bluuebunny/crossref_metadata_2025 huggingface dataset:
Remuneration in the German Broadcasting Sector: The Employers' Perspective
Authors: Bleses Peter
Published: March 2007

This article focuses on the managerial perspective in wage formation. The study concentrates on two questions: 1) Why do employers want more autonomy at the expense of collective agreements? 2) What do employers gain from a more or less autonomous system of remuneration? After a brief description of the wage formation framework, in particular the framework within the broadcasting sector, I will present the results of interviews with the management of private and public broadcasting stations. In matters of wage formation the study illustrates a clear division between companies with collective agreements and companies without collective agreements. All the managers interviewed for this article express an increasing need for autonomy, but some are convinced that autonomy can be achieved within the framework of collective agreements. Other companies demand absolute autonomy for the management and totally reject being bound by collective bargaining. Most of the companies without collective agreements refuse to undergo or accept the results of collective bargaining, citing that collective agreements could hamper their efforts to create their own remuneration system, which they say should be linked directly to the individual performances of each employee. Contrary to the assumptions of the German model of industrial relations, these employers see the individual conflict over remuneration as an opportunity to motivate employees and to preserve the management's future flexibility. Another interesting result emerges in respect to the role of labor law. Contrary to the assumption that German labor law hinders flexibility, employers in this study do not see the process of wage formation extremely restricted by labor law.
The Standard of Living Debate in Development Policy
Authors: Petras James , Veltmeyer Henry
Published: March 2007

The aim of this paper is to expose the ideological manipulation of the concept of poverty in the associated standard of living measurement tools in the development literature. The World Bank and its partners in the war on poverty fail to locate and analyze the critical contextual factors at issue in the prevalence and persistence of poverty. This is a problem that we trace back to a fundamental concern with advancing economic interests tied to global capital, interests that are in direct conflict with the stated concern of the World Bank and its partners in the project of cooperation for international development for world poverty — to reduce the incidence of absolute poverty an alleviate its worst effects. The implication of our findings is the need to construct methodologies and measurement techniques that are closer to the poor and their real living conditions. This, we conclude, is a matter of methodology and policy.
Organizations, Resources, and Class Analysis: The Distributional Model and the US Class Structure
Authors: Wysong Earl , Perrucci Robert
Published: March 2007

This article presents selected features of a theoretical schema we term the distributional model of class analysis which views large organizations, organizationally-based resources, and distributional processes as central to the US class structure. We first review what we term production models of class analysis and illustrate how some features of these models may be linked to insights from studies of class involving large organizations and distributional processes. Building on this foundation, we introduce the main ideas of our model and focus on two central features: generative capital and the distributive order . We identify four forms of generative capital as the basis of class membership: consumption, investment, credentialed skill, and social. Classes are viewed as consisting of individuals and families who possess, over time, similar levels of these resources. The class structure is illustrated with a figure divided into the privileged (top 20 percent) and new working classes (bottom 80 percent) which are posited as having oppositional class interests. We then identify four elements of the distributive order and discuss how each influences the distribution of generative capital forms to individuals and families. We conclude with a discussion of the merits of our model and with illustrations of new lines of inquiry in class analysis the model could stimulate.
Lean Production, Worker Empowerment, and Job Satisfaction: A Qualitative Analysis and Critique
Authors: Vidal Matt
Published: March 2007

Many argue that increased employee involvement in manufacturing is central to lean production. Increasing the responsibilities and abilities of front-line workers has been labeled empowerment. Such empowerment is said to increase job satisfaction. Yet, there is surprisingly little qualitative research directly addressing the relationship between participatory work arrangements and job satisfaction, and the quantitative evidence is much less clear than often presented. Qualitative data presented here show that workers can be satisfied under relatively traditional Fordist arrangements and that increasing employee involvement does not necessarily increase satisfaction. My research highlights the role of individual work orientations in mediating the effects of objective characteristics of job design — such as participatory work arrangements — on job satisfaction. Further, individual preferences for work arrangements are shown not to be consistent and invariable, but context-dependent and subject to reevaluation.
Moody's Account of Social Movement Unionism: An Analysis
Authors: Schiavone Michael
Published: March 2007

