bluuebunny/crossref_metadata_2025 huggingface dataset:
The Precautionary Principle and Traditional Risk Assessment
Authors: Carolan Michael S.
Published: April 2007

The article begins by problematizing the risk assessment and precautionary principle frameworks. From here, attention turns toward the development of an alternative, more holistic, scheme for assessing and mitigating environmental threats. Recognizing that the assessment and mitigation of environmental threats is a multilayered process, discussion centers on the question of who is involved in the production process—from research to development to threat assessment. Including a variety of stakeholders in both the “front” and “back” ends of production thus also places focus on the material side of this process, particularly in terms of what is being produced and released into the environment. Traditional risk assessment and the precautionary principle are therefore presented as shortsighted strategies for threat assessment. Instead, a more open approach is discussed, which involves greater public involvement through the entire life cycle of a product, from “cradle to cradle”.
Preservation and Freedom
Authors: Fleming Deborah
Published: April 2007

“Preservation and Freedom” discusses the importance of farmland preservation and certain individual efforts to preserve farmland in southern Ashland County, Ohio. The article concludes with a discussion of the relationship of preservation and freedom, stating that we in America need a new definition of economy that includes the long-term ramifications of what we do and asserts that our national goals should include more than addiction to progress, efficiency, and increasing materialism; it should include preserving our relationship to the land that made us who and what we are.
Digital Play and the Actualization of the Consumer Imagination
Authors: Molesworth Mike , Denegri-Knott Janice
Published: April 2007

In this article, the authors consider emerging consumer practices in digital virtual spaces. Building on constructions of consumer behavior as both a sense-making activity and a resource for the construction of daydreams, as well as anthropological readings of performance, the authors speculate that many performances during digital play are products of consumer fantasy. The authors develop an interpretation of the relationship between the real and the virtual that is better equipped to understand the movement between consumer daydreams and those practices actualized in the material and now also in digital virtual reality. The authors argue that digital virtual performances present opportunities for liminoid transformations through inversions, speculations, and playfulness acted out in aesthetic dramas. To illustrate, the authors consider specific examples of the theatrical productions available to consumers in digital spaces, highlighting the consumer imagination that feeds them, the performances they produce, and the potential for transformation in consumer-players.
Thoughtless Play
Authors: Saklofske Jon
Published: April 2007

Authorial responsibility has been increasingly decentralized by the collective manipulation of media parameters. Whereas this encourages a sense of freedom for those exposed to such narratives, participation in narrative realization and a lack of interpretative dislocation can actually impair a reader. To demonstrate how excessive mediation can liberate or limit an audience, this article will compare how William Blake's “The Fly” and Grand Theft Auto: San Andreas differently enable and disable the authority and agency of storytellers and readers.
The chemokine GROβ mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment
Authors: Fukuda Seiji , Bian Huimin , King Andrew G. , Pelus Louis M.
Published: April 2007

Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GROβ (GROβΔ4/CXCL2Δ4) or the combination of GROβΔ4 plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF–mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GROβ-mobilized grafts. PBSCs mobilized by GROβΔ4 alone or with G-CSF contained significantly more Sca-1+-c-kit+-lineage− (SKL) cells and more primitive CD34−-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GROβΔ4-mobilized SKL cells adhered better to VCAM-1+ endothelial cells compared with G-CSF–mobilized cells. GROβΔ4-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1α in vitro that was associated with higher CD26 expression. However, GROβΔ4-mobilized SKL and c-Kit+ lineage− (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GROβΔ4-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GROβΔ4-mobilized cells is less dependent on the SDF-1α/CXCR4 axis.
Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin α5 chain and Lu/BCAM
Authors: Wautier Marie-Paule , El Nemer Wassim , Gane Pierre , Rain Jean-Didier , Cartron Jean-Pierre , Colin Yves , Le Van Kim Caroline , Wautier Jean-Luc
Published: April 2007

