bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of Epidermal Growth Factor Receptors Chemosensitizes Breast Cancer Cells through Up-Regulation of Bnip3L
Authors: Real Pedro J. , Benito Adalberto , Cuevas Jorge , Berciano Maria T. , de Juan Ana , Coffer Paul , Gomez-Roman Javier , Lafarga Miguel , Lopez-Vega Jose M. , Fernandez-Luna Jose L.
Published: September 2005

Epidermal growth factor receptor-1 (EGFR) and EGFR-2 (HER2) have become major targets for cancer treatment. Blocking antibodies and small-molecule inhibitors are being used to silence the activity of these receptors in different tumors with varying efficacy. Thus, a better knowledge on the signaling pathways activated by EGFR and HER2 may help unravel novel therapeutic targets and molecular markers of response. Here, we show that treatment of breast cancer cell lines with blocking antibodies against EGFR (cetuximab) or HER2 (trastuzumab) promotes the specific induction of proapoptotic Bnip3L and chemosensitization. Moreover, we found that the Bnip3L gene is transcriptionally activated by FoxO3a. Trastuzumab-mediated induction of Bnip3L and nuclear translocation of FoxO3a was also shown in pleural effusion cells from a breast cancer patient. Transfection of breast cancer cells with constitutively active FoxO3a or with Bnip3L promotes sensitization to chemotherapy-induced apoptosis. On the contrary, blockade of Bnip3L expression by a small interfering RNA strategy significantly diminished the chemosensitizing effect of cetuximab. We found also an inverse correlation between EGFR and Bnip3L expression in surgical specimens from patients with breast cancer. Therefore, blockading EGFR or HER2 specifically up-regulates Bnip3L, which is required for chemosensitization of breast cancer cells. This novel pathway provides also the rationale for therapeutic strategies aimed to induce the expression of Bnip3L.
Suppression of Mammary Carcinoma Growth by Retinoic Acid: Proapoptotic Genes Are Targets for Retinoic Acid Receptor and Cellular Retinoic Acid–Binding Protein II Signaling
Authors: Donato Leslie J. , Noy Noa
Published: September 2005

Retinoic acid (RA) displays pronounced anticarcinogenic activities in several types of cancer. Whereas the mechanisms that underlie this activity remain incompletely understood, tumor suppression by RA is believed to emanate primarily from its ability to regulate transcription of multiple target genes. Here, we investigated molecular events through which RA inhibits the growth of MCF-7 mammary carcinoma cells, focusing on the involvement of the two proteins that mediate transcriptional activation by RA, the nuclear hormone receptor retinoic acid receptor (RAR) and the cellular retinoic acid-binding protein (CRABP) II, in this process. RA treatment of MCF-7 cells did not affect cell cycle distribution but triggered pronounced apoptosis. Accordingly, expression array analyses revealed that RA induces the expression of several proapoptotic genes, including caspase 7 and caspase 9. Whereas caspase 7 is an indirect responder to RA signaling, caspase 9 is a novel direct target for RAR, and it harbors a functional retinoic acid response element in its second intron. In agreement with the known role of CRABP-II in enhancing the transcriptional activity of RAR, the binding protein augmented RA-induced up-regulation of caspase 9, cooperated with RA in activating both caspase 7 and 9, and amplified the ability of RA to trigger apoptosis. Surprisingly, the data indicate that CRABP-II also displays proapoptotic activities on its own. Specifically, overexpression of CRABP-II, in the absence of RA, up-regulated the expression of Apaf1 and triggered caspase 7 and caspase 9 cleavage. These observations suggest that, in addition to its known role in direct delivery of RA to RAR, CRABP-II may have an additional, RA-independent, function.
Distinct and Overlapping Roles of Interleukin-10 and CD25+ Regulatory T Cells in the Inhibition of Antitumor CD8 T-Cell Responses
Authors: Dercamp Christophe , Chemin Karine , Caux Christophe , Trinchieri Giorgio , Vicari Alain P.
Published: September 2005

Lack of antitumor immunity is often related to impaired CD8 T-cell responses that could result from a poor priming capacity by tumor-infiltrating dendritic cells (TIDC) and/or further inhibition by regulatory T cells (Treg). Interleukin-10 (IL-10) has been implicated in the inhibition of TIDC as well as in the generation and functions of Treg. Here, we address some of the respective and possibly overlapping roles of IL-10 and CD25+ Treg in CD8 antitumor immunity. Whereas tumor antigen–specific CD8 T cells proliferated in vivo in the presence of IL-10 or Treg, optimal effector functions were observed in mice lacking both IL-10 and Treg. Indeed, tumors grown in normal but not in IL-10–deficient or CD25-depleted mice induced tumor antigen–specific CD8 suppressor T cells. Suppression involved transforming growth factor-β. Similarly, both IL-10 and Treg were responsible for impaired CD8 T cell priming by TIDCs, but IL-12 production by TIDCs was prevented only by Treg-independent IL-10. Subsequently, IL-10 defect and Treg depletion were required to achieve optimal induction of CD8 T-cell effectors by TIDC following CpG activation. Our results point out major redundant and nonredundant roles for IL-10 and Treg in the inhibition of TIDC-mediated generation of antitumor CD8 T-cell response.
Darpp-32: a Novel Antiapoptotic Gene in Upper Gastrointestinal Carcinomas
Authors: Belkhiri Abbes , Zaika Alexander , Pidkovka Nataliya , Knuutila Sakari , Moskaluk Christopher , El-Rifai Wa'el
Published: September 2005

