synergism between GATA Factors and the Nuclear Receptor, Liver Receptor Homolog-1, Regulates Human Aromatase (CYP19) PII Promoter Activity in Breast Cancer Cells
Authors: Bouchard Marie France , Taniguchi Hiroaki , Viger Robert S.
Published: August 2005

Cancers, including that of the breast, are the result of multiple contributing factors including aberrant gene expression. Indeed, the CYP19 gene encoding P450 aromatase, the key enzyme for estrogen biosynthesis, is up-regulated in breast tumors predominantly via the cAMP-responsive gonad-type PII promoter, ultimately leading to increased intratumoral estrogen production and tumor growth. Thus, identifying the molecular factors involved in aromatase PII promoter regulation is essential for our understanding and treatment of the disease. Because we have previously shown activity of the murine aromatase PII promoter to be markedly up-regulated by GATA factors with respect to the gonads, we hypothesized that GATA factors are also key determinants of human PII promoter-driven aromatase transcription in breast tumors. We now show that GATA3 and GATA4 are indeed expressed in several breast cancer cells lines. Consistent with the cAMP dependence of the PII promoter, activation elicited by GATA3 or GATA4 alone and the striking synergism between GATA3 or GATA4 and the nuclear receptor liver receptor homolog (LRH)-1 was intimately linked to forskolin treatment or overexpression of protein kinase A (PKA) catalytic subunit. PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. Finally, we show that the human LRH-1 promoter is itself a target for GATA factors. Thus, taken together, our results suggest that GATA factors likely contribute to aberrant aromatase expression in breast tumors through two distinct, yet complementary mechanisms.
Regulation of the Endothelin/Endothelin Receptor System by Interleukin-1β in Human Myometrial Cells
Authors: Breuiller-Fouché Michelle , Morinière Catherine , Dallot Emmanuelle , Oger Stéphanie , Rebourcet Régis , Cabrol Dominique , Leroy Marie-Josèphe
Published: August 2005

Proinflammatory cytokines produced at the fetomaternal interface, such as IL-1β, have been implicated in preterm and term labor. The present study was performed to evaluate the influence of IL-1β on the endothelin (ET)/ET receptor system in human myometrial cells. We report that myometrial cells under basal conditions not only respond to but also secrete ET-1, one of the main regulators of uterine contractions. Prolonged exposure of the cells to IL-1β led to a decrease in prepro-ET-1 and ET-3 mRNA correlated with a decrease in immunoreactive ET-1 and ET-3 levels in the culture medium. Whereas ETA receptor expression at both protein and mRNA levels was not affected by IL-1β treatment, we demonstrated an unexpected predominance of the ETB receptor subtype under this inflammatory condition. Whereas the physiological function of ETB remains unclear, we confirmed that only ETA receptors mediate ET-1-induced myometrial cell contractions under basal conditions. By contrast, prolonged exposure of the cells to IL-1β abolished the contractile effect induced by ET-1. Such a regulation of IL-1β on the ET release and the balance of ETA to ETB receptors leading to a loss of ET-1-induced myometrial cell contractions suggest that complex regulatory mechanisms take place to constraint the onset of infection-induced premature contractions.
Counteracting adriamycin-induced oxidative stress by administration of N-acetyl cysteine and vitamin E
Authors: Kalaiselvi Periandavan , Pragasam Viswanathan , Chinnikrishnan Srinivasan , Veena Coothan Kandaswamy , Sundarapandiyan Rajaguru , Varalakshmi Palaninathan
Published: August 2005

Adriamycin (ADR), a cytotoxic antineoplastic drug, is used in the treatment of various solid tumors. However, its efficacy continues to be challenged by significant toxicities including nephrotoxicity. In the present study, the effects of N-acetyl cysteine (NAC) and vitamin E, known antioxidants, were investigated on ADR-induced peroxidative damage in rat kidney. Adult male albino rats of Wistar strain were administered ADR as a single dose (10mg/kg body weight, i.v.). Histopathological studies indicated that ADR-treated kidney sections show focal tubular necrosis and casts. ADR-injected rats showed a significant decline in the activities/levels of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) and non-enzymic antioxidants (thiols, vitamin C and vitamin E) with high malondialdehyde levels. The extent of nephrotoxicity was evident from the increased activities of urinary marker enzymes (alkaline phosphatase, lactate dehydrogenase and γ-glutamyltransferase). Treatment with NAC and vitamin E (50mg/kg b.w., i.p.) 1day prior to ADR administration maintained near normal activities of the enzymes, significantly reduced lipid peroxidation and prevented the necrosis caused by ADR, thereby proving to be an effective thiol replenishing agent and antioxidant.
Measurement of troponin I 48h after admission as a tool to rule out impaired left ventricular function in patients with a first myocardial infarction
Authors: Panteghini Mauro , Bonetti Graziella , Pagani Franca , Stefini Francesca , Giubbini Raffaele , Cuccia Claudio
Published: August 2005

