bluuebunny/crossref_metadata_2025 huggingface dataset:
Polynesia and polygenism: the scientific use of travel literature in the early 19th century
Authors: Carhart Michael C.
Published: March 2009

Christoph Meiners (1747—1810) was one of 18th-century Europe's most important readers of global travel literature, and he has been credited as a founder of the disciplines of ethnology and anthropology. This article examines a part of his final work, Untersuchungen über die Verschiedenheiten der Menschennaturen [Inquiries on the differences of human natures], published posthumously in the 1810s. Here Meiners developed an elaborate argument, based on empirical evidence, that the different races of men emerged indigenously at different times and in different places in natural history. Specifically this article shows how a sedentary scholar who never left Europe constructed a narrative of human origins and migrations on the basis of (1) French theory from the 1750s (Charles de Brosses and Simon Pelloutier) and (2) data gathered by explorers as reported in travel literature (J. R. Forster, Pérouse, Cook, Marsden).
Test of Time
Authors: Field Andy P. , Nightingale Zoë C.
Published: March 2009

Watson and Rayner's (1920) `Little Albert' experiment has become one of the most famous studies in psychology. It is a staple of many general psychology textbooks and is part of the very fabric of the discipline's folklore. Despite this fame, the study has been widely criticized in the nearly 90 years since it was published for its lack of methodological rigour. This article attempts to evaluate the contribution of the `little Albert' study to modern clinical psychology by speculating on what theories and treatments of child anxiety would look like in a parallel universe in which the study never took place because `little Albert' escaped from the hospital in which Watson tested him.
The elephant in the living room: or extending the conversation about the politics of evidence
Authors: Denzin Norman K.
Published: March 2009

The controversies surrounding the evidence-based research movement are reviewed from a critical pedagogy framework. Standards for assessing quality are forms of interpretive practice that enact a politics of evidence and truth. Moral and ethical criteria for judging qualitative research are reviewed.
The truthful messenger: visual methods and representation in qualitative research in education
Authors: Galman Sally A.C.
Published: March 2009

The problems of representation in qualitative research have been widely documented and multiple means of addressing them have been offered. The purpose of this article is to illustrate ways in which employing collaborative visual methods may present one way to address such problems. While this approach is not without complications, a recent pilot study application suggests that the complexity of participant data is well-handled by integrating the graphic novel as a collaborative visual text in data collection, analysis and presentation.
Effect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary disease
Authors: Valerio Giuseppe , Bracciale Pierluigi , Grazia D'Agostino Anna
Published: March 2009

Background: Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is mainly determined by hypoxemia under respiratory failure by means of the functional hypoxemic vasoconstrictor response. Organic changes of vessels, pulmonary vascular remodelling, is gaining increasing relevance. An imbalance of endothelial products takes place with overload of vasoconstrictors and thrombogenic autacoids over vasodilators and anticoagulant factors. Among vasoconstrictors, endothelin is claimed to be an important factor. Our aim is to assess the effect of the anti-endothelin drug Bosentan on pulmonary hemodynamics and lung function in patients affected by COPD and PH.

Methods: Bosentan was administered to 16 patients for a period of 18 months, while another 16 patients with overlapping features was used as a control group. Pulmonary function test, hemodynamics, effort performance, dyspnoea ratings and quality of life were recorded at the beginning and after 18 months under stable state.

Results: Bosentan treatment resulted in a significant improvement of PH from 37 + 5 to 31 + 6mm Hg and pulmonary vascular resistance from 442 + 192 to 392 + 180dynes cm2 and 6MWD from 256 + 118 to 321 + 122m and BODE index from 6.6 + 2.8 to 5.5 + 3U. The effect was most striking in the 30% of patients in GOLD stage III and IV. Most patients in stage IV did not improve, but in all patients the treatment stopped the progressive worsening of hemodynamics over time. The study also highlights the need to identify patients with high pulmonary arterial pressure contrasting with moderate respiratory disease stages, in whom the predominant problem is evidently vascular disease.

Conclusion: This preliminary report suggests that the use of Bosentan in the treatment of PH in COPD is beneficial.
From large clinical trials to management of COPD in the real world
Authors: Cazzola Mario
Published: March 2009

Large clinical trials in chronic obstructive pulmonary disease (COPD) are analyzed and discussed. Unfortunately, all of them have failed to reach their primary endpoint, which has mainly been the effect on the rate of decline in mean FEV1 (forced expiratory volume in 1 second). Nonetheless, almost all trials have demonstrated benefits in important outcomes such as exacerbation frequency, symptoms, quality of life and other measures of health status, which are arguably more meaningful to individual patients than FEV 1 per se.
Smoking and depression: is smoking cessation effective?
Authors: Ischaki Eleni , Gratziou Christina
Published: March 2009