We show the molecular mechanisms involved in Darpp-32 overexpression and its biological role in upper gastrointestinal adenocarcinomas (UGC). A tumor tissue array of 377 samples was developed and used to detect DARPP-32 DNA amplification and protein overexpression, which occurred in 32% and 60% of UGCs, respectively. Concomitant overexpression of mRNA for Darpp-32 and its truncated isoform t-Darpp was observed in 68% of tumors (P < 0.001). When Darpp-32 and t-Darpp were overexpressed in AGS and RKO gastrointestinal cells, up to a 4-fold reduction in the apoptosis rate was observed (terminal deoxynucleotidyl transferase–mediated nick-end labeling and Annexin V assays) in response to camptothecin, sodium butyrate, and ceramide. However, the introduction of mutations in phosphorylation sites abrogated this effect. Expression of Darpp-32 and t-Darpp preserved the mitochondrial transmembrane potential and was associated with increased levels of Bcl2 protein. A reversal of Bcl2 protein level was obtained using small interfering RNAs for Darpp-32 and t-Darpp. Luciferase assays using the p53 and p21 reporter plasmids and probing of immunoblots with antibodies specific for p53 transcriptional targets, such as Hdm2 and p21, indicated that neither Darpp-32 nor t-Darpp interfere with p53 function. Altogether, we show more frequent mRNA and protein overexpression of Darpp-32 than DNA amplification, suggesting that, in addition to amplification, transcriptional or posttranscriptional mechanisms may play an important role. The expression of Darpp-32 and t-Darpp is associated with a potent antiapoptotic advantage for cancer cells through a p53-independent mechanism that involves preservation of mitochondrial potential and increased Bcl2 levels.
Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential
Authors: Simonson Sara J.S. , Difilippantonio Michael J. , Lambert Paul F.
Published: September 2005

High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6WT) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6WT mice with those of K14E6Δ146-151 mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6Δ146-151 transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6WT mice, they are infrequently seen in tumors arising on K14E6Δ146-151 mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53.
The APC Tumor Suppressor Promotes Transcription-Independent Apoptosis In vitro
Authors: Steigerwald Kira , Behbehani Gregory K. , Combs Kelly A. , Barton Michelle Craig , Groden Joanna
Published: September 2005

The APC tumor suppressor is found in nonproliferating epithelial cells of the colonic crypts and is mutated in most colorectal tumors. To understand the function of APC in normal epithelium and how its loss leads to tumor formation, we tested whether APC is a mediator of apoptosis using an in vitro assay that monitors caspase-3-mediated cleavage of lamin B protein or a colorimetric substrate in a cell-free Xenopus egg extract. Recombinant APC protein accelerates apoptosis-associated caspase activity independently of ongoing transcription and protein synthesis. Conversely, the addition of mutant APC and immunodepletion of Xenopus APC decelerates apoptosis-associated caspase activity. Acceleration of apoptosis by APC is abolished by the caspase-8 inhibitor Z-IETD-FMK, demonstrating that caspase-8 is an essential component of APC-mediated apoptosis. These results suggest that the induction of apoptosis may be one role of APC in tumor suppression and that this mechanism is independent of β-catenin-mediated effects on transcription.
Methylation Silencing of the Apaf-1 Gene in Acute Leukemia
Authors: Furukawa Yutaka , Sutheesophon Krittaya , Wada Taeko , Nishimura Miki , Saito Yasushi , Ishii Hideshi , Furukawa Yusuke
Published: September 2005

Apaf-1 is important for tumor suppression and drug resistance because it plays a central role in DNA damage–induced apoptosis. Inactivation of the Apaf-1 gene is implicated in disease progression and chemoresistance of some malignancies. In this study, we attempted to clarify the role of Apaf-1 in leukemogenesis. Apaf-1 mRNA levels were below the detection limit or very low in 5 of 20 human leukemia cell lines (25%) and 5 of 12 primary acute myeloblastic leukemia cells (42%). There were no gross structural abnormalities in the Apaf-1 gene in these samples. Expression of factors regulating Apaf-1 transcription, such as E2F-1, p53, and Sp-1, did not differ between Apaf-1-positive and Apaf-1-negative cells. Methylation of CpG in the region between +87 and +128 of the Apaf-1 gene was almost exclusively observed in Apaf-1-defective cell lines. Treatment of these cells with 5-aza-2′-deoxycytidine, a specific inhibitor of DNA methylation, restored the expression of Apaf-1. Furthermore, we showed that the region between +87 and +128 could act as a repressor element by recruiting corepressors such as methylated DNA-binding domain 2 and histone deacetylase 1 upon methylation. Overexpression of Dnmt1, a mammalian maintenance DNA methyltransferase, was associated with Apaf-1 gene methylation. DNAs from Dnmt1-overexpressing cells were more resistant to digestion with methylation-sensitive enzyme HpaII than those from cells with low Dnmt1 expression, suggesting that Dnmt1 mediates aberrant methylation of multiple genes. In conclusion, methylation silencing is a mechanism of the inactivation of Apaf-1 in acute leukemia, and Dnmt1 overexpression may underlie hypermethylation of the Apaf-1 gene.
A Nonclassic CCAAT Enhancer Element Binding Protein Binding Site Contributes to α-Methylacyl-CoA Racemase Expression in Prostate Cancer
Authors: Zha Shan , Isaacs William B.
Published: September 2005