Social movement unionism is becoming the strategy/ideology that North American unions should adopt. The most influential account of social movement unionism is that by Kim Moody. However, there has been very few systematic analysis of his work. This article analyzes Moody's account of social movement unionism by examining three crucial aspects of his argument: the importance of union democracy, union alliances with social movements, and the role of the rank-and-file. Furthermore, by analysing the Canadian Auto Workers (a social movement union) I argue that a social movement union under Moody's account has had success in organizing proportionally more new members, and achieving a better collective bargaining agreement than business unions.
South Korean Trade Union Movement at the Crossroads: A Critique of “Social-Movement” Unionism
Authors: Park Mi
Published: March 2007

This paper is a critique of the social movement unionism (SMU) theory. Arguing that characteristics of social movement unions reflect the very contradictory nature of unions under capitalism, it renders a view that the SMU theory romanticizes so-called social movement type unions (the COSATU in South Africa, the CUT in Brazil, and the KCTU in South Korea) and falls short of prescriptive measures for social transformation and a clear vision of a future society. Focusing on the case of the Korean Confederation of Trade Unions (KCTU) and Democratic Labor Party (DLP) in South Korea, it examines whether the SMU theory can adequately address the limitations of the current trade union movement in South Korea.
Bayesian methods for the analysis of inequality constrained contingency tables
Authors: Laudy Olav , Hoijtink Herbert
Published: March 2007

A Bayesian methodology for the analysis of inequality constrained models for contingency tables is presented. The problem of interest lies in obtaining the estimates of functions of cell probabilities subject to inequality constraints, testing hypotheses and selection of the best model. Constraints on conditional cell probabilities and on local, global, continuation and cumulative odds ratios are discussed. A Gibbs sampler to obtain a discrete representation of the posterior distribution of the inequality constrained parameters is used. Using this discrete representation, the credibility regions of functions of cell probabilities can be constructed. Posterior model probabilities are used for model selection and hypotheses are tested using posterior predictive checks. The Bayesian methodology proposed is illustrated in two examples.
Wei, Lin and Weissfeld's marginal analysis of multivariate failure time data
Authors: Metcalfe Chris , Thompson Simon G.
Published: March 2007

Wei, Lin and Weissfeld (WLW) have applied an elaboration of Cox's proportional hazards regression to the analysis of recurrent events data. This application is controversial and has attracted criticism in a piecemeal fashion over 15 years. A frequently raised concern is the method's `risk set': each individual is considered to be at risk of all recurrent events from the start of the observation period. The WLW method often gives estimates that exceed those provided by alternative approaches. This paper investigates whether the estimates are a consequence of biased estimation, or reflect a particular aspect of the treatment effect. Simulation studies show that the WLW method infringes the proportional hazards assumption when applied to recurrent events data, but that the bias this may cause is not behind the distinctive effect estimates. Instead, the method's risk set is demonstrated to be responsible, leading to discussion of the interpretation of the treatment effect being estimated. Analyses of medical data indicate that the infringement of the proportional hazards assumption is not necessarily greater than that experienced with other applications of proportional hazards regression and need not prohibit the application of WLW's method to recurrent events data.
Model-based or algorithm-based? Statistical evidence for diabetes and treatments using gene expression
Authors: Yulan Liang  , Kelemen Arpad , Tayo Bamidele
Published: March 2007

Gene expression profiles obtained from samples of diabetic and normal rats with and without treatments can be used to identify genes that distinguish normal and diabetic individuals and also to evaluate the effectiveness of drug treatments. This study examines changes in global gene expression in rat muscle caused by streptozotocin-induced diabetes and vanadyl sulfate treatment. We explored model-based and algorithm-based methods with gene screening measures for microarray gene expression data to classify and predict individuals with high risk of diabetes. Results show that the mixed ANOVA model-based approach provides an efficient way to conduct an investigation of the inherent variability in gene expression data and to estimate the effects of experimental factors such as treatments and diseases and their interactions. The algorithm-based weighted voting and neural network classifiers show good classification performance for the diabetes and treatment groups. Although neural network performs better than weighted voting with higher classification rate, the interpretation of weighted voting is more straightforward. The study indicates that the choice of the gene selection procedure is at least as important as the choice of the classification procedure. We conclude that both mixed model-based and algorithm-based approaches provide the statistical evidence of the biological hypotheses that vanadyl sulfate treatment of diabetic animals restores gene expression patterns to normal. Although model-based and algorithm-based methods provide different strengths and perspective for the analysis of the same set of data, in general both can be considered and developed for analyzing factorial design experiments with multiple groups and factors. This study represents a major step towards the discovery of responsible genes related to diabetes and its treatment.
Comparison of subject-specific and population averaged models for count data from cluster-unit intervention trials
Authors: Young Mary L. , Preisser John S. , Qaqish Bahjat F. , Wolfson Mark
Published: March 2007