Patients with depression tend to have a higher rate of smoking and an increased severity of nicotine dependence. It seems that common genetic and environmental factors may influence the bimodal relationship between smoking and depression. Nicotine has some positive reinforcing/rewarding effects that may affect people with mood disorders and smoking is also used as a `relief medication' in order to ameliorate symptoms of depression, as it is already known that nicotine, which is the major psychoactive ingredient in tobacco, may act as an antidepressant. To date, the data regarding the difficulty in smoking cessation in depressed smokers are conflicting. Low confidence and self-esteem among this group of smokers are significant predictors of failure during smoking cessation attempt. In the most recently published guidelines for smokers with psychiatric comorbidities the suggestion is for combination treatment (counseling and pharmaceutical treatment) and prolongation of a therapeutic approach.
Therapeutic targeting of MLL
Authors: Liedtke Michaela , Cleary Michael L.
Published: March 2009

Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.
Activation of an AMP-activated protein kinase is involved in post-diapause development of Artemia franciscana encysted embryos
Authors: Zhu Xiao-Jing , Dai Jie-Qiong , Tan Xin , Zhao Yang , Yang Wei-Jun
Published: March 2009

Background

Cysts of Artemia can remain in a dormant state for long periods with a very low metabolic rate, and only resume their development with the approach of favorable conditions. The post-diapause development is a very complicated process involving a variety of metabolic and biochemical events. However, the intrinsic mechanisms that regulate this process are unclear.

Results

Herein we report the specific activation of an AMP-activated protein kinase (AMPK) in the post-diapause developmental process of Artemia. Using a phospho-AMPKα antibody, AMPK was shown to be phosphorylated in the post-diapause developmental process. Results of kinase assay analysis showed that this phosphorylation is essential for AMPK activation. Using whole-mount immunohistochemistry, phosphorylated AMPK was shown to be predominantly located in the ectoderm of the early developed embryos in a ring shape; however, the location and shape of the activation region changed as development proceeded. Additionally, Western blotting analysis on different portions of the cyst extracts showed that phosphorylated AMPKα localized to the nuclei and this location was not affected by intracellular pH. Confocal microscopy analysis of immunofluorescent stained cyst nuclei further showed that AMPKα localized to the nuclei when activated. Moreover, cellular AMP, ADP, and ATP levels in developing cysts were determined by HPLC, and the results showed that the activation of Artemia AMPK may not be associated with cellular AMP:ATP ratios, suggesting other pathways for regulation of Artemia AMPK activity.

Conclusion

Together, we report evidence demonstrating the activation of AMPK in Artemia developing cysts and present an argument for its role in the development-related gene expression and energy control in certain cells during post-diapause development of Artemia.
Transcriptomic basis for an antiserum against Micrurus corallinus (coral snake) venom
Authors: Leão Luciana I , Ho Paulo L , Junqueira-de-Azevedo Inacio de LM
Published: March 2009

Background

Micrurus corallinus (coral snake) is a tropical forest snake belonging to the family Elapidae. Its venom shows a high neurotoxicity associated with pre- and post-synaptic toxins, causing diaphragm paralysis, which may result in death. In spite of a relatively small incidence of accidents, serum therapy is crucial for those bitten. However, the adequate production of antiserum is hampered by the difficulty in obtaining sufficient amounts of venom from a small snake with demanding breeding conditions. In order to elucidate the molecular basis of this venom and to uncover possible immunogens for an antiserum, we generated expressed sequences tags (ESTs) from its venom glands and analyzed the transcriptomic profile. In addition, their immunogenicity was tested using DNA immunization.

Results

A total of 1438 ESTs were generated and grouped into 611 clusters. Toxin transcripts represented 46% of the total ESTs. The two main toxin classes consisted of three-finger toxins (3FTx) (24%) and phospholipases A2 (PLA2s) (15%). However, 8 other classes of toxins were present, including C-type lectins, natriuretic peptide precursors and even high-molecular mass components such as metalloproteases and L-amino acid oxidases. Each class included an assortment of isoforms, some showing evidence of alternative splicing and domain deletions. Five antigenic candidates were selected (four 3FTx and one PLA2) and used for a preliminary study of DNA immunization. The immunological response showed that the sera from the immunized animals were able to recognize the recombinant antigens.