Patients with polycythemia vera (PV) have a JAK2 (a cytosolic tyrosine kinase) mutation and an increased risk of vascular thrombosis related to red blood cell (RBC) mass and platelet activation. We investigated functional RBC abnormalities that could be involved in thrombosis. RBC adhesion to human umbilical vein endothelial cells (HUVECs) was measured by a radiometric technique and in a flow system by video microscopy, and adhesion molecule expression was determined using specific antibodies (against CD36, CD49d, ICAM-4, Lu/BCAM, CD147, and CD47) and flow cytometry in a group of 38 patients with PV and a group of 36 healthy volunteers. Adhesion of PV RBCs was 3.7-fold higher than that of normal RBCs (P < .001). Adhesion was inhibited when PV RBCs were incubated with anti-Lutheran blood group/basal cell adhesion molecule (Lu/BCAM) or when HUVECs were treated with anti-laminin α5 and to a lesser extent with anti-α3 integrin. Lu/BCAM was constitutively phosphorylated in PV RBCs. Transfection of K562 cells with JAK2 617V>F resulted in increased expression and phosphorylation of Lu/BCAM. Phosphorylation of Lu/BCAM increases RBC adhesion. Our results indicate that JAK2 mutation might be linked to Lu/BCAM modification and increased RBC adhesiveness, which may be a factor favoring thrombosis in PV.
CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS)
Authors: Kordasti Shahram Y. , Ingram Wendy , Hayden Janet , Darling David , Barber Linda , Afzali Behdad , Lombardi Giovanna , Wlodarski Marcin W. , Maciejewski Jaroslaw P. , Farzaneh Farzin , Mufti Ghulam J.
Published: April 2007

Foxp3+ regulatory T cells (Tregs) play a central role in maintaining immune tolerance. A reduction in the function of Tregs is a key feature of autoimmune diseases, whereas their expansion in malignant diseases leads to the suppression of host antitumor responses. We analyzed the absolute number of CD4+ and CD8+ Tregs in the peripheral blood of 52 patients with myelodysplastic syndrome (MDS) and show a significant correlation between increased number of CD4+ Tregs and MDS subgroups with 5% or more bone marrow blasts (P < .001), high International Prognostic Scoring System (IPSS) score (P < .001), and disease progression (P < .001), whereas no correlation between CD8+ Tregs and prognostic variables was observed. The CD4+ Tregs showed a polyclonal spectratype, and the percentage of the naive subset was significantly higher in the high-risk patients compared with low-risk or healthy age-matched donors (P = .032). Our data suggest that CD4+ Treg expansion is a feature of high-risk MDS and progression to aggressive subtypes of the disease.
Poorly performing supervisors and trainers of trainee doctors
Authors: Faruqui Rafey A. , Ikkos George
Published: April 2007

Paice & Ginsburg (2003) surveyed postgraduate medical trainees in London and found that most considered their training as satisfactory and the proportion that evaluated their training as poor had fallen compared with a previous survey. They also reported, however, that the training experience for some trainees remains unsatisfactory and that the single most important factor in determining trainee satisfaction is the quality of supervision provided by the consultant trainer. In the light of this it is alarming that in a recent survey of psychiatric trainees in the West Midlands, 47% had experienced bullying and in 27% of cases of alleged bullying the perpetrators were senior medical staff (Hoosen & Callaghan, 2004). Paice et al (2004) reported consultants as the source of bullying in 27% of cases in a survey of bullying among doctors in training in north London.
Service innovation: an old age liaison psychiatry service
Authors: Whelan Paul , Lawson Kirsten , Burton Stephen W.
Published: April 2007

Service models differ for the provision of mental healthcare for elderly medical in-patients. Input by the general adult liaison psychiatry service with no age cutoff (Lipowski, 1983) and sector-based old age community mental health teams (CMHTs) (Scott et al, 1988; De Leo et al, 1989) have been described, as well as a consultation–liaison model. Holmes et al (2003) showed that old age psychiatrists favoured a liaison rather than a consultation model.
Multi-Institutional Validation of a New Renal Cancer–Specific Survival Nomogram
Authors: Karakiewicz Pierre I. , Briganti Alberto , Chun Felix K.-H. , Trinh Quoc-Dien , Perrotte Paul , Ficarra Vincenzo , Cindolo Luca , De La Taille Alexandre , Tostain Jacques , Mulders Peter F.A. , Salomon Laurent , Zigeuner Richard , Prayer-Galetti Tommaso , Chautard Denis , Valeri Antoine , Lechevallier Eric , Descotes Jean-Luc , Lang Herve , Mejean Arnaud , Patard Jean-Jacques
Published: April 2007

Purpose

We tested the hypothesis that the prediction of renal cancer–specific survival can be improved if traditional predictor variables are used within a prognostic nomogram.

Patients and Methods

Two cohorts of patients treated with either radical or partial nephrectomy for renal cortical tumors were used: one (n = 2,530) for nomogram development and for internal validation (200 bootstrap resamples), and a second (n = 1,422) for external validation. Cox proportional hazards regression analyses modeled the 2002 TNM stages, tumor size, Fuhrman grade, histologic subtype, local symptoms, age, and sex. The accuracy of the nomogram was compared with an established staging scheme.