Few studies have evaluated cardiac troponin I (cTnI) as a marker for infarct size and left ventricular (LV) dysfunction. Here we investigated the ability of a single-point cTnI, measured with a second-generation assay (Access AccuTnI), to estimate infarct size and assess LV function in patients with a first myocardial infarction (AMI). cTnI measurements were performed 12 and 48h after admission in 63 consecutive AMI patients. LV function was evaluated by gated single-photon emission computed tomography (SPECT) and infarct size was estimated by CK-MB peak and SPECT myocardial perfusion. LV function and infarct size were evaluated by SPECT before hospital discharge. SPECT was also repeated 3months later. Significant correlations (p<0.001) were found between cTnI at 12 and 48h and both the peak CK-MB (r=0.61 and r=0.82, respectively) and the perfusion defect size at SPECT (r=0.55 and r=0.61, respectively). cTnI at 12 and 48h were inversely related (p<0.001) to LV ejection fraction (LVEF) assessed both early (r=–0.45 and r=–0.57, respectively) and 3months after AMI (r=–0.51 and r=–0.69, respectively). cTnI >14.8 μg/L at 48h predicted an LVEF <40% at 3months with a sensitivity of 100% [95% confidence interval (CI) 73.5–100%], specificity of 65% (CI 49–79%), and a negative predictive value of 100%. Our findings demonstrate that a single cTnI measurement 48h after admission is useful for ruling out impaired LV function in a routine clinical setting.
Influence of short-term venous stasis on clinical chemistry testing
Authors: Lippi Giuseppe , Salvagno Gian Luca , Montagnana Martina , Brocco Giorgio , Guidi Gian Cesare
Published: August 2005

Control and standardization of preanalytical variability is a critical factor for achieving accuracy and precision in laboratory testing. Although venous stasis from tourniquet placement during venepuncture should be minimized, as it has been claimed to account for spurious and significant variations for several analytes in plasma, there is controversy surrounding its real impact on laboratory testing. The aim of the present study was the investigation of the influence of short-term venous stasis on routine biochemical testing, by measuring the plasma concentration of 12 common analytes, including proteins, protein-bound substances, enzymes and electrolytes, in plasma specimens collected either without venous stasis or following the application of standardized external pressure of 60mm Hg using a sphygmomanometer for 1 and 3min. Although the overall correlation between measures was acceptable, the pattern of change was mostly dependent on the length of stasis, size and protein-binding characteristics of the analytes, achieving clinical significance for albumin, calcium and potassium after 1-min stasis, and alanine aminotransferase, albumin, calcium, chloride, total cholesterol, glucose and potassium after 3-min stasis. Statistically significant differences could be observed in seven (alanine aminotransferase, albumin, calcium, total cholesterol, creatine kinase, iron and potassium) and ten (alanine aminotransferase, albumin, calcium, chloride, total cholesterol, creatine kinase, creatinine, glucose, iron and potassium) out of the 12 analytes tested, after 1- and 3-min venous stasis, respectively. The most clinically significant changes from standard venepuncture, when compared to the current analytical quality specifications for desirable bias, occurred for potassium (1-min stasis, −2.8%; 3-min stasis, −4.8%, both p<0.001), calcium (1-min stasis, +1.6%, p<0.05; 3-min stasis, +3.6%, p<0.001) and albumin (1-min stasis, +3.5%; 3-min stasis, +8.6%, both p<0.001). As most of these effects are dependent on the stasis time during venepuncture and biochemical or physiological characteristics of the analyte, these variations could likely be anticipated, allowing the most appropriate preventive measures to be adopted.
Isolation and Characterization of Bipotent Liver Progenitor Cells from Adult Mouse
Authors: Li Wen-Lin , Su Juan , Yao Yu-Cheng , Tao Xin-Rong , Yan Yong-Bi , Yu Hong-Yu , Wang Xin-Min , Li Jian-Xiu , Yang Yong-Ji , Lau Joseph T.Y. , Hu Yi-Ping
Published: August 2005