Conclusion

Besides an improvement in our knowledge of the composition of coral snake venoms, which are very poorly known when compared to Old World elapids, the expression profile suggests abundant and diversified components that may be used in future antiserum formulation. As recombinant production of venom antigens frequently fails due to complex disulfide arrangements, DNA immunization may be a viable alternative. In fact, the selected candidates provided an initial evidence of the feasibility of this approach, which is less costly and not dependent on the availability of the venom.
The mitochondrial genomes of Ancylostoma caninum and Bunostomum phlebotomum – two hookworms of animal health and zoonotic importance
Authors: Jex Aaron R , Waeschenbach Andrea , Hu Min , van Wyk Jan A , Beveridge Ian , Littlewood D Timothy J , Gasser Robin B
Published: March 2009

Background

Hookworms are blood-feeding nematodes that parasitize the small intestines of many mammals, including humans and cattle. These nematodes are of major socioeconomic importance and cause disease, mainly as a consequence of anaemia (particularly in children or young animals), resulting in impaired development and sometimes deaths. Studying genetic variability within and among hookworm populations is central to addressing epidemiological and ecological questions, thus assisting in the control of hookworm disease. Mitochondrial (mt) genes are known to provide useful population markers for hookworms, but mt genome sequence data are scant.

Results

The present study characterizes the complete mt genomes of two species of hookworm, Ancylostoma caninum (from dogs) and Bunostomum phlebotomum (from cattle), each sequenced (by 454 technology or primer-walking), following long-PCR amplification from genomic DNA (~20–40 ng) isolated from individual adult worms. These mt genomes were 13717 bp and 13790 bp in size, respectively, and each contained 12 protein coding, 22 transfer RNA and 2 ribosomal RNA genes, typical for other secernentean nematodes. In addition, phylogenetic analysis (by Bayesian inference and maximum likelihood) of concatenated mt protein sequence data sets for 12 nematodes (including Ancylostoma caninum and Bunostomum phlebotomum), representing the Ascaridida, Spirurida and Strongylida, was conducted. The analysis yielded maximum statistical support for the formation of monophyletic clades for each recognized nematode order assessed, except for the Rhabditida.

Conclusion

The mt genomes characterized herein represent a rich source of population genetic markers for epidemiological and ecological studies. The strong statistical support for the construction of phylogenetic clades and consistency between the two different tree-building methods employed indicate the value of using whole mt genome data sets for systematic studies of nematodes. The grouping of the Spirurida and Ascaridida to the exclusion of the Strongylida was not supported in the present analysis, a finding which conflicts with the current evolutionary hypothesis for the Nematoda based on nuclear ribosomal gene data.
Discovery and identification of potential biomarkers of pediatric Acute Lymphoblastic Leukemia
Authors: Shi Linan , Zhang Jun , Wu Peng , Feng Kai , Li Jing , Xie Zhensheng , Xue Peng , Cai Tanxi , Cui Ziyou , Chen Xiulan , Hou Junjie , Zhang Jianzhong , Yang Fuquan
Published: March 2009

Background

Acute lymphoblastic leukemia (ALL) is a common form of cancer in children. Currently, bone marrow biopsy is used for diagnosis. Noninvasive biomarkers for the early diagnosis of pediatric ALL are urgently needed. The aim of this study was to discover potential protein biomarkers for pediatric ALL.

Methods

Ninety-four pediatric ALL patients and 84 controls were randomly divided into a "training" set (45 ALL patients, 34 healthy controls) and a test set (49 ALL patients, 30 healthy controls and 30 pediatric acute myeloid leukemia (AML) patients). Serum proteomic profiles were measured using surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy (SELDI-TOF-MS). A classification model was established by Biomarker Pattern Software (BPS). Candidate protein biomarkers were purified by HPLC, identified by LC-MS/MS and validated using ProteinChip immunoassays.

Results

A total of 7 protein peaks (9290 m/z, 7769 m/z, 15110 m/z, 7564 m/z, 4469 m/z, 8937 m/z, 8137 m/z) were found with differential expression levels in the sera of pediatric ALL patients and controls using SELDI-TOF-MS and then analyzed by BPS to construct a classification model in the "training" set. The sensitivity and specificity of the model were found to be 91.8%, and 90.0%, respectively, in the test set. Two candidate protein peaks (7769 and 9290 m/z) were found to be down-regulated in ALL patients, where these were identified as platelet factor 4 (PF4) and pro-platelet basic protein precursor (PBP). Two other candidate protein peaks (8137 and 8937 m/z) were found up-regulated in the sera of ALL patients, and these were identified as fragments of the complement component 3a (C3a).

Conclusion

Platelet factor (PF4), connective tissue activating peptide III (CTAP-III) and two fragments of C3a may be potential protein biomarkers of pediatric ALL and used to distinguish pediatric ALL patients from healthy controls and pediatric AML patients. Further studies with additional populations or using pre-diagnostic sera are needed to confirm the importance of these findings as diagnostic markers of pediatric ALL.
Construction and validation of a short-form Quality-Of-Life Scale for Chinese Patients with Benign Prostatic Hyperplasia
Authors: Guo Yanfang , Shi Jingcheng , Hu Ming , Sun Zhenqiu
Published: March 2009

Background

In 2003, a 74-item quality-of-life (QOL) scale for Chinese benign prostatic hyperplasia (BPH) patients (BPH-QLS) was developed. Although the scale displayed good reliability and validity, the time required to complete it may limit its use. The purpose of this study was to construct and validate a short-form quality-of-life (QOL) scale for Chinese patients with Benign Prostatic Hyperplasia (BPH).