α-Methylacyl-CoA racemase (AMACR), an enzyme involved in branched-chain fatty acid β-oxidation that is normally expressed at high levels in human liver, is specifically and consistently overexpressed at both mRNA and protein levels in human prostate cancer and potentially other cancer types. To characterize the mechanisms underlying transcriptional regulation of AMACR at the genetic and epigenetic levels, we performed a series of methylation and reporter assays in prostate cancer tissues and cell lines. The results ruled out altered methylation patterns as the cause of overexpression in prostate cancer cells. However, promoter deletion analysis identified an 8-bp nonclassic CCAAT enhancer element located ∼80 bp upstream of the transcriptional initiation site that is responsible for AMACR expression in both prostate cancer cell lines and cell lines of liver origin. Deletion or mutation of this element completely abolished AMACR promoter activity. Ectopic expression of CCAAT/enhancer binding protein β increased luciferase activity driven by a wild-type AMACR promoter sequence but not by the sequence in which the putative CCAAT/enhancer binding protein binding element had been mutated. These results implicate a nonclassic CCAAT enhancer element in the AMACR gene promoter as playing a critical role in the regulation of AMACR gene expression.
Artful Discussion
Authors: Kosnoski Jason
Published: September 2005

This essay uses John Dewey’s understanding of classroom discussion to construct a model of democratic deliberation that stresses the importance of the formal aesthetics of dialog. It claims that qualities such as the rhythm and direction of face-to-face political talk affects interlocutors’ effectiveness in persuading others and stimulating interest. Because participants primarily focus on responding to the substance of individual utterances, the model employs Dewey’s understanding of the teacher as a moderator who regulates the spatial and temporal quality of the entire deliberation. Although some might claim the presence of such an authority figure endangers the deliberators’ autonomy, Dewey stresses that good teachers assist students in constructing their own solutions to their own problems, and therefore a moderator could actively intervene and respect the normative principles of deliberative democracy. Finally, the essay discusses the distinctive role implied by such an association in a larger theory of deliberative politics.
The Relevance of Locke’s Religious Arguments for Toleration
Authors: Schwartzman Micah
Published: September 2005

John Locke’s theory of toleration has been criticized as having little relevance for politics today because it rests on controversial theological foundations. Although there have been some recent attempts to develop secular, or publicly accessible, arguments out of Locke’s writings, these tend to obscure and distort the religious arguments that Locke used to defend toleration. More importantly, these efforts ignore the role that religious arguments may play in supporting the development of a normative consensus on the legitimacy of liberal political principles. Bracketing the search for publicly accessible justifications makes it possible to appreciate the continued relevance of Locke’s religious arguments for toleration.
Effective Delivery of Workplace Discipline
Authors: Brett Joan F. , Atwater Leanne E. , Waldman David A.
Published: September 2005

This study investigated the effectiveness of male and female managers when they engaged in the masculine-oriented managerial behavior of discipline. A sample of 155 employed students rated their managers. When managers reportedly allowed two-way discussion with employees, their subordinates reported improved behavior. Two-way discussion and timely and private discipline behaviors were related to fewer negative outcomes. Male and female managers did not differ on discipline behaviors; however, manager gender by behavior interactions indicated that when women were low on two-way discussion, employees reported fewer improvements. This finding suggests that women may experience costs that men do not when they fail to discipline in a considerate way. Our results suggest that when females provide two-way discussion and discipline in private, they realize more improvements in employee behavior than males.
In Search of the Motor Engram: Motor Map Plasticity as a Mechanism for Encoding Motor Experience
Authors: Monfils Marie -H. , Plautz Erik J. , Kleim Jeffrey A.
Published: September 2005

Motor skill acquisition occurs through modification and organization of muscle synergies into effective movement sequences. The learning process is reflected neurophysiologically as a reorganization of movement representations within the primary motor cortex, suggesting that the motor map is a motor engram. However, the specific neural mechanisms underlying map plasticity are unknown. Here the authors review evidence that 1) motor map topography reflects the capacity for skilled movement, 2) motor skill learning induces reorganization of motor maps in a manner that reflects the kinematics of acquired skilled movement, 3) map plasticity is supported by a reorganization of cortical microcircuitry involving changes in synaptic efficacy, and 4) motor map integrity and topography are influenced by various neurochemical signals that coordinate changes in cortical circuitry to encode motor experience. Finally, the role of motor map plasticity in recovery of motor function after brain damage is discussed.
Construct Validity of a General Training Climate Scale
Authors: Tracey J. Bruce , Tews Michael J.
Published: September 2005

There is growing evidence that an organization’s training climate can influence the effectiveness of formal and informal training activities. Unfortunately, there is limited data regarding the psychometric properties of climate measures that have been used in training research. The purpose of this article is to examine the construct validity of a training climate measure. Results from content adequacy, reliability, aggregation, and convergent, discriminant, and criterion-related validity assessments provide support for the measure’s use in diagnostic and theory testing efforts.
Eliciting Managers’ Personal Values: An Adaptation of the Laddering Interview Method
Authors: Bourne Humphrey , Jenkins Mark
Published: September 2005