Liver progenitor cells have drawn a great deal of attention both for their therapeutic potential and for their usefulness in exploring the molecular events surrounding liver development and regeneration. Despite the intensive studies on liver progenitors from rats, equivalent progenitor cells derived from mice are relatively rare. We used retrosine treatment followed by partial hepatectomy to elicit liver progenitors in mice. From these animals showing prominent ductular reactions, mouse-derived liver progenitor cell lines (LEPCs) were isolated by single-cell cloning. Phenotypic and lineage profiling of the LEPC clones were performed using immunochemistry, reverse transcription–polymerase chain reaction, and a dual-color system comprising the reporter EGFP under the control of the cytokeratin 19 promoter and the DsRed reporter under the control of the albumin promoter. LEPCs expressed liver progenitor cell markers. LEPCs also expressed some markers shared by bone marrow-derived hematopoietic stem cells c-Kit and Thy-1 but not CD34 and CD45. When cultured as aggregates in Matrigel, LEPCs differentiated into hepatocyte upon treatment with 50 ng/ml epithelial growth factor or differentiated into biliary lineage cells upon treatment with 20 ng/ml hepatocyte growth factor. In the presence of 2% dimethyl sulfoxide and 2% Matrigel, LEPCs acquired predominantly bile lineage phenotypes, with occasional patches of cells exhibiting hepatocyte phenotypes. Upon transplantation into CCl4-injured-liver, LEPCs engrafted into liver parenchyma and differentiated into hepatocytes. Considering the amenability of the mouse to genetic manipulation, these mouse-derived LEPCs may be useful tools as in vitro models to study molecular events in liver development and regeneration and can shed light in studying the therapy potential of liver stem cells.
Growth factor signalling in clinical breast cancer and its impact on response to conventional therapies: the Edinburgh experience
Authors: Miller W R , Anderson T J , White S , Evans D , Krause A , Dixon J M
Published: August 2005

Neoadjuvant endocrine treatment in which therapy is given while the primary tumour is still in the breast provides a highly useful model system by which to identify mechanisms associated with de novo resistance and signs of early acquired resistance. Most importantly, the model is clinically relevant. It has been confirmed that the absence of tumour oestrogen receptors confers resistance to endocrine therapy. Early changes in tumour cell proliferation following neoadjuvant treatment with the third-generation aromatase inhibitor, letrozole, do not predict accurately for subsequent clinical response. Additionally, changes in proliferation seen at later times can be the consequence of response and may be associated with early resistance. High expression of c-erbB2 does not reduce tumour responses to neoadjuvant treatment with aromatase inhibitors, but is associated with high tumour proliferation before and during treatment. It remains to be determined whether these characteristics confer subsequent resistance to treatment and early relapse in the adjuvant setting.
Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy
Authors: Bianco Roberto , Troiani Teresa , Tortora Giampaolo , Ciardiello Fortunato
Published: August 2005

The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Among a variety of approaches used to target EGFR signaling, EGFR blocking monoclonal antibodies and small molecular weight EGFR tyrosine kinase compounds have been successfully developed. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could represent a significant contribution to cancer therapy. Both types of agent exert a significant antiproliferative activity when used alone or in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. Although the advanced clinical development of EGFR blocking drugs demonstrates their efficacy in some human metastatic diseases, such as lung, head and neck and colorectal cancers, the issue of constitutive resistance in a large number of patients and the development of acquired resistance in the responders remains an unexplored subject of investigation. Recent evidence suggests the role of specific activating mutations within the tyrosine kinase domain of EGFR to explain the dramatic responses to small molecule tyrosine kinase inhibitors in a subgroup of lung cancer patients. However, the intrinsic molecular mechanisms of resistance to these drugs are still unclear. This review will focus on the preclinical findings on therapeutic resistance to EGFR targeting agents.
Overview of the impact of conventional systemic therapies on breast cancer
Authors: Howell Anthony , Wardley Andrew M
Published: August 2005

Survival in women with breast cancer is improving in the western world, in part related to improved surgery, radiotherapy and adjuvant systemic therapy. Aromatase inhibitors are superior to tamoxifen in this clinical situation and several studies indicate that taxane-based chemotherapy is superior to non-taxane-based regimens. Herceptin is active alone in HER-2/neu +ve advanced breast cancer and four clinical trials are testing this agent in the adjuvant situation. It seems likely that herceptin will add to conventional therapies and thus will be the paradigm for the introduction of other biological therapies to improve cure rates.
Inhibitors of growth factor signalling
Authors: Wakeling A E
Published: August 2005