Methods

According to the previously published 74-item quality of life scale for BPH (BPH-QLS), we developed a pool of items, then condensed these items and validated the shortened scale, based on collected data from 163 patients with BPH. We used eight methods to reduce the items.

Results

A 33-item QOL scale for BPH (short-form of BPH-QLS) was constructed. The time take by the new scale was much shorter than the original one. There was no significant difference between the 33-item scale and 74-item scale, in terms of reliability. Moreover, the 33-item BPH-QLS showed a high correlation with the 74-item BPH-QLS (r = 0.971). Scores generated by the two scales were not only parallel and coincident but also at the same level.

Conclusion

We concluded that the reliability and validity of the short form of BPH-QLS is close to those of the 74-item BPH-QLS. It should be a good choice in clinical practice for its greater compliance and clinical feasibility.
Alterations of T cell activation signalling and cytokine production by postmenopausal estrogen levels
Authors: Ku Lowell T , Gercel-Taylor Cicek , Nakajima Steven T , Taylor Douglas D
Published: March 2009

Background

Immunosenescence is an age-associated disorder occurring primarily in T cell compartments, including altered subset composition, functions, and activation. In women, evidence implicates diminished estrogen in the postmenopausal period as a contributing factor to diminished T cell responsiveness. Since hypoestrogenism is present in postmenopausal women, our objective focused on whether T cell activation, defined as signalling molecule expressions and activation, and function, identified as IL-2 production, were affected by low estrogen.

Methods

Using Jurkat 6.1 T cells, consequences of 4 pg/ml (corresponding to postmenopausal levels) or 40 pg/ml (premenopausal levels) of estradiol (E2) were analyzed on signalling proteins, CD3-zeta, JAK2, and JAK3, determined by Western immunoblotting. These consequences were correlated with corresponding gene expressions, quantified by real time-polymerase chain reaction. Tyrosine phosphorylation of CD3-zeta was defined by immunoprecipitation and western immunoblotting following activation by T cell receptor (TcR) cross-linking. CD3-zeta expression and modulation was also confirmed in T cells from pre- and postmenopausal women. To assess functional consequences, IL-2 production, induced by PMA and ionomycin, was determined using enzyme-linked immunosorbent spot assay (ELISpot).

Results

At 40 pg/ml E2, the level of signalling protein CD3-zeta was elevated 1.57-fold, compared with cells exposed to 4 pg/ml E2. The CD3-zeta proteins also exhibited altered levels of activation-induced phosphorylation in the presence of 40 pg/ml E2 versus 4 pg/ml: 23 kD phosphorylated form increased 2.64-fold and the 21 kD form was elevated 2.95-fold. Examination of kinases associated with activation signalling also demonstrated that, in the presence of 40 pg/ml E2, JAK2 protein expression was increased 1.64-fold (p < 0.001) and JAK3 enhanced 1.79-fold (p < 0.001) compared to 4 pg/ml. mRNA levels for CD3-zeta, JAK2, and JAK3 were significantly increased following exposure to 40 pg/ml E2 (2.39, 2.01, and 2.21 fold, respectively) versus 4 pg/ml. These findings were confirmed in vivo, since T cells from postmenopausal women exhibited 7.2-fold diminished CD3-zeta expression, compared to pre-menopausal controls and this expression was elevated 3.8-fold by addition of 40 pg/ml E2. Functionally, Jurkat cells exposed to 40 pg/ml E2 and activated exhibited significantly elevated numbers of IL-2 producing colonies compared to 4 pg/ml (75.3 ± 2.2 versus 55.7 ± 2.1 colonies, p < 0.0001).

Conclusion

Jurkat T cells exposed to 4 pg/ml E2 expressed significantly diminished activation signalling proteins, correlating with reduced IL-2 production. Lower signalling protein levels appear to result from decreased CD3-zeta, JAK2, and JAK3 gene expressions. These findings may provide a molecular basis for immunosenescence associated with the postmenopausal state.
Using non-invasive brain stimulation to augment motor training-induced plasticity
Authors: Bolognini Nadia , Pascual-Leone Alvaro , Fregni Felipe
Published: March 2009

Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.
MUTYH Gln324His gene polymorphism and genetic susceptibility for lung cancer in a Japanese population
Authors: Miyaishi Aiko , Osawa Kayo , Osawa Yasunori , Inoue Natsuko , Yoshida Kana , Kasahara Mayumi , Tsutou Akimitsu , Tabuchi Yoshiki , Sakamoto Kazuo , Tsubota Noriaki , Takahashi Juro
Published: March 2009

Background

Genetic polymorphisms of DNA repair enzymes in the base excision repair (BER) pathway, may lead to genetic instability and lung cancer carcinogenesis. We investigated the interactions among the gene polymorphisms in DNA repair genes and lung cancer.