The authors describe an adaptation of the laddering method that allows interpretive researchers to uncover informants’ personal values during the course of a single interview where other subjects are also explored. The authors explain laddering and illustrate its outcomes by means of case examples. The method allows the exploration of personal values to be integrated into a more flexible interview method, providing greater scope for probing salient issues while optimizing the (potentially limited) time available with informants.
Latino Faculty Development in U.S. Medical Schools: A Hispanic Center of Excellence Perspective
Authors: Soto-Greene Maria L. , Sanchez Jorge , Churrango Jose , Salas-Lopez Debbie
Published: September 2005

Traditionally, faculty development programs and fellowships have been shown to successfully address the developmental needs of individual faculty members. Despite positive results, there are very few programs targeted specifically toward career development for Latino and other minority faculty. The Hispanic Center of Excellence, as a Bureau of Health Professions grant, provides New Jersey Medical School a unique opportunity to focus its efforts at developing and implementing a program dedicated to the advancement of Latino faculty in medical schools nationwide.
Evaluation of niobium carbide coatings on AISI M2 and AISI H13 steels produced by thermoreactive deposition
Authors: Oliveira C. K. N. , Casteletti L. C.
Published: September 2005

In this work, AISI M2 and AISI H13 steels were treated at 1000°C in molten borax containing dissolved ferroniobium and aluminium. Durations of treatment were 4 and 9 h for AISI H13 steel and 4 h for AISI M2 steel. Samples were characterised by optical microscopy, scanning electron microscopy (SEM), X-ray diffraction, microabrasive wear test and Vickers microhardness. Well defined layers were obtained with excellent thickness regularity. AISI H13 steel revealed layers that measured 6·2 μm for treatment lasting 4 h and 10·0 μm for treatment lasting 9 h. The AISI M2 steel was treated for 4 h, and the layer thickness obtained measured 9·0 μm. SEM with energy dispersive X-ray spectrometry results showed a predominance of niobium and absence of iron in the layers on both types of steel. These layers consisted of niobium carbide according to X-ray analyses, and its microhardness values were about 2300 HV.
Influence of laser surface modification on corrosion behavior of stainless steel 316L and Ti–6Al–4V in simulated biofluid
Authors: Singh R. , Martin M. , Dahotre N. B.
Published: September 2005

Laser surface engineering has been explored as a possible method for improving the functional surface properties of biomedical materials such as stainless steels and titanium alloys. This study emphasises the influence of laser surface processing, carried out at a range of laser powers from 500 to 1500 W in ambient atmosphere, on the surface microstructure and corrosion behaviour of stainless steel 316L (SS316L) and Ti–6Al–4V, and metal ions released during the corrosion process. A homogeneous surface microstructure includes columnar dendrites and fine grains in the resolidified region of SS316L. A gradual increase in grain size from the processed surface towards the substrate was revealed. The laser processing of Ti–6Al–4V produced a surface full of dendrites followed by acicular martensite in the interface region. The corrosion studies in Ringer's physiological solution showed an increase in the open circuit potential (OCP) as a result of laser surface treatment of both SS316L and Ti–6Al–4V (more noble than untreated). After laser processing, the corrosion properties of SS316L were seen to deteriorate, and those of Ti–6Al–4V to improve, as compared to their respective untreated counterparts. The variation of laser power influenced the corrosion resistance of SS316L, while that of Ti–6Al–4V did not vary significantly. Laser surface treatments at higher powers (>1000 W) reduced the leaching of specific metallic ions from SS316L and Ti–6Al–4V during corrosion in Ringer's physiological solution.
Particle induced X-ray emission spectroscopic (PIXE) and surface morphological (AFM) studies on electron beam evaporated WO3 thin films
Authors: Sivakumar R. , Ganesan V. , Vijayan V. , Jayachandran M. , Sanjeeviraja C.
Published: September 2005

The present work is concerned with tungsten oxide (WO3) thin films, which feature strongly in electrochromic applications. The films were deposited on glass substrates and fluorine doped tin oxide (FTO) coated glass substrates by the electron beam evaporation technique using a WO3 target. The elemental analysis of the films was performed by particle induced X-ray emission (PIXE) spectroscopy, and the surface morphology of the films was studied using atomic force microscopy (AFM). To the best of our knowledge, this is the first time that PIXE has been used for the analysis of elements present in electron beam evaporated WO3 films. In this study, PIXE was applied to confirm the presence of constituent element in the films. Atomic force microscopic studies revealed that the deposited WO3 films are homogeneous, crack-free surfaces with uniform spherical nanograins. These characterisation studies were carried out for the films prepared on different substrates, and at different deposition temperatures and annealing temperatures. The increase in cluster size with increasing substrate temperature can be explained by the increased diffusion kinetics of the neighbouring particles and/or clusters in the film, causing them to coalesce to form a dense surface coating. This would provide a better understanding of the electrochemical behaviour of the films.
Comparison of prevalence and severity of asthma among adolescents in the Caribbean islands of Trinidad and Tobago: results of a nationwide cross-sectional survey
Authors: Monteil Michele A , Joseph Gina , Changkit Catherine , Wheeler Gillian , Antoine Robin M
Published: September 2005

Background

Asthma is a growing problem in the Caribbean but the prevalence in most islands is unknown and possible inter-island variation in prevalence has not been determined. A nationwide cross-sectional survey was conducted to compare the prevalence of asthma symptoms among high school students in the two islands of the Republic of Trinidad and Tobago.