The therapeutic utility of trastuzumab (‘Herceptin’) in breast cancer patients with tumours that overexpress erbB2 established the principle that targeted inhibition of specific signal transduction pathways can provide a new approach to cancer treatment. The ErbB family of protein tyrosine kinases, in particular the epidermal growth factor receptor (EGFR), are commonly overexpressed in many solid human tumours and EGFR was the initial target for a drug discovery programme seeking small molecule inhibitors of the EGFR tyrosine kinase (TK) enzyme activity. The description of the anilinoquinazoline class of potent and selective TK inhibitors led to several candidate drugs from this chemical class, for example gefitinib (‘Iressa’) and erlotinib (‘Tarceva’), which are being evaluated in breast cancer patients. Rapid advances in cancer molecular genetics have identified numerous potential drug targets associated with abnormal control of cell division either downstream of the ErbBs, for example Ras and MEK, or in erbB-associated signalling networks, like Src kinase, which affect the tumour cell motility and invasiveness. Candidate drugs for several of these targets are currently being evaluated; for example, the prenylation inhibitor AZD3409, a mimetic of the CAAX box of K-Ras, inhibits protein farnesyl and geranylgeranyl tranferases and a novel, selective, orally active Src kinase inhibitor AZD0530 have entered Phase I clinical trials and may have utility in breast cancer therapy.
Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer
Authors: Duncan R , Vicent M J , Greco F , Nicholson R I
Published: August 2005

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.
Consensus Statement
Authors: Gee J M W , Howell A , Gullick W J , Benz C C , Sutherland R L , Santen R J , Martin L-A , Ciardiello F , Miller W R , Dowsett M , Barrett-Lee P , Robertson J F R , Johnston S R , Jones H E , Wakeling A E , Duncan R , Nicholson R I
Published: August 2005

Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.
Trisomy 10 mosaicism and maternal uniparental disomy 10 in a liveborn infant with severe congenital malformations
Authors: Hahnemann Johanne M.D. , Nir Marta , Friberg M. , Engel Ulla , Bugge Merete
Published: August 2005

We report on a liveborn infant with trisomy 10 mosaicism combined with maternal uniparental heterodisomy for chromosome 10. The mosaicism 47,XY,+10/46,XY was found in five different tissues, including one blood sample, while cultured lymphocytes from two other blood samples showed a normal karyotype, 46,XY. DNA analysis with six PCR‐based microsatellite markers demonstrated the trisomic cell line to be a result of maternal meiotic nondisjunction, and revealed maternal uniparental heterodisomy in the diploid cell line, suggesting that the formation of the diploid cell line was due to trisomy rescue. The boy had severe growth retardation, major dysmorphism, and malformations, and died at 37 days. We reviewed the previous nine reports of infants and fetuses with trisomy 10 mosaicism reported in the literature. We suggest that a common clinical syndrome can be defined comprising skull, jaw and ear abnormalities, cleft lip/palate, malformations of eyes, heart and kidneys, deformity of hands and feet, and most often death neonatally or in early infancy. The cytogenetic findings in the present patient demonstrate the importance of karyotyping more than one tissue, and not only lymphocytes, when a chromosomal aberration is strongly suspected. © 2005 Wiley‐Liss, Inc.
Structure, Protonation State and Dynamics of Catalase Compound II
Authors: Rovira Carme
Published: August 2005

Density functional calculations are performed to investigate the protonation state of the compound II intermediate (Cpd II) of the catalase reaction cycle. Several scenarios are considered, depending on the protonation state of the active center (heme) and the catalytic His residue. Only the form with a protonated FeO unit (i.e. FeOH) is in agreement with the recent high‐resolution crystal structure, while the traditional description of Cpd II as an oxoferryl species corresponds to a configuration slightly higher in energy. The computed FeO stretch frequency is in agreement with the available experimental data. Molecular dynamics simulations show that the pocket water remains in the region between the His61 and Asn133 catalytic residues, but it occasionally tries to escape towards the main channel in a concerted motion with the Asn133 residue. A possible role for this residue in the process of ligand entry/escape from the binding pocket is proposed.
A Lutetium Cyclopentadienyl‐Phosphazene Constrained Geometry Complex (CGC): First Isolobal Analogues of Group 4 Cyclopentadienyl‐Silylamido CGC Systems
Authors: Rufanov Konstantin A. , Petrov Alex R. , Kotov Vasili V. , Laquai Frédéric , Sundermeyer Jörg
Published: August 2005

C5Me4HPMe2 reacts with 1‐adamantyl azide to form the firstexample of a new family of cyclopentadienylideneaminophosphorane ligands (1). Metallation of 1 with Lu(CH2SiMe3)3(THF)2 leads to the first cyclopentadienyl‐phosphazene CGC 2, isolobal to known group 4 cyclopentadienyl‐silylamido CGC systems. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)