Methods

We analyzed associations among OGG1 Ser326Cys and MUTYH Gln324His gene polymorphisms in relation to lung cancer risk using PCR-RFLP. The study involved 108 lung cancer patients and 121 non-cancer controls divided into non-smokers, smokers according to pack-years smoked in Japanese.

Results

The results showed that the MUTYH His/His genotype compared with Gln/Gln genotype showed an increased risk for lung cancer (adjusted odds ratio [OR] 3.03, confidence interval [95%CI], 1.31–7.00, p = 0.010), whereas there was no significant increase for the Gln/His genotype (adjusted OR 1.35, 95%CI 0.70–2.61, p = 0.376). The MUTYH His/His genotype was at a borderline increased risk for both adenocarcinoma and squamous cell carcinoma (adjusted OR 2.50, 95%CI 0.95–6.62, p = 0.065 for adenocarcinoma; adjusted OR 3.20, 95%CI 0.89–11.49, p = 0.075 for squamous cell carcinoma, respectively). However, the OGG1 Ser/Cys or Cys/Cys genotypes compared with the Ser/Ser genotype did not have significantly increased risk for lung cancer, containing either adenocarcinoma or squamous cell carcinoma. The joint effect of tobacco exposure and the MUTYH His/His genotype compared with the Gln/Gln genotype showed a significant association with lung cancer risk in smokers, and there was not significantly increased in non-smokers (adjusted OR 3.82, 95%CI 1.22–12.00, p = 0.022 for smokers; adjusted OR 2.60, 95%CI 0.60–11.25, p = 0.200 for non-smokers, respectively). The effect of tobacco exposure and the OGG1 Ser326Cys showed also no significant risk for lung cancer.

Conclusion

Our findings suggest that the MUTYH Gln324His polymorphism appear to play an important role in modifying the risk for lung cancer in the Japanese population.
Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome
Authors: Charles Pierre Emmanuel , Tinel Claire , Barbar Saber , Aho Serge , Prin Sébastien , Doise Jean Marc , Olsson Nils Olivier , Blettery Bernard , Quenot Jean Pierre
Published: March 2009

Introduction

Management of the early stage of sepsis is a critical issue. As part of it, infection control including appropriate antibiotic therapy administration should be prompt. However, microbiological findings, if any, are generally obtained late during the course of the disease. The potential interest of procalcitonin (PCT) as a way to assess the clinical efficacy of the empirical antibiotic therapy was addressed in the present study.

Methods

An observational cohort study including 180 patients with documented sepsis was conducted in our 15-bed medical intensive care unit (ICU). Procalcitonin measurement was obtained daily over a 4-day period following the onset of sepsis (day 1 (D1) to D4). The PCT time course was analyzed according to the appropriateness of the first-line empirical antibiotic therapy as well as according to the patient outcome.

Results

Appropriate first-line empirical antibiotic therapy (n = 135) was associated with a significantly greater decrease in PCT between D2 and D3 (ΔPCT D2–D3) (-3.9 (35.9) vs. +5.0 (29.7), respectively; P < 0.01). In addition, ΔPCT D2–D3 was found to be an independent predictor of first-line empirical antibiotic therapy appropriateness. In addition, a trend toward a greater rise in PCT between D1 and D2 was observed in patients with inappropriate antibiotics as compared with those with appropriate therapy (+5.2 (47.4) and +1.7 (35.0), respectively; P = 0.20). The D1 PCT level failed to predict outcome, but higher levels were measured in the nonsurvivors (n = 51) when compared with the survivors (n = 121) as early as D3 (40.8 (85.7) and 21.3 (41.0), respectively; P = 0.04). Moreover, PCT kinetics between D2 and D3 were also found to be significantly different, since a decrease ≥ 30% was expected in the survivors (log-rank test, P = 0.04), and was found to be an independent predictor of survival (odds ratio = 2.94; 95% confidence interval 1.22 to 7.09; P = 0.02).