Maximum likelihood estimation techniques for subject-specific (SS) generalized linear mixed models and generalized estimating equations for marginal or population-averaged (PA) models are often used for the analysis of cluster-unit intervention trials. Although both classes of procedures account for the presence of within-cluster correlations, the interpretations of fixed effects including intervention effect parameters differ in SS and PA models. Furthermore, closed-form mathematical expressions relating SS and PA parameters from the two respective approaches are generally lacking. This paper investigates the special case of correlated Poisson responses where, for a log-linear model with normal random effects, exact relationships are available. Equivalent PA model representations of two SS models commonly used in the analysis of nested cross-sectional cluster trials with count data are derived. The mathematical results are illustrated with count data from a large non-randomized cluster trial to reduce underage drinking. Knowledge of relationships among parameters in the respective mean and covariance models is essential to understanding empirical comparisons of the two approaches.
The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera
Authors: Dupont Sabrina , Massé Aline , James Chloé , Teyssandier Irène , Lécluse Yann , Larbret Frédéric , Ugo Valérie , Saulnier Patrick , Koscielny Serge , Le Couédic Jean Pierre , Casadevall Nicole , Vainchenker William , Delhommeau François
Published: March 2007

The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events.
14–3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1–transformed hematopoietic cells
Authors: Dong Shaozhong , Kang Sumin , Gu Ting-Lei , Kardar Sean , Fu Haian , Lonial Sagar , Khoury Hanna Jean , Khuri Fadlo , Chen Jing
Published: March 2007

Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14–3-3 to prevent apoptosis. We used a peptide-based 14–3-3 competitive antagonist, R18, to disrupt 14–3-3–ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14–3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14–3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14–3-3–ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.
The role of complement C3 opsonization, C5a receptor, and CD14 inE. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood
Authors: Brekke Ole-Lars , Christiansen Dorte , Fure Hilde , Fung Michael , Mollnes Tom E
Published: March 2007

The relative role of complement and CD14 in Escherichia coli-induced leukocyte CD11b up-regulation, phagocytosis, and oxidative burst in human whole blood was examined. The highly specific thrombin inhibitor lepirudin was used as anticoagulant, as it does not affect complement activation. Complement inhibition at the level of C3 (anti-C2 and anti-factor D) and C5 (C5a receptor antagonist and anti-C5/C5a) efficiently inhibited CD11b up-regulation, phagocytosis, and oxidative burst in granulocytes. Monocyte activation was generally less complement-dependent, but when C3 activation was blocked, a pronounced inhibition of phagocytosis and oxidative burst was obtained. Only the combination of anti-C2 and antifactor D blocked E. coli C3 opsonization completely. Whole E. coli, disrupted E. coli, and the C3-convertase activator cobra venom factor up-regulated CD11b rapidly on both cell types, proportional to their complement activation potential in the fluid phase. In comparison, purified LPS at concentrations comparable with that present in the E. coli preparations did not activate complement. Oxidative burst was induced only by whole bacteria. Finally, the combination of complement inhibition and anti-CD14 completely blocked E. coli-induced granulocyte and monocyte CD11b up-regulation and quantitatively, virtually abolished phagocytosis. The results indicate that complement and CD14, despite differential effects on granulocytes and monocytes, are the two crucial, quantitative factors responsible for E. coli-induced CD11b, phagocytosis, and oxidative burst in both cell types.
4-1BB triggers IL-13 production from T cells to limit the polarized, Th1-mediated inflammation
Authors: Shin Su M , Kim Young H , Choi Beom K , Kwon Patrick M , Lee Hyeon-Woo , Kwon Byoung S
Published: March 2007