Results

Cancer-specific mortality was observed in 598 (23.6%) patients, whereas 200 (7.9%) died as a result of other causes. Follow-up ranged from 0.1 to 286 months (median, 38.8 months). External validation of the nomogram at 1, 2, 5, and 10 years after nephrectomy revealed predictive accuracy of 87.8%, 89.2%, 86.7%, and 88.8%, respectively. Conversely, the alternative staging scheme predicting at 2 and 5 years was less accurate, as evidenced by 86.1% (P = .006) and 83.9% (P = .02) estimates.

Conclusion

The new nomogram is more contemporary, provides predictions that reach further in time and, compared with its alternative, which predicts at 2 and 5 years, generates 3.1% and 2.8% more accurate predictions, respectively.
Serum CA-125 in Relation to Adnexal Dysplasia and Cancer in Women at Hereditary High Risk of Ovarian Cancer
Authors: Hermsen Brenda B.J. , von Mensdorff-Pouilly Silvia , Berkhof Johannes , van Diest Paul J. , Gille Johan J.P. , Menko Fred H. , Blankenstein Marinus A. , Kenemans Peter , Verheijen René H.M.
Published: April 2007

Purpose

Serum CA-125 level is commonly used as indicator for ovarian cancer recurrence. However, its value for the prediction of neoplastic lesions is unknown. The aim of this study was to investigate whether CA-125 concentrations are indicative of adnexal dysplasia and cancer in women at hereditary high risk of ovarian/tubal cancer.

Patients and Methods

CA-125 was obtained from 424 women at hereditary high risk of ovarian/tubal cancer attending the VU University Medical Center (Amsterdam, the Netherlands) between 1993 and 2005. Serum samples obtained at the second-to-last (n = 64) and last (n = 98) visit before surgery were tested in women who underwent adnexal surgery for diagnostic (n = 9) or prophylactic (n = 89) reasons. Serum samples obtained from 370 age-matched healthy women were used as controls.

Results

Both the absolute value (P < .0001) and the serial change (P < .0001) of CA-125 were predictive for ovarian cancer (n = 8). For adnexal dysplasia (n = 23), the absolute value of CA-125 (P = .003) was predictive, but the serial change in CA-125 was not (P = .32). The odds ratio for adnexal dysplasia versus nondysplasia in the highest tertile (CA-125 levels ≥ 14 U/mL) compared with the lowest tertile (CA-125 < 10 U/mL) was 6 (95% CI, 1.32 to 36.66).

Conclusion

In patients at hereditary high risk for adnexal cancer, both the absolute value of serum CA-125 and the change in serial CA-125 are predictors for ovarian cancer. Remarkably, the absolute value of CA-125 is also predictive for adnexal dysplasia. CA-125 values should, therefore, be taken into account in the decision toward prophylactic bilateral salpingo-oophorectomy.
Late Effects of Cancer and Hematopoietic Stem-Cell Transplantation on Spouses or Partners Compared With Survivors and Survivor-Matched Controls
Authors: Bishop Michelle M. , Beaumont Jennifer L. , Hahn Elizabeth A. , Cella David , Andrykowski Michael A. , Brady Marianne J. , Horowitz Mary M. , Sobocinski Kathleen A. , Rizzo J. Douglas , Wingard John R.
Published: April 2007

Purpose

Little is known about the long-term effects of cancer and hematopoietic stem-cell transplantation (HCT) on spouses or partners. The purpose of this study was to examine the health-related quality of life and post-traumatic growth (PTG) of spouses/partners compared with survivors and controls and to identify factors associated with those outcomes.

Patients and Methods

HCT survivor/partner pairs (n = 177), coupled continuously since HCT, were drawn from 40 North American transplantation centers. Married peer-nominated acquaintances (of survivors) served as controls (n = 133). Outcomes were measured a mean of 6.7 years after HCT (range, 1.9 to 19.4 years).

Results

As expected, self-reported partner physical health was similar to controls and better than survivors (P < .001). However, partners reported more fatigue and cognitive dysfunction than controls (P < .001 for both), although less than survivors. Partners and survivors reported more depressive symptoms and sleep and sexual problems than controls (P < .001, P < .01, and P < .01, respectively). Odds of partner depression were nearly 3.5 times that of controls (P < .002). Depressed partners were less likely than depressed survivors to receive mental health treatment (P < .04). Partners reported less social support (P < .001), dyadic satisfaction (P < .05), and spiritual well-being (P < .05) and more loneliness (P < .05) than both survivors and controls. In contrast to survivors, partners reported little PTG (P < .001). Factors associated with partner outcomes included partner health problems, coping, female sex, social constraint, survivor depression, optimism, multiple life changes, and social support.