Conclusions

In our study in an ICU, appropriateness of the empirical antibiotic therapy and the overall survival were associated with a greater decline in PCT between D2 and D3. Further studies are needed to assess the utility of the daily monitoring of PCT in addition to clinical evaluation during the early management of sepsis.
Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas
Authors: Puget Stéphanie , Grill Jacques , Valent Alexander , Bieche Ivan , Dantas-Barbosa Carmela , Kauffmann Audrey , Dessen Philippe , Lacroix Ludovic , Geoerger Birgit , Job Bastien , Dirven Clemens , Varlet Pascale , Peyre Mathieu , Dirks Peter B. , Sainte-Rose Christian , Vassal Gilles
Published: March 2009

Purpose

The molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression.

Patients and Methods

We characterized 59 ependymoma samples (33 at diagnosis and 26 at relapse) using array-comparative genomic hybridization (aCGH). Specific chromosomal imbalances were confirmed by fluorescent in situ hybridization, and candidate genes were assessed by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, sequencing, and in vitro functional studies.

Results

aCGH analysis revealed a significant increase in genomic imbalances on relapse compared with diagnosis, such as gain of 9qter and 1q (54% v 21% and 12% v 0%, respectively) and loss of 6q (27% v 6%). Supervised tumor classification showed that gain of 9qter was associated with tumor recurrence, age older than 3 years, and posterior fossa location. Using a candidate-gene strategy, we found an overexpression of two potential oncogenes at the locus 9qter: Tenascin-C and Notch1. Moreover, Notch pathway analysis (qPCR) revealed overexpression of Notch ligands, receptors, and target genes (Hes-1, Hey2, and c-Myc), and downregulation of Notch repressor Fbxw7. We confirmed by immunohistochemistry the overexpression of Tenascin-C and Hes-1. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Furthermore, inhibition of Notch pathway with a γ-secretase inhibitor impaired the growth of ependymoma stem cell cultures.

Conclusion

The activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. We report, to our knowledge for the first time, recurrent oncogenic mutations in pediatric posterior fossa ependymomas.
Genomic Strategy for Targeting Therapy in Castration-Resistant Prostate Cancer
Authors: Mendiratta Prateek , Mostaghel Elahe , Guinney Justin , Tewari Alok K. , Porrello Alessandro , Barry William T. , Nelson Peter S. , Febbo Phillip G.
Published: March 2009

Purpose

Despite treatments which lower circulating androgens, advanced prostate cancers often maintain androgen receptor (AR) signaling. The variable response to secondary hormonal manipulations in men with castrate-resistant prostate cancer (CRPC) creates a compelling need for strategies to individualize therapy based on the molecular features of each patient's tumor.

Methods

A transcription-based AR activity signature was developed from an androgen-sensitive prostate cancer cell (LNCaP) and tested on independent data sets of prostate cancer cell lines and human tumors to assess its precision and accuracy in detecting AR activity. The AR signature was applied to multiple sets of prostate specimens to determine how AR activity changes with hormone therapy and progression and oncogenic pathway analysis was used to identify biologic pathways correlating with AR activity.

Results

A robust AR signature accurately predicts AR activity in multiple prostate cancer cell lines, has minimal variation between replicate samples, and accurately reflects an individual's hormone status and intraprostatic dihydrotestosterone levels. The AR signature finds AR activity to be high in local, untreated prostate tumors and decreased in prostate tissue after neoadjuvant hormone therapy and in CRPC. Heterogeneity of AR activity exists along the spectrum of prostate cancer progression and decreasing predicted AR activity correlates with increasing predicted Src activity and sensitivity to dasatinib (Src-targeting kinase inhibitor).

Conclusion

A transcription-based AR signature can detect AR activity within individual prostate cancer specimens and has the potential to help individualize and improve care for patients with CRPC.
Systematic Review and Meta-Analysis of Randomized and Nonrandomized Trials on Safety and Efficacy of Video-Assisted Thoracic Surgery Lobectomy for Early-Stage Non–Small-Cell Lung Cancer
Authors: Yan Tristan D. , Black Deborah , Bannon Paul G. , McCaughan Brian C.
Published: March 2009

Purpose

The current randomized trials comparing video-assisted thoracic surgery (VATS) lobectomy with open lobectomy for patients with early-stage non–small-cell lung cancer (NSCLC) have been of small size. We performed the present meta-analysis of the randomized and nonrandomized comparative studies in an attempt to assess the safety and efficacy of VATS lobectomy.

Methods

Electronic searches identified 21 eligible comparative studies (two randomized and 19 nonrandomized) for inclusion. Two reviewers independently appraised each study. Meta-analysis was performed by combining the results of reported incidence of morbidity and mortality, recurrence, and 5-year mortality rates. The relative risk (RR) was used as a summary statistic.