4-1BB (CD137) triggering typically induces Th1 response by increasing IFN-γ from T cells upon TCR ligation. We found recently that 4-1BB costimulation increased the expression of IL-13 from CD4+ T cells, as well as CD8+ T cells. The enhanced IL-13 expression by agonistic anti-4-1BB treatment was mediated via MAPK1/2, PI-3K, JNK, mammalian target of rapamycin, NF-AT, and NF-κB signaling pathways. The signaling for IL-13 induction was similar to that of IFN-γ production by anti-4-1BB treatment in T cells. When the anti-4-1BB-mediated IL-13 expression was tested in an in vivo viral infection model such as HSV-1 and vesicular stomatitis virus, 4-1BB stimulation enhanced IL-13 expression of CD4+ T, rather than CD8+ T cells. Although IL-13 was enhanced by anti-4-1BB treatment, the increased IL-13 did not significantly alter the anti-4-1BB-induced Th1 polarization of T cells—increase of T-bet and decrease of GATA-3. Nevertheless, anti-4-1BB treatment polarized T cells excessively in the absence of IL-13 and even became detrimental to the mice by causing liver inflammation. Therefore, we concluded that IL-13 was coinduced following 4-1BB triggering to maintain the Th1/2 balance of immune response.
Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Authors: Robertson Michael J. , Kahl Brad S. , Vose Julie M. , de Vos Sven , Laughlin Mary , Flynn Patrick J. , Rowland Kendrith , Cruz Jose C. , Goldberg Stuart L. , Musib Luna , Darstein Christelle , Enas Nathan , Kutok Jeffery L. , Aster Jon C. , Neuberg Donna , Savage Kerry J. , LaCasce Ann , Thornton Donald , Slapak Christopher A. , Shipp Margaret A.
Published: March 2007

Purpose

Protein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL.

Patients and Methods

Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity.

Results

Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.

Conclusion

Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.
Serum Insulin and Inflammatory Markers in Overweight Individuals with and without Dyslipidemia
Authors: Barter Philip , McPherson Y. Ruth , Song Kijoung , Kesäniemi Y. Antero , Mahley Robert , Waeber Gérard , Bersot Thomas , Mooser Vincent , Waterworth Dawn , Grundy Scott M.
Published: March 2007

Context: The worldwide epidemic of overweight and obesity is setting the scene for a new wave of premature cardiovascular disease.

Objective: The objective of this study was to define relationships between dyslipidemia and other metabolic abnormalities in overweight subjects.

Design: This study included comparison of overweight subjects with and without dyslipidemia.

Setting: The setting was an institutional practice.

Patients: Dyslipidemic subjects (n = 715) had plasma triglyceride greater than or equal to the 75th percentile in combination with high-density lipoprotein cholesterol (HDL-C) less than or equal to the 25th percentile. Unrelated, normolipidemic controls (n = 1073) had HDL-C higher than the median and triglyceride lower than the median. It was a requirement for the control subjects to have a body mass index (BMI) greater than 25 kg/m2.

Main Outcome Measures: The main outcome measures included BMI, inflammatory markers, adipokines, blood pressure, and fasting plasma glucose and insulin.

Results: The mean BMI in the subjects and controls was 28.7 and 28.2 kg/m2, respectively. Subjects had higher levels of plasma high-sensitivity C-reactive protein (3.0 vs. 2.0 mg/liter; P < 0.001), lower levels of adiponectin (4.7 vs. 6.6 mg/liter; P < 0.001), and, after adjustment for age, BMI, gender, smoking, statin, and β-blocker use, higher systolic (P = 0.001) and diastolic (P = 0.05) blood pressures. Fasting plasma glucose, insulin, and homeostasis model of assessment-insulin resistance were all significantly higher in subjects than controls (P < 0.0001).

Conclusions: Identification of people solely on the basis of an elevated plasma triglyceride and a low HDL-C uncovers an overweight group of people who have a generalized metabolic disorder. In contrast, overweight people with normal plasma lipids have normal glucose and insulin metabolism, low levels of inflammatory markers, and normal blood pressure. Such people may thus be at relatively low risk of developing diabetes and cardiovascular disease despite being overweight.
The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta-Analysis
Authors: Pittas Anastassios G. , Lau Joseph , Hu Frank B. , Dawson-Hughes Bess
Published: March 2007

Context: Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus (type 2 DM).

Evidence Acquisition and Analyses: MEDLINE review was conducted through January 2007 for observational studies and clinical trials in adults with outcomes related to glucose homeostasis. When data were available to combine, meta-analyses were performed, and summary odds ratios (OR) are presented.

