bluuebunny/crossref_metadata_2025 huggingface dataset:
Who's Ambivalent and Who's Not? Social Welfare Ambivalence Across Ideology
Authors: Gainous Jason
Published: February 2008

This study uses a fresh approach to measure social welfare ambivalence, addressing the question of who is more ambivalent about such policies— liberals or conservatives. The findings presented here challenge previous assertions that liberals are typically more ambivalent. I argue that conservatives are now more ambivalent than liberals because a change in the tone of elite discourse altered the priming of the potential sources of such ambivalence. The models of ambivalence presented suggest that these primed sources are conflicting thoughts or beliefs (cognitive conflict), conflicting feelings (affective conflict), or beliefs in conflict with feelings (cognitive—affective conflict). The implications of these findings are discussed.
Aggression in Individuals Newly Diagnosed With Dementia
Authors: Orengo Claudia A. , Khan Jennifer , Kunik Mark E. , Snow Andrea L. , Morgan Robert , Steele Avila , Cully Jeffrey A. , Graham David P.
Published: February 2008

Aggression is often associated with dementia. In this study, aggression in veterans newly diagnosed with dementia was examined and characterized. Participants were ≥60 years diagnosed with dementia at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, from 2001 to 2004. Aggression was defined as a positive caregiver response to 1 or more of 3 probes from the Ryden Aggression Scale, administered during a telephone screen. Of 1276 contacts, 385 (30%) were eligible and agreed to participate; at initial screening, 75 (19.5%) were aggressive (23 [31%] verbally, 9 [12%] physically, 24 [32%] verbally and physically, and 19 [25%] with unspecified aggression). The surprisingly high prevalence of aggression in individuals newly diagnosed with dementia suggests the potential usefulness of early screening for aggression in this population.
`It's All About Me!': Gendered Narcissism and Leaders' Identity Work
Authors: Pullen Alison , Rhodes Carl
Published: February 2008

This article develops and illustrates a gendered theorization of narcissism as it relates to the self-identity of leaders in organizations. While the value of existing theories of leadership and narcissism are acknowledged, it is noted that they treat narcissism in an implicitly masculine fashion. In so doing they limit narcissistic leadership identity to relatively aggressive, self-oriented, and domineering forms. To develop a more thorough and nuanced appreciation of the implications of narcissism for leaders' identity work, the article articulates a gendered perspective on narcissism that accounts for forms of leadership that are self-focused but not necessarily traditionally masculine. Four types of leadership narcissism are identified and illustrated: the bully, the star performer, the servant, and the victim. While each of these forms is narcissistic in that identity is associated with the defence of a grandiose self-image (ego ideal) through the admiration of others and the love of the self, they achieve this in markedly different, and gendered, ways. The article concludes by arguing how a gendered reading of narcissism and leadership provides a richer understanding of the narcissistic behaviours of men and women in contemporary organizations.
An Unseen Hand: The Role of Sociology Professor Ernst Borinski in Mississippi's Struggle for Racial Integration in the 1950s and 1960s
Authors: Lowe Maria
Published: February 2008

Based on archival and interview research, the current article examines the leadership roles of Tougaloo College's Sociology Professor Ernst Borinski, a German-Jewish Holocaust refugee, in Mississippi's racial integration struggles in the 1950s and 1960s. Embodying characteristics of both a bridge leader and a transformative intellectual, Professor Borinski worked behind the scenes and utilized the academy's resources and his status as an `outsider' to contribute to undermining Mississippi's racial status quo. As a bridge leader, Dr Borinski directly linked black and white groups together so that they could regularly meet, talk with one another, and develop critiques of racial segregation. As a transformative intellectual, Professor Borinski ensured that students understood their constitutional rights as American citizens and supported students and colleagues who were involved in the Mississippi civil rights movement. These two interlocking leadership roles encapsulate the contributions of Ernst Borinski to Mississippi's development from a `closed society' to a more racially integrated state.
A PRACTICAL ELECTROPHYSIOLOGICAL GUIDE FOR NON-SURGICAL AND SURGICAL TREATMENT OF CARPAL TUNNEL SYNDROME
Authors: CHANG C. -W. , WANG Y. -C. , CHANG K. -F.
Published: February 2008