Conclusion

Spouses/partners experience similar emotional and greater social long-term costs of cancer and HCT than survivors without the potential compensatory benefits of PTG. Some of the factors associated with partner outcomes are amenable to intervention.
Melanoma in Children and Teenagers: An Analysis of Patients From the National Cancer Data Base
Authors: Lange Julie R. , Palis Bryan E. , Chang David C. , Soong Seng-Jaw , Balch Charles M.
Published: April 2007

Purpose

This study examines the demographics, presentation, and outcomes of children and teenagers with melanoma using a US hospital-based oncology database.

Patients and Methods

Data from the National Cancer Data Base from 1985 through 2003 were examined for demographics, presentation, and survival of patients aged 1 to 19 years, as well as a comparison group of patients aged 20 to 24 years. Two-sided linear and Pearson χ2 tests were calculated to examine associations. Proportions were compared using two-sided z tests. Five-year overall observed survival was evaluated using the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression was used to estimate risk of mortality.

Results

Of 3,158 patients aged 1 to 19 years, 96.3% had cutaneous melanoma, 3.0% had ocular melanoma, and 0.7% had an unknown primary tumor. Cutaneous melanoma in patients aged 1 to 19 years was more common in girls (55.5%) and patients older than 10 years (90.5%). The demographics and presentation of cutaneous melanoma were age related; younger children were significantly more likely to be nonwhite and male and more likely to present with a head and neck primary tumors and with regional or distant metastases (linear χ2, P < .001 for sex, race, and extent of disease). Poorer survival was associated with higher stage and younger age. In contrast to patients aged 20 to 24 years, survival was not related to thickness in patients aged 1 to 19 years with localized invasive melanoma.

Conclusion

Melanoma in children and teenagers differs from melanoma in young adults in demographics, presentation, and survival. Further investigation is warranted to elucidate possible biologic correlates of the unique aspects of melanoma in children and teenagers.
Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1
Authors: Tolcher Anthony W. , Mita Monica , Meropol Neal J. , von Mehren Margaret , Patnaik Amita , Padavic Kristin , Hill Monique , Mays Theresa , McCoy Therese , Fox Norma Lynn , Halpern Wendy , Corey Alfred , Cohen Roger B.
Published: April 2007

Purpose

To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor–related apoptosis-inducing ligand receptor-1 (TRAIL-R1).

Patients and Methods

Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry.

Results

Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (± standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (± 1.5 mL/d/kg) and 18.8 days (± 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months.

Conclusion

Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.
Does One Person Provide It All? Primary Support and Advanced Care Planning for Women With Cancer
Authors: Dizon Don S. , Gass Jennifer S. , Bandera Christina , Weitzen Sherry , Clark Melissa
Published: April 2007

Purpose

We challenged a common clinical assumption that female cancer patients designate the same individual who provides them with primary support in advanced care planning roles.

Patients and Methods

During 6 months, we conducted a survey of female cancer patients seen in a women's oncology program. Women were asked to name their health care proxy (HCP), emergency contact (EC), and primary support, and to define their own meaning of primary support. The person identified by chart review (C-ID) as that patient's primary contact was also abstracted. The frequency that the same person served all three roles was determined. Concordance between the C-ID and surveyed responses was calculated.

Results

Two hundred fifteen (98%) of 219 women agreed to participate. The median age was 58 years (range, 29 to 85 years). Women were surveyed a median of 14.3 months since diagnosis (range, 0.3 to 214 months). Although 80.4% of women surveyed named a first-degree relative to fill all three roles, only 56.7% of respondents identified the same individual for each of these roles. For those in relationships, 54% named their partner in all three roles. The majority of women characterized support as emotional (46.7%) or as emotional and structural (22.6%). Concordance was strongest between the C-ID and both EC and HCP.

Conclusion

More than 40% of women with cancer in our sample did not name the same person for support and for advanced care planning roles. We also discovered a lack of uniformity in definitions of primary support. The implications of these findings on decision making and outcomes in women with cancer require additional study.
Palliative Radiotherapy Trials for Bone Metastases: A Systematic Review
Authors: Chow Edward , Harris Kristin , Fan Grace , Tsao May , Sze Wai M.
Published: April 2007

Purpose

The objective is to update previous meta-analyses with a systematic review of randomized palliative radiotherapy (RT) trials comparing single fractions (SFs) versus multiple fractions (MFs).

Methods

The analysis includes all published reports from randomized trials comparing SF or MF schedules for the treatment of painful bone metastases with localized RT. A systematic review was performed using the random-effects model with Review Manager version 4.1 (Cochrane Collaboration, Oxford, UK). The odds ratio and 95% CI were calculated for each trial and presented in a forest plot.