Methods

Questionnaire and video instruments based on those developed by the International Study of Asthma & Allergy in Childhood (ISAAC) were used to assess asthma prevalence among 6394 children (age range, 11–19 years; mean age, 14.08 yrs) in the second and third years of 35 randomly selected high schools in Trinidad and Tobago. This cross sectional survey was conducted between September and December 2002.

Results

A total of 4988 questionnaires were available for analysis (3519 in Trinidad and 1469 in Tobago). Among respondents from the two islands, there were no significant differences in the prevalence of ever wheezing (24.1% and 24.3% for Trinidad and Tobago, respectively, RR 0.99, 95% CI, 0.90–1.08); wheezing in the previous 12 months (13.1% & 13.4%, RR 0.98, 95% CI 0.84–1.15); a previous or current diagnosis of asthma (12.8% & 13.5%, RR 0.95, 95% CI 0.82–1.12) and night cough in the past 12 months (35.4% & 38.3%, RR0.93, 95% CI 0.86–1.00). However, symptoms of severe asthma were significantly more common among students from Tobago and included having had more than one acute attack in the past year (13.4% & 15.8%, RR 0.85, 95% CI 0.73–1.00, p = 0.0004), night waking as a result of wheeze (7.4% & 10.9%, RR 0.68, 95% CI 0.56–0.83, p < 0.0001) and speech limitation in the past year (5.2% & 8.7%, RR 0.59, 95% CI 0.47–0.74, p < 0.001) Exercise-associated wheezing was also more frequent among Tobagonian adolescents (17.5% & 20.2%, RR 0.87, 95% CI 0.76 – 0.98, p = 0.04).

Conclusion

Self-reported wheeze is common among adolescents in Trinidad and Tobago. Variation in symptoms was found between the two territories; high school students from Tobago, the less industrialized of the two islands, reported more symptoms of severe asthma and exercise-induced wheeze. Difference in the ethnic composition rather than socio-economic factors may be contributing to the observed differences in symptom prevalence.
Lessons learned in developing family medicine residency training programs in Japan
Authors: Murai Mitsuya , Kitamura Kazuya , Fetters Michael D
Published: September 2005

Background

While family medicine is not well established as a discipline in Japan, a growing number of Japanese medical schools and training hospitals have recently started sougoushinryoubu (general medicine departments). Some of these departments are incorporating a family medicine approach to residency training. We sought to learn from family medicine pioneers of these programs lessons for developing residency training.

Methods

This qualitative project utilized a long interview research design. Questions focused on four topics: 1) circumstances when becoming chair/faculty member; 2) approach to starting the program; 3) how Western ideas of family medicine were incorporated; and 4) future directions. We analyzed the data using immersion/crystallization to identify recurring themes. From the transcribed data, we selected representative quotations to illustrate them. We verified the findings by emailing the participants and obtaining feedback.

Results

Participants included: five chairpersons, two program directors, and three faculty members. We identified five lessons: 1) few people understand the basic concepts of family medicine; 2) developing a core curriculum is difficult; 3) start with undergraduates; 4) emphasize clinical skills; and 5) train in the community.

Conclusion

While organizational change is difficult, the identified lessons suggest issues that merit consideration when developing a family medicine training program. Lessons from complexity science could inform application of these insights in other countries and settings newly developing residency training.
Slit-mediated repulsion is a key regulator of motor axon pathfinding in the hindbrain
Authors: Hammond Rachel , Vivancos Valerie , Naeem Arifa , Chilton John , Mambitisaeva Elvira , Andrews William , Sundaresan Vasi , Guthrie Sarah
Published: September 2005

The floor plate is known to be a source of repellent signals for cranial motor axons, preventing them from crossing the midline of the hindbrain. However, it is unknown which molecules mediate this effect in vivo. We show that Slit and Robo proteins are candidate motor axon guidance molecules, as Robo proteins are expressed by cranial motoneurons, and Slit proteins are expressed by the tissues that delimit motor axon trajectories, i.e. the floor plate and the rhombic lip. We present in vitro evidence showing that Slit1 and Slit2 proteins are selective inhibitors and repellents for dorsally projecting, but not for ventrally projecting, cranial motor axons. Analysis of mice deficient in Slit and Robo function shows that cranial motor axons aberrantly enter the midline, while ectopic expression of Slit1 in chick embryos leads to specific motor axon projection errors. Expression of dominant-negative Robo receptors within cranial motoneurons in chick embryos strikingly perturbs their projections, causing some motor axons to enter the midline, and preventing dorsally projecting motor axons from exiting the hindbrain. These data suggest that Slit proteins play a key role in guiding dorsally projecting cranial motoneurons and in facilitating their neural tube exit.
Genotyping cytochrome P450 3A5 using the Light Cycler
Authors: Fredericks Salim , Moreton Michelle , MacPhee Iain AM , Mohamed Maha , Marlowe Sharon , Jorga AnaMaria , Johnston Atholl , Carter Nicholas D , Holt David W.
Published: September 2005