In the present study, we illustrate the use of an electrophysiological classification as a guide to the treatment of carpal tunnel syndrome (CTS). A total of 113 CTS patients were assessed with symptom severity scores, hand functional scores and electrophysiological studies. By setting criteria of electrophysiological tests, 179 hands in 113 patients were classified into mild, moderate and severe degrees of CTS. Of these, the 41 hands with severe CTS were referred for surgery. The 58 hands with moderate CTS and 80 hands with mild CTS received conservative treatment. The improvement ratios in the severe group were greater than that in the moderate and mild groups, both at 6 months and at 1 year. Eighteen hands with moderate or mild CTS returned to normal electrophysiology with the conservative treatments. No patient recovered to normal electrophysiology in the severe group. This electrophysiological classification is objective and it may serve as a useful guide for non-surgical and surgical treatment of CTS.
Combined Medical – Surgical Management of Cervical Ectopic Pregnancy – A Case Report
Authors: Pathak Sangeeta , Khalil Haroona , Fastovets Galena , Greenwood Peter
Published: February 2008

Cervical pregnancy accounts for less than 1% of extrauterine gestations but is one of the most serious ectopic pregnancies associated with significant morbidity due to the potential of extensive haemorrhage, perforation of cervical canal, and devastating effects on future fertility. There are different medical and surgical management options for cervical ectopic pregnancy. In our case, we chose to give the patient a single dose of systemic intramuscular methotrexate+oral mifepristone with explanation of risks and benefits of chosen methods and discussion of alternate methods. She had successful evacuation of cervical pregnancy without much blood loss, followed by hysteroscopy.

We believe that there are not many cases reported of cervical ectopic pregnancy in UK and the management of cervical pregnancy is still a great challenge for the physicians. In this case, the unique feature was that we chose a stepwise successful combined medical and surgical approach to treat this ectopic pregnancy.
High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia
Authors: Loriaux Marc M. , Levine Ross L. , Tyner Jeffrey W. , Fröhling Stefan , Scholl Claudia , Stoffregen Eric P. , Wernig Gerlinde , Erickson Heidi , Eide Christopher A. , Berger Roland , Bernard Olivier A. , Griffin James D. , Stone Richard M. , Lee Benjamin , Meyerson Matthew , Heinrich Michael C. , Deininger Michael W. , Gilliland D. Gary , Druker Brian J.
Published: February 2008

To determine whether aberrantly activated tyrosine kinases other than FLT3 and c-KIT contribute to acute myeloid leukemia (AML) pathogenesis, we used high-throughput (HT) DNA sequence ana-lysis to screen exons encoding the activation loop and juxtamembrane domains of 85 tyrosine kinase genes in 188 AML patients without FLT3 or c-KIT mutations. The screen identified 30 nonsynonymous sequence variations in 22 different kinases not previously reported in single-nucleotide polymorphism (SNP) databases. These included a novel FLT3 activating allele and a previously described activating mutation in MET (METT1010I). The majority of novel sequence variants were stably expressed in factor-dependent Ba/F3 cells. Apart from one FLT3 allele, none of the novel variants showed constitutive phosphorylation by immunoblot analysis and none transformed Ba/F3 cells to factor-independent growth. These findings indicate the majority of these alleles are not potent tyrosine kinase activators in this cellular context and that a significant proportion of nonsynonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Although some sequence variants may represent SNPs, these data are consistent with recent reports that a significant fraction of such sequence variants are “passenger” rather than “driver” alleles and underscore the importance of functional assessment of candidate disease alleles.
Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival
Authors: Dayyani Farshid , Wang Jianfeng , Yeh Jing-Ruey J. , Ahn Eun-Young , Tobey Erica , Zhang Dong-Er , Bernstein Irwin D. , Peterson Randall T. , Sweetser David A.
Published: February 2008

Deletions on chromosome 9q are seen in a subset of acute myeloid leukemia (AML) cases and are specifically associated with t(8;21) AML. We previously defined the commonly deleted region in del(9q) AML and characterized the genes in this interval. To determine the critical lost gene(s) that might cooperate with the AML1-ETO fusion gene produced by t(8;21), we developed a set of shRNAs directed against each gene in this region. Within this library, shRNAs to TLE1 and TLE4 were the only shRNAs capable of rescuing AML1-ETO expressing U937T-A/E cells from AML1-ETO–induced cell-cycle arrest and apoptosis. Knockdown of TLE1 or TLE4 levels increased the rate of cell division of the AML1-ETO–expressing Kasumi-1 cell line, whereas forced expression of either TLE1 or TLE4 caused apoptosis and cell death. Knockdown of Gro3, a TLE homolog in zebrafish, cooperated with AML1-ETO to cause an accumulation of noncirculating hematopoietic blast cells. Our data are consistent with a model in which haploinsufficiency of these TLEs overcomes the negative survival and antiproliferative effects of AML1-ETO on myeloid progenitors, allowing preleukemic stem cells to expand into AML. This study is the first to implicate the TLEs as potential tumor suppressor genes in myeloid leukemia.
Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study
Authors: Bluhm Elizabeth C. , Ronckers Cécile , Hayashi Robert J. , Neglia Joseph P. , Mertens Ann C. , Stovall Marilyn , Meadows Anna T. , Mitby Pauline A. , Whitton John A. , Hammond Sue , Barker Joseph D. , Donaldson Sarah S. , Robison Leslie L. , Inskip Peter D.
Published: February 2008

Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. We assessed mortality and second malignant neoplasms (SMNs) among 1082 5-year survivors of non-Hodgkin lymphoma (NHL) in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of cancer survivors diagnosed from 1970 to 1986. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated using US population rates. Relative risks for death and solid tumor SMNs were calculated based on demographic, clinical, and treatment characteristics using Poisson regression models. There were 87 observed deaths (SMR = 4.2; 95% CI, 1.8-4.1) with elevated rates of death from solid tumors, leukemia, cardiac disease, and pneumonia. Risk for death remained elevated beyond 20 years after NHL. Risk factors for death from causes other than NHL included female sex (rate ratio [RR] = 3.4) and cardiac radiation therapy exposure (RR = 1.9). There were 27 solid tumor SMNs (SIR = 3.9; 95% CI, 2.6-5.7) with 3% cumulative incidence between 5 and 20 years after NHL diagnosis. Risk factors were female sex (RR = 3.1), mediastinal NHL disease (RR = 5.2), and breast irradiation (RR = 4.3). Survivors of childhood NHL, particularly those treated with chest RT, are at continued increased risk of early mortality and solid tumor SMNs.
New role for AML1/ETO in leukemogenesis
Authors: Carroll Martin
Published: February 2008

The AML1/ETO fusion protein induces DNA double-strand breaks, p53 expression, and a DNA damage response, suggesting a new role in AML pathogenesis.
PACAP: a new player in thrombopoiesis
Authors: Paola Jorge Di
Published: February 2008

Freson and colleagues have identified a role (see figure) for the megakaryocyte VPAC1 receptor and its 2 major agonists, PACAP and VIP, in the regulation of platelet production.
New entry for angiostatic cancer treatment
Authors: Griffioen Arjan W.
Published: February 2008

A member of the small heat shock protein family is found to regulate the formation of vasculature. A study by Dimberg and colleagues combines novel insights into the mechanisms of tumor angiogenesis with therapeutic opportunities for the treatment of cancer.
Duplicate gene evolution and expression in the wake of vertebrate allopolyploidization
Authors: Chain Frédéric JJ , Ilieva Dora , Evans Ben J
Published: February 2008

Background

The mechanism by which duplicate genes originate – whether by duplication of a whole genome or of a genomic segment – influences their genetic fates. To study events that trigger duplicate gene persistence after whole genome duplication in vertebrates, we have analyzed molecular evolution and expression of hundreds of persistent duplicate gene pairs in allopolyploid clawed frogs (XenopusandSilurana). We collected comparative data that allowed us to tease apart the molecular events that occurred soon after duplication from those that occurred later on. We also quantified expression profile divergence of hundreds of paralogs during development and in different tissues.

Results

Our analyses indicate that persistent duplicates generated by allopolyploidization are subjected to strong purifying selection soon after duplication. The level of purifying selection is relaxed compared to a singleton ortholog, but not significantly variable over a period spanning about 40 million years. Despite persistent functional constraints, however, analysis of paralogous expression profiles indicates that quantitative aspects of their expression diverged substantially during this period.

Conclusion

These results offer clues into how vertebrate transcriptomes are sculpted in the wake of whole genome duplication (WGD), such as those that occurred in our early ancestors. That functional constraints were relaxed relative to a singleton ortholog but not significantly different in the early compared to the later stage of duplicate gene evolution suggests that the timescale for a return to pre-duplication levels is drawn out over tens of millions of years – beyond the age of these tetraploid species. Quantitative expression divergence can occur soon after WGD and with a magnitude that is not correlated with the rate of protein sequence divergence. On a coarse scale, quantitative expression divergence appears to be more prevalent than spatial and temporal expression divergence, and also faster or more frequent than other processes that operate at the protein level, such as some types of neofunctionalization.
LcrG secretion is not required for blocking of Yops secretion in Yersinia pestis
Authors: Reina Laura D , O'Bryant Deanna M , Matson Jyl S , Nilles Matthew L
Published: February 2008

Background

LcrG, a negative regulator of the Yersinia type III secretion apparatus has been shown to be primarily a cytoplasmic protein, but is secreted at least in Y. pestis. LcrG secretion has not been functionally analyzed and the relevance of LcrG secretion on LcrG function is unknown.