Results

A total of 16 randomized trials from 1986 onward were identified. For intention-to-treat patients, the overall response (OR) rates for pain were similar for SF at 1,468 (58%) of 2,513 patients and MF RT at 1,466 (59%) of 2,487 patients. The complete response (CR) rates for pain were 23% (545 of 2,375 patients) for SF and 24% (558 of 2,351 patients) for MF RT. No significant differences were found in response rates. Trends showing an increased risk for SF RT arm patients in terms of pathological fractures and spinal cord compressions were observed, but neither were statistically significant (P = .75 and P = .13, respectively). The likelihood of re-treatment was 2.5-fold higher (95% CI, 1.76 to 3.56) in SF RT arm patients (P < .00001). Repeated analysis of these end points, excluding dropout patients, did not alter the conclusions. Generally, no significant differences with respect to acute toxicities were observed between the arms.

Conclusion

No significant differences in the arms were observed for overall and CR rates in both intention-to-treat and assessable patients. However, a significantly higher re-treatment rate with SFs was evident.
Individual Patient Data Meta-Analysis of Docetaxel Administered Once Every 3 Weeks Compared With Once Every Week Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer
Authors: Di Maio Massimo , Perrone Francesco , Chiodini Paolo , Gallo Ciro , Camps Carlos , Schuette Wolfgang , Quoix Elisabeth , Tsai Chun-Ming , Gridelli Cesare
Published: April 2007

Purpose

Although several randomized trials have been performed comparing weekly docetaxel (wD) with standard docetaxel once every 3 weeks (3wD) as second-line treatment of advanced non–small-cell lung cancer (NSCLC), no single trial had sufficient power to detect clinically relevant differences in survival.

Methods

We performed a meta-analysis based on individual patient data from all identified randomized trials comparing wD with 3wD as second-line treatment of advanced NSCLC. Baseline characteristics, treatment assigned, and outcome data were collected for each patient. The primary end point was overall survival. All statistical analyses were stratified by trial.

Results

Five eligible trials were identified for a total of 865 patients: 433 patients had been assigned to 3wD, and 432 patients had been assigned to wD. Median age was 62 years (range, 26 to 80 years). Performance status was 0 in 23%, 1 in 58%, and 2 in 16% of patients; 91% of the patients had received previous platinum, and 14% had received previous paclitaxel. With 733 deaths recorded (85%), median survival was 27.4 weeks for patients treated with 3wD, and 26.1 weeks for patients treated with wD (P = .24, log-rank test). There was no significant heterogeneity among the five trials. No relevant differential effect was detected in subgroup analyses. Significantly less severe and febrile neutropenia was reported with wD (P < .00001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxicity.

Conclusion

wD shows similar efficacy compared with 3wD, and represents an alternative for second-line treatment of advanced NSCLC.
Direct Regulation of Androgen Receptor-Associated Protein 70 by Thyroid Hormone and Its Receptors
Authors: Tai Pei-Ju , Huang Ya-Hui , Shih Chung-Hsuan , Chen Ruey-Nan , Chen Chi-De , Chen Wei-Jan , Wang Chia-Siu , Lin Kwang-Huei
Published: April 2007

Thyroid hormone (T3) regulates multiple physiological processes during development, growth, differentiation, and metabolism. Most T3 actions are mediated via thyroid hormone receptors (TRs) that are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. The effects of T3 treatment on target gene regulation was previously examined in TRα1-overexpressing hepatoma cell lines (HepG2-TRα1). Androgen receptor (AR)-associated protein 70 (ARA70) was one gene found to be up-regulated by T3. The ARA70 is a ligand-dependent coactivator for the AR and was significantly increased by 4- to 5-fold after T3 treatment by Northern blot analyses in the HepG2-TRα1 stable cell line. T3 induced a 1- to 2-fold increase in the HepG2-TRβ1 stable cell line. Both stable cell lines attained the highest fold expression after 24 h treatment with 10 nm T3. The ARA70 protein was increased up to 1.9-fold after T3 treatment in HepG2-TRα1 cells. Similar findings were obtained in thyroidectomized rats after T3 application. Cycloheximide treatment did not suppress induction of ARA70 transcription by T3, suggesting that this regulation is direct. A series of deletion mutants of ARA70 promoter fragments in pGL2 plasmid were generated to localize the thyroid hormone response element (TRE). The DNA fragments (−234/−190 or +56/+119) gave 1.55- or 2-fold enhanced promoter activity by T3. Thus, two TRE sites exist in the upstream-regulatory region of ARA70. The TR-TRE interaction was further confirmed with EMSAs. Additionally, ARA70 could interfere with TR/TRE complex formation. Therefore, the data indicated that ARA70 suppresses T3 signaling in a TRE-dependent manner. These experimental results suggest that T3 directly up-regulates ARA70 gene expression. Subsequently, ARA70 negatively regulates T3 signaling.
Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway
Authors: Dagvadorj Ayush , Collins Sean , Jomain Jean-Baptiste , Abdulghani Junaid , Karras James , Zellweger Tobias , Li Hongzhen , Nurmi Martti , Alanen Kalle , Mirtti Tuomas , Visakorpi Tapio , Bubendorf Lukas , Goffin Vincent , Nevalainen Marja T.
Published: April 2007