Cytochrome P450 3A5 (CYP3A5) is involved in the biotransformation of many orally administered drugs, some of which are dose optimized using therapeutic drug monitoring. The CYP3A5 gene exhibits variable inter-individual expression, which is related to a single-nucleotide polymorphism. Producers of the enzyme possess at least one CYP3A5* 1 allele. Knowledge of patients' CYP3A5 genotype, in conjunction with therapeutic drug monitoring (TDM), may aid patient management. Real-time polymerase chain reaction (PCR) was used to genotype the A6986G mutation of the CYP3A5 gene. Specific primers were employed to generate a DNA product, co-amplified with two internal hybridization probes, using a LightCycler. DNA melt curve analysis readily identified the genotypes CYP3A5* 1/* 1, CYP3A5* 1/* 3 and CYP3A5* 3/* 3. Results were confirmed using DNA sequencing with 100% correlation. Genotypes were determined from 263 individuals and compared with the genotypes of a pseudogene CYP3AP1, which is in disequilibrium with CYP3A5.

This is a rapid and reliable method for genotyping the CYP3A5 polymorphism which may be used as an important adjunct to the TDM service offered by laboratories to optimize drug prescription.
Recommended standards for biochemical markers of myocardial damage: All Wales Clinical Biochemistry Audit Group
Authors: Williams EJ , Jones CJH , McDowell IFW , Tovey JA , Thomas MA , Wayte AMO , Brown N , Jenkins GH , Oleesky DA
Published: September 2005

The effective use of cardiac-specific troponin estimations in the diagnosis of acute myocardial infarction (AMI) is clouded by the imprecise definition surrounding the decision limits. This has led to a wide variation of criteria for the diagnosis of myocardial infarction. A survey of troponin measurements in Welsh laboratories, undertaken in 2003 under the auspices of the All Wales Clinical Biochemistry Audit Group, revealed significant variations in laboratory and clinical practice. Extensive discussion and consultation led by a working group of clinical biochemists and cardiologists in Wales culminated in recommendations concerning the use of troponin assays to establish myocardial damage.

The key recommendations are:

•Cardiac troponin (T or I) should be the first-line test for myocardial damage;

•Two samples should be collected, at admission and 12-24 h later. The first sample is used for 'rule in' purposes, but not to 'rule out' myocardial damage;

•Only one threshold (cut-off) value for troponin should be quoted on laboratory reports, values above which are indicative of myocardial damage.

A study by the Wales External Quality Assurance Scheme (WEQAS) enabled the derivation of the recommended cut-off concentrations of troponin for defining myocardial damage, defined for each assay as the concentration that can be reliably distinguished, with a confidence interval of 99%, from the 99th percentile reference limit.

These recommended standards provide a rationale for a uniform approach for troponin assays for patients with chest pain, working towards a standardized approach to the diagnosis and management of patients presenting with acute coronary syndromes.
Subcellular Distribution of Components of the Ubiquitin-Proteasome System in Non-diseased Human and Rat Brain
Authors: Ádori Csaba , Lőw Péter , Moszkovkin Georgij , Bagdy György , László Lajos , Kovács Gábor G.
Published: September 2005

Our aim was to investigate and to compare the intracellular distribution of ubiquitin, 20S proteasome, and all six proteasomal regulatory ATPases in non-diseased human and rat brains. Ubiquitin and ATPases S4 and S7 show dominant nuclear immunostaining, whereas subunits S6a, S6b, and S10b show mainly cytoplasmic immunostaining in both species. However, S8 localization is inconsistent, prevailing nuclear in rat and cytoplasmic in human. In rat brain, small clastosome-like nuclear bodies demonstrate strong ubiquitin, 20S, and S6a immunoreactivity both in neurons and glial cells. Prominent nuclear immunolocalization of members of the ubiquitin-proteasome system provides morphological evidence for function of these proteins in transcription regulation and/or DNA repair.
Influence of Molecular Hindered Rotations on NQR Spin Echoes
Authors: Sergeev N. A.
Published: September 2005

The influence of the hindered reorientations of CCl3 groups on the decay of NQR spin echo signals has been investigated. In contrast to the well known literature approaches to the solution of this problem we do not use the perturbation theory of Bloembergen, Purcell and Pound. (PACS codes: 76.60.-k; 76.60.Gv; 76.60.Lz)
Aerobic Oxidation of Benzyl Alcohol by Fe-System Catalyst
Authors: Xiong Yonglian , Xiao Dehai , Li Jing , Xie Xiaofan , Yang Xiangguang , Wu Yue
Published: September 2005

The catalytic oxidation of benzyl alcohol has been carried out by using dioxygen as oxidant in the presence of Fe(acac)3 (acetyl acetone)/1,10-phenanthroline/base system in toluene at 80°. Oxygen was activated successfully by the Fe-catalyst and oxidized benzyl alcohol to benzyl aldehyde in ∼100% selectivity. It was found that the oxidation of benzyl alcohol was very sensitive to water in this reaction system, and small amount of water could obviously decrease the reactivity. Based on the results of cyclic voltammetry and ESR, a binuclear-Fe mechanism was also proposed.
Photochemical Reactivity of Trifluoromethyl Aromatic Amines: The Example of 3,5‐diamino‐trifluoromethyl‐benzene (3,5‐DABTF)
Authors: Chaignon Philippe , Cortial Sylvie , Guerineau Vincent , Adeline Marie‐Thérèse , Giannotti Charles , Fan Gérard , Ouazzani Jamal
Published: September 2005