Results

There were no significant statistical differences between VATS and open lobectomy in terms of postoperative prolonged air leak (P = .71), arrhythmia (P = .86), pneumonia (P = .09), and mortality (P = .49). VATS did not demonstrate any significant difference in locoregional recurrence (P = .24), as compared with the open lobectomy arm, but the data suggested a reduced systemic recurrence rate (P = .03) and an improved 5-year mortality rate of VATS (P = .04). There was no evidence to suggest heterogeneity of trial results. Fourteen studies reported VATS to open lobectomy conversion rate ranging from 0% to 15.7% (median = 8.1%).

Conclusion

Both randomized and nonrandomized trials suggest that VATS lobectomy is an appropriate procedure for selected patients with early-stage NSCLC when compared with open surgery.
Phase II Study of Picoplatin As Second-Line Therapy for Patients With Small-Cell Lung Cancer
Authors: Eckardt John R. , Bentsion Dimitri L. , Lipatov Oleg N. , Polyakov Igor S. , MacKintosh Frederick R. , Karlin David A. , Baker Gizelle S. , Breitz Hazel B.
Published: March 2009

Purpose

This study was designed to confirm the efficacy and safety of picoplatin, a cisplatin analog designed to overcome platinum resistance, in patients with small-cell lung cancer (SCLC) with platinum-refractory/-resistant disease.

Patients and Methods

All patients received intravenous picoplatin 150 mg/m2 every 3 weeks. Tumor response, progression-free survival, and overall survival were evaluated. Adverse events were assessed for frequency, severity, and relationship to treatment. Quality of life was assessed with the Lung Cancer Symptom Scale instrument.

Results

Seventy-seven patients were treated with picoplatin (median number of cycles, two; range one to 10). Three patients (4%) had a partial response, 33 (43%) had stable disease (four of these were unconfirmed partial responses), 36 (47%) had progressive disease, and five were not assessable for response. Median progression-free survival was 9.1 weeks (95% CI, 7.0 to 12.1 weeks). Median overall survival was 26.9 weeks (95% CI, 21.1 to 33.4). The most common grade 3 and 4 toxicities were thrombocytopenia (48%), neutropenia (25%), and anemia (20%). The most commonly reported adverse events of any severity included thrombocytopenia (64%), anemia (49%), neutropenia (39%), nausea (27%), fatigue (16%), and dyspnea (16%). No severe neurotoxicity or nephrotoxicity were observed. There were no treatment-related deaths.

Conclusion

Picoplatin demonstrated clinical efficacy in platinum-refractory SCLC. The major toxicity was hematologic. These results warrant further evaluation in this patient population.
Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study
Authors: von Minckwitz Gunter , du Bois Andreas , Schmidt Marcus , Maass Nicolai , Cufer Tanja , de Jongh Felix E. , Maartense Eduard , Zielinski Christoph , Kaufmann Manfred , Bauer Wolfgang , Baumann Klaus H. , Clemens Michael R. , Duerr Ralph , Uleer Christoph , Andersson Michael , Stein Robert C. , Nekljudova Valentina , Loibl Sibylle
Published: March 2009

Purpose

Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)–positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression.

Methods

Patients with HER-2–positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m2 body-surface area on days 1 through 14 [1,250 mg/m2 semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression.

Results

We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity.

Conclusion

Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2–positive breast cancer who experienced progression during trastuzumab treatment.
Baseline C-Reactive Protein Is Associated With Incident Cancer and Survival in Patients With Cancer
Authors: Allin Kristine H. , Bojesen Stig E. , Nordestgaard Børge G.
Published: March 2009

Purpose

We tested the hypothesis that baseline plasma levels of C-reactive protein (CRP) are associated with risk of incident cancer in the general population and early death in patients with cancer.

Patients and Methods

A total of 10,408 individuals from the Danish general population who had CRP measured at baseline were observed for up to 16 years; 1,624 developed cancer, and of these, 998 patients died during follow-up. Follow-up was 100% complete. We excluded individuals with a cancer diagnosis at baseline.

Results

Baseline CRP levels more than 3 versus less than 1 mg/L were associated with multifactorially adjusted hazard ratios of 1.3 (95% CI, 1.0 to 1.6) for cancer of any type, 2.2 (95% CI, 1.0 to 4.6) for lung cancer, 1.9 (95% CI, 0.8 to 4.6) for colorectal cancer, and 0.7 (95% CI, 0.4 to 1.4) for breast cancer. Corresponding hazard ratios for the highest versus the lowest quintile of baseline CRP levels were 1.3 (95% CI, 1.0 to 1.6), 2.1 (95% CI, 1.2 to 3.8), 1.7 (95% CI, 0.8 to 3.2), and 0.9 (95% CI, 0.5 to 1.7), respectively. Multifactorially adjusted hazard ratios for early death in patients with cancer were 1.8 (95% CI, 1.2 to 2.7) for CRP more than 3 versus less than 1 mg/L and 1.4 (95% CI, 1.1 to 1.7) for the highest versus the lowest quintile. Elevated CRP levels were associated with early death in patients with cancer having localized disease, but not in those with metastases (interaction; P = .03).