The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Δ1–9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.
Optimization of Dosing Schedule of Daily Inhalant Dexamethasone to Minimize Phase Shifting of Clock Gene Expression Rhythm in the Lungs of the Asthma Mouse Model
Authors: Hayasaka Naomi , Yaita Tsuyoshi , Kuwaki Tomoyuki , Honma Sato , Honma Ken-ichi , Kudo Takashi , Shibata Shigenobu
Published: April 2007

Glucocorticoid receptor agonists such as dexamethasone (DEXA) have been recommended for the treatment of asthma. An increased frequency of dosing with these drugs seems preferable for cases of severe or uncontrolled asthma. The purpose of this experiment was to find the appropriate dosing schedule (frequency and timing) for DEXA inhalation based on chronotherapeutic dosing to minimize phase shifts of clock function in the lungs of the ovalbumin-treated asthmatic mouse. The daily rhythm of clock gene expression was similar between control and ovalbumin-treated mice. Acute inhalation of DEXA significantly increased mPer1 gene expression in the lungs but not the liver of mice. Daily exposure of DEXA at zeitgeber time 0 (lights on) or at zeitgeber time 18 (6 h after lights off) for 6 d caused a phase advance or phase delay of bioluminescence rhythm in the lungs, respectively, similar to light-induced phase shifts in locomotor activity rhythm. Daily zeitgeber time 0 exposure to DEXA attenuated the expression level of the mClca3 gene, which is associated with mucus overproduction, and there was a phase-advancing peak time of the mClca3 rhythm. The present results denote the importance of selecting the most appropriate time of day for nebulizer administration of DEXA to minimize adverse effects such as the phase shifting of clock function in asthmatic lungs. This is the first report of a successful protocol that could obtain phase shifts of clock gene expression rhythm in isolated peripheral organs in vivo.
Estrogen Receptor-β Mediates Dihydrotestosterone-Induced Stimulation of the Arginine Vasopressin Promoter in Neuronal Cells
Authors: Pak Toni R. , Chung Wilson C. J. , Hinds Laura R. , Handa Robert J.
Published: April 2007

Arginine vasopressin (AVP) is a neuropeptide involved in the regulation of fluid balance, stress, circadian rhythms, and social behaviors. In the brain, AVP is tightly regulated by gonadal steroid hormones in discrete regions with gonadectomy abolishing and testosterone replacement restoring normal AVP expression in adult males. Previous studies demonstrated that 17β-estradiol, a primary metabolite of testosterone, is responsible for restoring most of the AVP expression in the brain after castration. However, 5α-dihydrotestosterone (DHT) has also been shown to play a role in the regulation of AVP expression, thus implicating the involvement of both androgen and estrogen receptors (ER). Furthermore, DHT, through its conversion to 5α-androstane-3β,17β-diol, has been shown to modulate estrogen response element-mediated promoter activity through an ER pathway. The present study addressed two central hypotheses: 1) that androgens directly modulate AVP promoter activity and 2) the effect is mediated by an estrogen or androgen receptor pathway. To that end, we overexpressed androgen receptor, ERβ, and ERβ splice variants in a neuronal cell line and measured AVP promoter activity using a firefly luciferase reporter assay. Our results demonstrate that DHT and its metabolite 5α-androstane-3β,17β-diol stimulate AVP promoter activity through ERβ in a neuronal cell line.
Vasopressin Mediates Mitogenic Responses to Adrenalectomy in the Rat Anterior Pituitary
Authors: Subburaju Sivan , Aguilera Greti
Published: April 2007