This work presents the application of an on‐line photoreactor to the detection of 3,5‐diamino‐trifluoromethyl‐benzene (3,5‐DABTF) in aqueous solutions. When irradiated at 310 nm, this compound is defluorinated to 3,5‐diaminobenzoic acid by a nucleophilic substitution of the fluoride by water. Concomitantly, defluorination intermediates polymerize through amide bonds to give dark‐colored compounds. We take advantage of the photocatalyzed defluorination and the subsequent decrease in pH to develop an original and specific photoreactor. Continuous recording of pH and temperature in the outlet of the reactor by a dual electrode gives us an opportunity to optimize the system. In the photoreactor, 3,5‐DABTF is immediately and totally transformed as attested by the rapid drop of the flowing solution pH from 6.2 to 3.2 and the chromatographic analysis of the outgoing solutions. The detection remains effective from 1 to 1000 parts per million.
Adsorptive denitrogenation of light gas oil by silica‐zirconia cogel
Authors: Bae Youn‐Sang , Kim Min‐Bae , Lee Hyun‐Jung , Lee Chang‐Ha , Wook Ryu Jae
Published: September 2005

The characteristics of adsorption and desorption of nitrogen‐containing compounds (NCCs) on the SiZr cogel were studied with regard to denitrogenation of light gas oil (LGO) through batch and dynamic experiments. The SiZr cogel adsorbent showed a high selectivity of NCCs due to the role of the zirconia on the cogel, regardless of the amount and types of sulfur‐containing compounds (SCCs) in the LGO. When the temperature increased from 283 to 323 K, the adsorbed amount of NCCs increased and the time taken to reach the adsorption equilibrium grew shorter. On the other hand, the adsorbent regeneration by the solvent grew worse at higher temperatures when the desorption temperature was applied to the adsorbent used at the corresponding adsorption temperature. At 283 and 303 K, the methyl isobutyl ketone (MIBK) with higher polarity showed a better desorption of NCCs, while the degree of regeneration by methyl tertiary butyl ether (MTBE) at 323 K was the best. The adsorption of NCCs on the cogel was significantly affected by the presence of water in the LGO. While MTBE and MIBK effectively desorbed the adsorbed water with NCCs from the cogel, methyl phenyl ether (Anisole) with aromatic ring was not effective in treating the water. Since the adsorbent could select only the NCCs with high capacity from the LGO at mild temperature and ambient pressure, success in the adsorption technology process would lead to major advances in petroleum refining by facilitating the improvement of HDS as well as fuel cell applications by offering greater protection of the nitrogen‐selective adsorbent. © 2005 American Institute of Chemical Engineers AIChE J, 2006
Experimental study on phase change materials and plastics compatibility
Authors: Lázaro A. , Zalba B. , Bobi M. , Castellón C. , Cabeza L. F.
Published: September 2005

Energy storage is a useful tool to increase energy efficiency and energy savings. Solid‐Liquid phase change materials (PCMs) are used in latent heat thermal energy storage systems. Plastics are currently used as encapsulate materials with PCM, but previously a compatibility test should be made to ensure long term stability. It is not possible to find experimental studies of organic PCM migration in plastics in the literature. The main objective of this work is an experimental study of the compatibility of some PCMs typically used for thermal energy storage with a melting temperature around 22°C and some plastic materials currently used as encapsulate materials. The PCMs tested are molecular alloy C16‐C18, RT20, RT25, RT26, and TH24, and plastic materials tested are PP, LDPE, HDPE, and PET. As a consequence of the results, the best plastic to be used with each PCM and combinations that should be avoided are chosen. © 2005 American Institute of Chemical Engineers AIChE J, 2006
Study of enzymatic G6P synthesis using polymer‐bound ATP in membrane reactors
Authors: Abdelmoez Wael , Ishimi Kosaku , Ishikawa Haruo
Published: September 2005

The performance of membrane reactors, in which the enzymatic synthesis of glucose 6‐phosphate from glucose and polymer‐bound cofactor ATP with simultaneous regeneration of polymer‐bound ATP from polymer‐bound ADP and acetyl phosphate are performed, was analyzed theoretically. Simplified and realistic models for two different membrane reactors, a plug‐flow–type membrane reactor (PFMR) in a diffusion mode and a continuous stirred tank reactor–type membrane reactor (CSTMR) in a filtration mode, were presented and compared theoretically. The results showed that the reactor performance mainly depends on the operating conditions and that, in most cases, the PFMR in a diffusion mode was found to be superior to the CSTR in a filtration mode. This study provides useful information for selecting and optimizing of the reactor for enzymatic reactions requiring cofactors. © 2005 American Institute of Chemical Engineers AIChE J, 2006
Copolymerization of styrene with N‐phenyl maleimide in the presence of montmorillonite
Authors: Liu Guodong , Zhang Liucheng , Gao Changhong , Qu Xiongwei
Published: September 2005