Evidence Synthesis: Observational studies show a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM prevalence, 0.36 (0.16–0.80) among nonblacks for highest vs. lowest 25-hydroxyvitamin D; metabolic syndrome prevalence, 0.71 (0.57–0.89) for highest vs. lowest dairy intake]. There are also inverse associations with incident type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM incidence, 0.82 (0.72–0.93) for highest vs. lowest combined vitamin D and calcium intake; 0.86 (0.79–0.93) for highest vs. lowest dairy intake]. Evidence from trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in populations at high risk (i.e. glucose intolerance). The available evidence is limited because most observational studies are cross-sectional and did not adjust for important confounders, whereas intervention studies were short in duration, included few subjects, used a variety of formulations of vitamin D and calcium, or did post hoc analyses.

Conclusions: Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism.
Phosphorylation of a Conserved Serine in the Deoxyribonucleic Acid Binding Domain of Nuclear Receptors Alters Intracellular Localization
Authors: Sun Kai , Montana Vedrana , Chellappa Karthikeyani , Brelivet Yann , Moras Dino , Maeda Yutaka , Parpura Vladimir , Paschal Bryce M. , Sladek Frances M.
Published: March 2007

Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4α (HNF4α). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4α and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4α (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4α as well as decreased endogenous HNF4α protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor α, retinoid X receptor α, and thyroid hormone receptor β) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor α and peroxisome proliferator-activated receptor α. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.
Oocytes determine cumulus cell lineage in mouse ovarian follicles
Authors: Diaz Francisco J. , Wigglesworth Karen , Eppig John J.
Published: March 2007

The two principal functions of ovarian follicles are developmental and endocrine. The cumulus cells surrounding the oocyte are specialized to serve the development of the oocyte and steroidogenesis is a principal role of mural granulosa cells that line the follicle wall. The findings in this report demonstrate that oocytectomy or treatment with an inhibitor of SMAD2/3 activation results in decreased cumulus marker mRNA transcript levels and allows FSH to induce mural marker transcripts in cumulus cells. In addition, SMAD2/3 signaling is involved in enabling cumulus expansion and EGF-induced increases in Ptx3, Ptgs2 and Has2 mRNA levels. By contrast, follicle-stimulating hormone (FSH) stimulated expression of mural transcripts, but suppressed levels of cumulus transcripts. Thus, FSH and oocyte-stimulated SMAD2/3 signaling establish opposing gradients of influence in the follicle. These specify the mural and cumulus granulosa cell phenotypes that are pivotal for appropriate endocrine function and oocyte development.
Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells
Authors: Joo Jae-Yeol , Kim Byung-Woo , Lee Jeong-Sik , Park Jin-Yong , Kim Sunoh , Yun Young-Joo , Lee Sang-Hun , Lee Suk-Ho , Rhim Hyewhon , Son Hyeon
Published: March 2007

The prolonged effects of N-methyl-D-aspartate (NMDA) receptor activation on the proliferation and differentiation of hippocampal neural progenitor cells (NPCs) were studied. Under conditions of mitogen-mediated proliferation, a single NMDA pulse (5 μM) increased the fraction of 5-bromo-2-deoxyuridine (BrdU)-positive (BrdU+) cells after a delay of 72 hours. Similarly, a single systemic injection of NMDA (100 mg/kg) increased the number of BrdU+ cells in the dentate gyrus (DG) after 28 days, but not after 3 days. NMDA receptor activation induced an immediate influx of Ca2+ into the NPCs and the NPCs expressed and released vascular endothelial growth factor (VEGF) in an NMDA receptor-dependent manner within 72 hours. With repetitive stimulation at the same dose, NMDA stimulated the acquisition of a neuronal phenotype accompanied by an increase in the expression of proneural basic helix-loop-helix (bHLH) factors. Together these findings suggest that neurogenesis in the developing brain is likely to be both directly and indirectly regulated by complex interactions between Ca2+ influx and excitation-releasable cytokines, even at mild levels of excitation. In addition, our results are the first to show that stimulation of NPCs may lead to either proliferation or neuronal differentiation, depending on the level of NMDA receptor activation.
FHL3 binds MyoD and negatively regulates myotube formation
Authors: Cottle Denny L. , McGrath Meagan J. , Cowling Belinda S. , Coghill Imogen D. , Brown Susan , Mitchell Christina A.
Published: March 2007