To determine whether increased vasopressinergic activity during chronic stress or adrenalectomy mediates trophic changes in the corticotroph, we examined the effect of peripheral V1 receptor blockade in rats, using the antagonist, dGly[Phaa1,d-tyr(et), Lys, Arg]vasopressin (VP), on the number of pituitary cells taking up bromodeoxyuridine (BrdU) and cells containing immunoreactive ACTH (irACTH). Adrenalectomy significantly increased the number of BrdU- and ACTH-labeled cells at 3 and 6 d, and a much larger increase was observed at 28 d. Minipump infusion of V1 antagonist for 28 d, at doses blocking the increases in ACTH and corticosterone induced by exogenous VP, prevented the increases in BrdU incorporation, but not irACTH cells observed 28 d after adrenalectomy. Unexpectedly, colocalization of BrdU with ACTH-positive cells was minor (about three cells per pituitary section), and this was unaffected by adrenalectomy or V1 antagonist infusion. In contrast, adrenalectomy for 6 or 14 d failed to increase BrdU incorporation or irACTH cells in V1b receptor knockout mice while inducing the expected increase in wild-type mice. The data show that VP is required for pituitary mitogenesis after adrenalectomy but, at least in rats, not for increasing the number of corticotrophs. The lack of colocalization of ACTH in mitotic cells suggests that recruitment of corticotrophs during adrenalectomy occurs from undifferentiated cells.
Constitutive Activity of the Osteoblast Ca2+-Sensing Receptor Promotes Loss of Cancellous Bone
Authors: Dvorak Melita M. , Chen Tsui-Hua , Orwoll Benjamin , Garvey Caitlin , Chang Wenhan , Bikle Daniel D. , Shoback Dolores M.
Published: April 2007

Changes in extracellular [Ca2+] modulate the function of bone cells in vitro via the extracellular Ca2+-sensing receptor (CaR). Within bone microenvironments, resorption increases extracellular [Ca2+] locally. To determine whether enhanced CaR signaling could modulate remodeling and thereby bone mass in vivo, we generated transgenic mice with a constitutively active mutant CaR (Act-CaR) targeted to their mature osteoblasts by the 3.5 kb osteocalcin promoter. Longitudinal microcomputed tomography of cancellous bone revealed reduced bone volume and density, accompanied by a diminished trabecular network, in the Act-CaR mice. The bone loss was secondary to an increased number and activity of osteoclasts, demonstrated by histomorphometry of secondary spongiosa. Histomorphometry, conversely, indicates that bone formation rates were unchanged in the transgenic mice. Constitutive signaling of the CaR in mature osteoblasts resulted in increased expression of RANK-L (receptor activator of nuclear factor-κB ligand), the major stimulator of osteoclast differentiation and activation, which is the likely underlying mechanism for the bone loss. The phenotype of Act-CaR mice is not attributable to systemic changes in serum [Ca2+] or PTH levels. We provide the first in vivo evidence that increased signaling by the CaR in mature osteoblasts can enhance bone resorption and further propose that fluctuations in the [Ca2+] within the bone microenvironment may modulate remodeling via the CaR.
Approach to the Growth Hormone-Deficient Child during Transition to Adulthood
Authors: Radovick Sally , DiVall Sara
Published: April 2007

The observation that some adults with childhood-onset GH deficiency have low bone mineral density, low lean body mass, diminished quality of life, abnormal lipids, and impaired cardiac function, all of which may improve after treatment with GH, has prompted pediatric endocrinologists to reevaluate the practice of discontinuing GH in all patients after attainment of final adult height. The treatment of adolescents to prevent the metabolic complications of GH deficiency is an emerging practice. Studies addressing the evaluation and care of adolescents during this period and the benefits of GH in this setting are conflicting. Our approach in determining which adolescents to retest, when and how to test for persistent GH deficiency, and which subjects to treat is discussed in the context of available clinical data.
Functional importance of polymerization and localization of calsequestrin inC. elegans
Authors: Cho J. H. , Ko K. M. , Singaruvelu Gunasekaran , Lee Wonhae , Kang Gil Bu , Rho Seong-Hwan , Park Byung-Jae , Yu Jae-Ran , Kagawa Hiroaki , Eom S. H. , Kim D. H. , Ahnn Joohong
Published: April 2007

Dual roles of calsequestrin (CSQ-1) being the Ca2+ donor and Ca2+ acceptor make it an excellent Ca2+-buffering protein within the sarcoplasmic reticulum (SR). We have isolated and characterized a calsequestrin (csq-1)-null mutant in Caenorhabditis elegans. To our surprise, this mutant csq-1(jh109) showed no gross defects in muscle development or function but, however, is highly sensitive to perturbation of Ca2+ homeostasis. By taking advantage of the viable null mutant, we investigated the domains of CSQ-1 that are important for polymerization and cellular localization, and required for its correct buffering functions. In transgenic animals rescued with various CSQ-1 constructs, the in vivo patterns of polymerization and localization of several mutated calsequestrins were observed to correlate with the structure-function relationship. Our results suggest that polymerization of CSQ-1 is essential but not sufficient for correct cellular localization and function of CSQ-1. In addition, direct interaction between CSQ-1 and the ryanodine receptor (RyR) was found for the first time, suggesting that the cellular localization of CSQ-1 in C. elegans is indeed modulated by RyR through a physical interaction.
Changes in high‐school students' competence beliefs, utility value and achievement goals in mathematics
Authors: Chouinard Roch. , Roy Normand.
Published: April 2007