Conclusion

Elevated levels of CRP in cancer-free individuals are associated with increased risk of cancer of any type, of lung cancer, and possibly of colorectal cancer. Moreover, elevated levels of baseline CRP associate with early death after a diagnosis of any cancer, particularly in patients without metastases.
Predictors of Postoperative Quality of Life After Esophagectomy for Cancer
Authors: Djärv Therese , Blazeby Jane M. , Lagergren Pernilla
Published: March 2009

Purpose

To identify factors predictive of health-related quality of life (HRQL) 6 months after surgery for esophageal cancer.

Patients and Methods

A Swedish nationwide population-based study of patients undergoing esophagectomy for cancer was undertaken between 2001 and 2005. Clinical details (sex, age, body mass index [BMI], comorbidity) and tumor details (histology, stage, and location) were prospectively recorded and validated. HRQL questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and OES18) were used to assess HRQL 6 months postoperatively. HRQL outcome was categorized as good or poor by collapsing the four response categories. Logistic regression models adjusting for potential confounding factors were used to assess the association between preoperative patient and tumor characteristics and HRQL outcome 6 months after surgery.

Results

A total of 355 patients (77% of eligible) responded to the HRQL questionnaires. Age, sex, and BMI showed no associations with HRQL 6 months after surgery, but patients with comorbidity, a more advanced tumor stage (III to IV), or a tumor located in the middle or upper esophagus had an increased risk of poor HRQL. Patients with adenocarcinoma had a lower risk of poor HRQL than patients with squamous cell carcinoma.

Conclusion

Knowledge of risk factors for poor postoperative HRQL may be relevant for clinical decision making. More research to see whether these factors are further predictive of poor HRQL in long-term survivors is needed.
Production and Necessity
Authors: deRosset Louis
Published: March 2009

A major source of latter-day skepticism about necessity is the work of David Hume. Hume is widely taken to have endorsed the Humean claim: there are no necessary connections between distinct existences. The Humean claim is defended on the grounds that necessary connections between wholly distinct things would be mysterious and inexplicable. Philosophers deploy this claim in the service of a wide variety of philosophical projects. But Saul Kripke has argued that it is false. According to Kripke, there are necessary connections between distinct existences; in particular, there are necessary connections between material objects and their material origins. This essay argues that the primary motivation for the Humean claim, Hume's datum, also motivates the key premise in an argument for the necessity of origins. The very considerations that the Humean takes to show that necessary connections between wholly distinct things would be mysterious and inexplicable indicate that there must be some such necessary connections. Thus, in the absence of alternative support, there is no reason to believe the Humean claim.
Conflict Resolution in the Scheduling of Television Commercials
Authors: Gaur Daya Ram , Krishnamurti Ramesh , Kohli Rajeev
Published: March 2009

We extend a previous model for scheduling commercial advertisements during breaks in television programming. The proposed extension allows differential weighting of conflicts between pairs of commercials. We formulate the problem as a capacitated generalization of the max k-cut problem in which the vertices of a graph correspond to commercial insertions and the edge weights to the conflicts between pairs of insertions. The objective is to partition the vertices into k capacitated sets to maximize the sum of conflict weights across partitions. We note that the problem is NP-hard. We extend a previous local-search procedure to allow for the differential weighting of edge weights. We show that for problems with equal insertion lengths and break durations, the worst-case bound on the performance of the proposed algorithm increases with the number of program breaks and the number of insertions per break, and that it is independent of the number of conflicts between pairs of insertions. Simulation results suggest that the algorithm performs well even if the problem size is small.
RFQ Auctions with Supplier Qualification Screening
Authors: Wan Zhixi , Beil Damian R.
Published: March 2009

We consider a manufacturer using a request-for-quotes (RFQ) reverse auction in combination with supplier qualification screening to determine which qualified supplier will be awarded a contract. Supplier qualification screening is costly for the manufacturer—for example, involving reference checks, financial audits, and on-site visits. The manufacturer seeks to minimize its total procurement costs, i.e., the contract payment plus qualification costs. Although suppliers can be qualified prior to the auction (prequalification), we allow the manufacturer to delay all or part of the qualification until after the auction (postqualification). Using an optimal mechanism analysis, we analytically explore the trade-offs between varying levels of pre- and postqualification. Although using postqualification causes the expected contract payment to increase (bids from unqualified suppliers are discarded), we find that standard industrial practices of prequalification can be improved upon by judicious use of postqualification, particularly when supplier qualification screening is moderately expensive relative to the value of the contract to the manufacturer.