The copolymerization of styrene with N‐phenyl maleimide in the presence of organomodified montmorillonite or Na+ montmorillonite was investigated. The conversion of the monomer was determined dilatometrically or gravimetrically. The copolymerization rate was accelerated and the polymerization activation energy in bulk and solution copolymerization decreased in the presence of montmorillonite. The tendency of alter‐copolymerization was enhanced for bulk and solution polymerization, but not affected for emulsion polymerization, by the addition of organomodified montmorillonite or Na+ montmorillonite. X‐ray diffraction studies showed that the methods of emulsion and bulk intercalative polymerization were more appropriate techniques for preparing nanocomposites with good dispersibility of clay. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1932–1937, 2005
Chitosan application on wool before enzymatic treatment
Authors: Vílchez S. , Jovancic P. , Manich A. M. , Julià M. R. , Erra P.
Published: September 2005

The influence of a chitosan application on wool fabric before a treatment with a proteolytic enzyme has been investigated. The enzymatic treatment enhances whiteness and confers shrink resistance to wool, but an increase in the enzyme concentration leads to a detrimental effect on the physicomechanical properties. A chitosan treatment before the enzymatic treatment additionally improves the shrink resistance and increases the weight loss. To better investigate the role played by the chitosan, surface‐related properties, such as the friction coefficient, the compressional behavior (compressibility, linearity of compression, and thickness), the wearing resistance (weight loss after abrasion), the bursting resistance (bursting strength and deformation), and surface topography, have been studied. The results suggest that the chitosan pretreatment reduces the damage caused by the subsequent enzymatic treatment. They also imply a protective effect of the bursting and wearing resistance, which prevent excessive weight loss due to abrasion. A significant influence of the wool fiber cell membrane complex on the surface‐related properties has been demonstrated through regression analysis and scanning electron microscopy observations. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1938–1946, 2005
Response of a sequential‐valve‐gate system used for thin‐wall injection molding
Authors: Chen Shia‐Chung , Chien Rean Der , Tseng Hsien‐Hsun , Huang Jeng‐Sheng
Published: September 2005

Sequential injection molding using a valve‐gate‐controlled hot runner system has attracted attention for industrial applications in recent years. Because of the complexity of the operation mechanisms, a commercial valve gate usually delays for about 0.3–0.5 s once the valve‐opening command is given. The signal‐to‐operation delay is acceptable for the conventional injection molding of large parts. However, this operation delay limits its application to thin‐wall molded parts for computer, communication, and consumer electronics, for which the required filling time is very short. In this study, a gas‐driven fast‐response sequential‐valve‐gate system was developed for thin‐wall injection molding by the adoption of valve‐gate control performance. The characteristics and verifications of the valve‐gate opening were monitored with a charge‐coupled device (CCD) camera (nonmelt condition) and cavity pressure transducers and an accelerometer (melt‐filled condition). The influence of the tolerance between the inner piston and cylinder and the gas pressure on the valve‐gate opening was investigated in detail. Tensile bar parts 1 mm thick were used for the molding experiments. The delay time has been found to be intimately related to the response of the gas‐pressure delivery controlling the valve‐gate movement. In a nonmelt environment, the delay time of the valve‐gate opening decreases with increasing driven gas slightly. In a melt‐filled environment, the delay time is quite sensitive to the operating gas pressure because of the extra resistance between the shaft and the melt. A threshold pressure as high as 100 bar is required to keep the delay time below 15 ms. With the proper choice of the piston size and driven gas pressure, the delay time can be reduced to about 8 ms in a nonmelt environment and to about 12 ms in a melt‐filled environment. Molding using this improved system for sequential valve opening can provide thin‐wall injection parts without a weld line, and good cosmetic quality and better tensile strength require a lower injection pressure than molding using single‐gate and concurrent‐valve‐gate opening. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1969–1977, 2005
Kinetics of the enthalpy relaxation process for an epoxy network as determined with a peak shift model
Authors: Fraga F. , Castro‐Díaz C. , Rodríguez‐Núñez E. , Martínez‐Ageitos J. M.
Published: September 2005

The relaxation kinetics of the epoxy network diglycidyl ether of bisphenol A (n = 0) and m‐xylylenediamine were studied with differential scanning calorimetry experimental data with a shift peak model. Nonlinear parameters were calculated with aging experiments. The nonexponential parameter and the apparent activation energy were found from intrinsic cycles. Adam–Gibbs theory was used to provide a molecular interpretation based on the enthalpy relaxation. Different assumptions of the variation of specific heat capacity (cp) were used to determine the macroscopic molar configurational entropy of the system. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 2003–2008, 2005
Micellization of casein‐graft‐dextran copolymer prepared through Maillard reaction
Authors: Pan Xiaoyun , Mu Minfang , Hu Bin , Yao Ping , Jiang Ming
Published: September 2005

Casein is almost insoluble at around pH 4.6, which is its isoelectric point (pI). Grafting copolymer, casein‐g‐dextran, was prepared through the Amadori rearrangement of the Maillard reaction. The copolymer has a reversible pH sensitive property: micellization at the pI of casein forming a casein core and dextran shell structure and dissociation when pH differs from the pI. The micelles produced at pH 4.6 have a spherical shape and their size is dependent on the Maillard reaction: reaction time, molar ratio of casein to dextran, and molecular weight of dextran used. Typically, the hydrodynamic diameter of the micelles is about 100 nm and the critical micelle concentration is about 10 mg/L. The micelles are very stable in aqueous solution and can be stored as lyophiled powder. The micelles are able to encapsulate hydrophobic compounds such as pyrene. © 2005 Wiley Periodicals, Inc. Biopolymers 81: 29–38, 2006

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