MyoD initiates muscle differentiation and promotes skeletal myogenesis by regulating temporal gene expression. MyoD-interacting proteins induce regulatory effects, and the identification of new MyoD-binding partners may provide mechanistic insights into the regulation of gene expression during myogenesis. FHL3 is one of three members of the FHL protein family that are expressed in skeletal muscle, but its function in myogenesis is unknown. Overexpression of human FHL3 in mouse C2C12 cells retarded myotube formation and decreased the expression of muscle-specific regulatory genes such as myogenin but not MyoD. By contrast, short interfering RNA (siRNA)-mediated FHL3 protein knockdown enhanced myoblast differentiation associated with increased myogenin, but not MyoD protein expression, early during differentiation. We demonstrate that FHL3 is a MyoD-associated protein by direct binding assays, colocalisation in the nucleus of myoblasts and GST pull-down studies. Moreover, we determined that FHL3 interacts with MyoD, functioning as its potent negative co-transcriptional regulator. Ectopic expression of FHL3 in myoblasts impaired MyoD-mediated transcriptional activity and muscle gene expression. By contrast, siRNA-mediated FHL3 knockdown enhanced MyoD transcriptional activity in a dose-dependent manner. These findings reveal that FHL3 association with MyoD may contribute to the regulation of MyoD-dependent transcription of muscle genes and thereby myogenesis.
HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions
Authors: Tran Andy Dong-Anh , Marmo Timothy P. , Salam Ambar A. , Che Sally , Finkelstein Erik , Kabarriti Rafi , Xenias Harry S. , Mazitschek Ralph , Hubbert Charlotte , Kawaguchi Yoshiharu , Sheetz Michael P. , Yao Tso-Pang , Bulinski J. Chloë
Published: March 2007

Genetic or pharmacological alteration of the activity of the histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of α-tubulin, and not other HDAC6 substrates, yielded a motility reduction equivalent to agents that block all NAD-independent HDACs. Accordingly, we investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited cells. Testing the hypothesis that motility is reduced because cellular adhesion is altered, we found that inhibiting HDAC6 activity towards tubulin rapidly increased total adhesion area. Next, we investigated the mechanism of the adhesion area increase. Formation of adhesions proceeded normally and cell spreading was more rapid in the absence of active HDAC6; however, photobleaching assays and adhesion breakdown showed that adhesion turnover was slower. To test the role of hyperacetylated tubulin in altering adhesion turnover, we measured microtubule dynamics in HDAC6-inhibited cells because dynamic microtubules are required to target adhesions for turnover. HDAC6 inhibition yielded a decrease in microtubule dynamics that was sufficient to decrease focal adhesion turnover. Thus, our results suggest a scenario in which the decreased dynamics of hyperacetylated microtubules in HDAC6-inhibited cells compromises their capacity to mediate the focal adhesion dynamics required for rapid cell migration.
Syntaxin 16 and syntaxin 5 are required for efficient retrograde transport of several exogenous and endogenous cargo proteins
Authors: Amessou Mohamed , Fradagrada Alexandre , Falguières Thomas , Lord J. Michael , Smith Daniel C. , Roberts Lynne M. , Lamaze Christophe , Johannes Ludger
Published: March 2007

Retrograde transport allows proteins and lipids to leave the endocytic pathway to reach other intracellular compartments, such as trans-Golgi network (TGN)/Golgi membranes, the endoplasmic reticulum and, in some instances, the cytosol. Here, we have used RNA interference against the SNARE proteins syntaxin 5 and syntaxin 16, combined with recently developed quantitative trafficking assays, morphological approaches and cell intoxication analysis to show that these SNARE proteins are not only required for efficient retrograde transport of Shiga toxin, but also for that of an endogenous cargo protein – the mannose 6-phosphate receptor – and for the productive trafficking into cells of cholera toxin and ricin. We have found that the function of syntaxin 16 was specifically required for, and restricted to, the retrograde pathway. Strikingly, syntaxin 5 RNA interference protected cells particularly strongly against Shiga toxin. Since our trafficking analysis showed that apart from inhibiting retrograde endosome-to-TGN transport, the silencing of syntaxin 5 had no additional effect on Shiga toxin endocytosis or trafficking from TGN/Golgi membranes to the endoplasmic reticulum, we hypothesize that syntaxin 5 also has trafficking-independent functions. In summary, our data demonstrate that several cellular and exogenous cargo proteins use elements of the same SNARE machinery for efficient retrograde transport between early/recycling endosomes and TGN/Golgi membranes.
The Construction of the Two-dimensional Array of the Fibrous Objects from the Mixture of RFDF16–PEG and RFDF16 at Air/Water Interface
Authors: Tanaka Masayoshi , Hattori Makoto , Kinoshita Takatoshi
Published: March 2007