Background

Many studies have revealed that there is a significant decrease over time in high‐school students' attitudes towards mathematics learning. Some authors conclude that motivation in mathematics stabilizes or improves around grade 9; others propose that the decline is continuous. It is unclear if girls or boys are more affected by this phenomenon.

Aims

The present study aims to further examine changes in competence beliefs, utility value and achievement goals in mathematics during high school, taking gender and period of the academic year into account.

Sample

1,130 participants from 18 secondary schools, distributed in two cohorts (grades 7 and 9).

Method

Attitudinal scales designed to measure competence beliefs, utility value and achievement goals in mathematics were administered at the beginning and end of three academic years in a longitudinal cohort‐sequential research design using two sequential cohorts. Hierarchical linear modelling was used to analyse the data.

Results

Results showed an ongoing reduction of most of the variables measured. This was the case for both cohorts and genders. However, boys were more affected than girls. Furthermore, for all variables, motivation tended to be lower at the end of the academic year than at the beginning.

Conclusions

Our results support the hypothesis of a regular decline of motivation in mathematics during high school, accentuated between grades 9 and 11. Moreover, our results illustrate gender convergence in mathematics rather than gender differentiation. Finally, the gradual drop in motivation in mathematics appears to be a two‐step phenomenon: a decrease between and within grade levels.
An empirical definition of clinical supervision
Authors: Milne Derek
Published: April 2007

Objectives The growing recognition of clinical supervision as the basis for high‐quality mental health services is apparent in policy, research and clinical practice, but an empirical definition is required to progress research and practice.

Method A logical analysis was used to draft a working definition, and then a systematic review of 24 empirical studies of clinical supervision produced a best evidence synthesis, which was used to test and improve this definition.

Results The logical analysis indicated that the most popular definition (Bernard & Goodyear, 1992) failed all four necessary tests of a good definition: precision, specification, operationalization and corroboration. The systematic review synthesis was then used to test the working definition, which passed these tests (with two amendments).

Conclusion These two complementary review approaches created a firmer basis for advancing research and practice.
Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden
Authors: Malm Tarja M. , Iivonen Henna , Goldsteins Gundars , Keksa-Goldsteine Velta , Ahtoniemi Toni , Kanninen Katja , Salminen Antero , Auriola Seppo , Van Groen Thomas , Tanila Heikki , Koistinaho Jari
Published: April 2007

Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-κB (NF-κB), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia–ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3β (GSK-3β). Because chronic inflammation, oxidative stress, and increased GSK-3β activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering β-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-κB were not part of the brain pathology. Instead, the phosphorylated form of GSK-3β was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3β. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric Aβ and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt–GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu2+into a cell, and, in turn, Cu2+is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu2+-activated Akt pathway.
Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening KATPChannels
Authors: Ma Weiyuan , Berg Jim , Yellen Gary
Published: April 2007

A low-carbohydrate ketogenic diet remains one of the most effective (but mysterious) treatments for severe pharmacoresistant epilepsy. We have tested for an acute effect of physiological ketone bodies on neuronal firing rates and excitability, to discover possible therapeutic mechanisms of the ketogenic diet. Physiological concentrations of ketone bodies (β-hydroxybutyrate or acetoacetate) reduced the spontaneous firing rate of neurons in slices from rat or mouse substantia nigra pars reticulata. This region is thought to act as a “seizure gate,” controlling seizure generalization. Consistent with an anticonvulsant role, the ketone body effect is larger for cells that fire more rapidly. The effect of ketone bodies was abolished by eliminating the metabolically sensitive KATPchannels pharmacologically or by gene knock-out. We propose that ketone bodies or glycolytic restriction treat epilepsy by augmenting a natural activity-limiting function served by KATPchannels in neurons.
Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord
Authors: Wang Zhi , Li Ling Ying , Taylor Michael D. , Wright Douglas E. , Frank Eric
Published: April 2007

Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are primarily unknown. In this study, we report that embryonic overexpression of neurotrophin-3 (NT3) in muscles disrupts the development of these specific Ia–MN connections, using transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic EPSPs evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia–MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.