The mixture of β-sheet peptide–PEG diblock copolymer and β-sheet peptide spread at air/water interface formed a two-dimensional array of the fibrous objects. The fibrous objects constructed by intermolecular hydrogen bonding of β-sheet peptides were regulated by compressing of the monolayer. When the spread peptide moieties fully located on the water surface, the distance between the fibers was efficiently modulated by the fraction of PEG segments.
Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction
Authors: Sugimura Takashi , Hagiya Kazutake
Published: March 2007

Di-2-methoxyethyl azodicarboxylate (DMEAD) was prepared as an alternative of DEAD or DIAD for the Mitsunobu reaction. Removal of the hydrazinedicarboxylate generated from DMEAD becomes much easier owing to the polar and water-soluble property.
Prioritizing health technologies in a Primary Care Trust
Authors: Wilson Edward , Sussex Jon , Macleod Christine , Fordham Richard
Published: March 2007

Background: In the English National Health Service (NHS), Primary Care Trusts (PCTs) are responsible for commissioning health-care services on behalf of their populations. As resources are finite, decisions are required as to which services best fulfil population needs. Evidence on effectiveness varies in quality and availability. Nevertheless, decisions still have to be made.

Methods: We report the development and pilot application of a multi-criteria prioritization mechanism in an English PCT, capable of accommodating a wide variety of evidence to rank six service developments.

Results: The mechanism proved valuable in assisting prioritization decisions and feedback was positive. Two community-based interventions were expected to save money in the long term and were ranked at the top of the list. Based on weighted benefit score and cost, two preventive programmes were ranked third and fourth. Finally, two National Institute for Health and Clinical Excellence (NICE)-approved interventions were ranked fifth and sixth. Sensitivity analysis revealed overlap in benefit scores for some of the interventions, representing diversity of opinion among the scoring panel.

Conclusion: The method appears to be a practical approach to prioritization for commissioners of health care, but the pilot also revealed interesting divergences in relative priority between nationally mandated service developments and local health-care priorities.
Commoditization of the international teleradiology market
Authors: McLean Thomas
Published: March 2007

Telemedicine improves access to medical care. However, telemedicine will also increase market volatility because of its ability to stimulate price competition and the insidious way it shifts liability for providing medical services. To cope with increased volatility, other economic sectors have evolved commodities markets by making greater use of standardized forward/future contracts.

In the past, the need for medical services to be produced and consumed locally and a lack of an objective definition for medical quality, prohibited the use of forward contracts for health-care services. However, telemedicine, and the increasing use of statistical definitions of medical quality now make standardized forward contracts for health-care services conceivable.

Commoditization of teleradiology would offer several advantages including increasing market transparency, a mechanism for ensuring medical quality, and a means for bringing capital into the health-care sector. To reap the benefits of a commodities market in teleradiology, the key will be for market stakeholders to overcome their fear of the unknown in order to organize a central exchange.
How should cost-effectiveness analysis be used in health technology coverage decisions? Evidence from the National Institute for Health and Clinical Excellence approach
Authors: Williams Iestyn , Bryan Stirling , McIver Shirley
Published: March 2007

Background: In the National Health Service in England and Wales, technology coverage decisions are taken by the National Institute for Health and Clinical Excellence (NICE). The intention formally to apply cost-effectiveness analysis to the decision-making process distinguishes NICE from most other bodies making similar policy recommendations. We carried out a case study of the NICE Appraisals Committee to explore the influence and use of economic evaluation in the decision-making process.

Methods: Qualitative case study methodology. This involved analysis of all relevant secondary sources, observations of Appraisals Committee deliberations and interviews with a cross-section of Committee members.

Findings: Economic evaluation is integrated into the Committee's work. There are two main ways in which the use of economic analysis is understood by Committee members: an ordinal approach, whereby cost-effectiveness is only considered if the technology has passed a clinical effectiveness hurdle; and a framework approach, whereby the economic evaluation and model provide a structure for considering the decision problem and the evidence. These two approaches appear to operate simultaneously but are, in essence, inconsistent.

Conclusions: The NICE 'experiment' has seen cost-effectiveness analysis move to the centre-ground of UK national policy deliberations regarding technology coverage. However, our case study implies that there may be room for further refinement of the appraisal process in order to resolve the observed tension between two different ways of incorporating cost-effectiveness analysis in NICE's decision-making.
Is the British National Health Service equitable? The evidence on socioeconomic differences in utilization
Authors: Dixon Anna , Le Grand Julian , Henderson John , Murray Richard , Poteliakhoff Emmi
Published: March 2007

Is the British National Health Service (NHS) equitable? This paper considers one part of the answer to this: the utilization of the NHS by different socioeconomic groups (SEGs). It reviews recent evidence from studies on NHS utilization as a whole based on household surveys (macro-studies) and from studies of the utilization of particular services in particular areas (micro-studies). The principal conclusion from the majority of these studies is that, while the distribution of use of general practitioners (GPs) is broadly equitable, that for specialist treatment is pro-rich. Recent micro-studies of cardiac surgery, elective surgery, cancer care, preventive care and chronic care support the findings of an earlier review that use of services was higher relative to need among higher SEGs.
The effect of telephone reminders on attendance in respiratory outpatient clinics
Authors: Roberts Nicola , Meade Karen , Partridge Martyn
Published: March 2007

Introduction: Patient non-attendance is an area of concern for all health care providers. A randomized controlled trial was undertaken to investigate whether reminder telephone calls improved attendance at respiratory outpatient clinics in the English National Health Service (NHS).

Methods: Patients were randomly allocated into one of two groups, either telephone reminder group or usual care. The telephone reminder group received a reminder telephone call between 9 am and 5 pm during the week prior to their appointment. Attendance and demographic information (age, sex, diagnosis and home postcode) were recorded.

Results: A total of 504 patients were recruited, 258 patients were allocated to the control group and 246 patients were allocated to the telephone reminder group. Fifty-eight percent of the patients allocated to the telephone reminder group were not contactable. Within the telephone reminder group, of the 104 patients who could be contacted, 86% attended. There was a significant 15% increase in attendance in the contacted group ( n = 104) when compared both with the control group (71%, n = 258) and with the patients who could not be contacted (68%, n = 142) ( P = 0.007; P = 0.004). It was estimated that the cost of telephoning 200 patients could be offset by preventing one non-attendance.

Conclusion: Routine telephoning of outpatients should become standard practice if reducing non-attendance is thought to be desirable, but general practitioner (GP) referral letters and hospital records of current hospital outpatients need to include an up-to-date telephone number. Consideration should be given to 'out-of-hours' reminder calls to maximize the contact rate.
Inequality in the face of death? Public expenditure on health care for different socioeconomic groups in the last year of life
Authors: Hanratty Barbara , Burström Bo , Walander Anders , Whitehead Margaret
Published: March 2007

Objective: To investigate the association between public expenditure on health care in the last year of life and individual socioeconomic status in Sweden.

Methods: Population-based study of public expenditure using linked registers for all 16,617 deaths among Stockholm County Council residents in 2002 (population 1.8 million). Age-standardized, total and per capita spend were calculated by income categories, age and specialty. Multivariate analysis examined the association between socioeconomic status and public expenditure.

Results: County council expenditure on health care in the last year of life rose with increasing income of the deceased person. Median per capita expenditure increased from 55,417 Swedish Kronor (SEK) (US$ 7542) in the lowest income group to SEK 94,678 (US$ 12,887) in the highest. Total age-standardized spend increased by 60% across the same interval (80,227 [95% confidence interval (CI) 79,946–80,497] to SEK 127,344 [95% CI 126,969–127,719]). Expenditure decreased with increasing age over 65 years in all income groups. Higher income was independently associated with greater total public health spend in multivariate analysis, adjusting for age, sex, health-care utilization and major diagnostic groups.

Conclusions: There is inequality in public expenditure on health care at the end of life across socioeconomic groups in Stockholm. This phenomenon merits attention within Sweden, and beyond, in countries with less comprehensive welfare systems.