Results

An LcrG-GAL4AD chimera, originally constructed for two-hybrid analyses to analyze LcrG protein interactions, appeared to be not secreted but the LcrG-GAL4AD chimera retained the ability to regulate Yops secretion. This result led to further investigation to determine the significance of LcrG secretion on LcrG function. Additional analyses including deletion and substitution mutations of amino acids 2–6 in the N-terminus of LcrG were constructed to analyze LcrG secretion and LcrG's ability to control secretion. Some changes to the N-terminus of LcrG were found to not affect LcrG's secretion or LcrG's secretion-controlling activity. However, substitution of poly-isoleucine in the N-terminus of LcrG did eliminate LcrG secretion but did not affect LcrG's secretion controlling activity.

Conclusion

These results indicate that secretion of LcrG, while observable and T3SS mediated, is not relevant for LcrG's ability to control secretion.
Inducing apoptosis of human colon cancer cells by an IGF-I D domain analogue peptide
Authors: Yang Shi Yu , Sales Kevin M , Fuller Barry J , Seifalian Alexander M , Winslet Marc C
Published: February 2008

Background

The resistance of tumour cells to apoptosis is a major contributor to the limited effectiveness of chemotherapies. Insulin-like growth factor I (IGF-I) has potential to protect cancer cells from variety of apoptotic challenges. This study was carried out to investigate the effect of a novel IGF-I receptor antagonist on apoptosis in colon cancer cells.

Results

We have designed and synthesised a novel antagonist of IGF-I receptor. The effect of this antagonist on human colon cancer cell proliferation was examined by a non-radioactive assay; the apoptosis was revealed by determining the activities of cellular caspases3/7, 8 and 9. The apoptosis pathways were investigated by examining the levels of pro-apoptosis proteins with Western blotting. Following 40 hours treatment with the novel antagonist peptide, colon cancer cell Caspase 3/7 activities increased 2–7 times; Caspase 8 activities increased 2–5 times and Caspase 9 increased 1.2–1.6 times. The proliferation of cancer cell was inhibited by 14–15%. The data showed that the antagonist induced colon cancer cell apoptosis and inhibited cancer cell proliferation. The different changes of Caspase 3/7, 8 and 9 activities suggested that the extrinsic pathways may play a major role in the antagonist peptide-induced apoptosis.

Conclusion

This is the first report on this novel antagonist to induce human colon cancer cell apoptosis and inhibit cancer cell proliferation. These results suggest that IGF-I receptor antagonists may have the potential to be developed as a novel therapy for colon cancers in the future.
Regression of sporadic intra-abdominal desmoid tumour following administration of non-steroidal anti-inflammatory drug
Authors: Tanaka Keita , Yoshikawa Reigetsu , Yanagi Hidenori , Gega Makoto , Fujiwara Yoshinori , Hashimoto-Tamaoki Tomoko , Hirota Syozo , Tsujimura Tohru , Tomita Naohiro
Published: February 2008

Background

Desmoid tumours or fibromatoses are rare entities characterized by the benign proliferation of fibroblasts, which can be life-threatening due to their locally aggressive properties. Surgery is widely accepted as the first line of treatment for extra-abdominal desmoids; however, it is not recommended for intra-abdominal desmoids because of the high-risk of recurrence and difficulties with the operation. Here, we report on a patient with sporadic intra-abdominal desmoid tumours, who showed partial response following the intake of non-steroidal anti-inflammatory drugs.

Case presentation

A 73-year-old man presented with swelling and pain of the right leg. Computed tomography showed an abnormal multilocular soft-tissue mass (95 × 70 mm) in the right pelvis, which was revealed by biopsy to be a desmoid tumour. Immunohistochemical analysis showed that the tumour cells expressed vimentin, but not smooth-muscle actin, CD34, or desmin. Very few Ki-67-positive cells were found. Non-cytotoxic treatment with etodolac (200 mg/day) was chosen because of the patient's age, lack of bowel obstruction, and the likelihood of prostate cancer. Two years after the commencement of non-steroidal anti-inflammatory drug administration, computed tomography showed a decrease in tumour size (63 × 49 mm), and the disappearance of intratumoural septa.

Conclusion

Our case report suggests that non-steroidal anti-inflammatory drug treatment should be taken into consideration for use as first-line treatment in patients with sporadic intra-abdominal desmoid tumours.
HIV-1 infection induces changes in expression of cellular splicing factors that regulate alternative viral splicing and virus production in macrophages
Authors: Dowling Dinushka , Nasr-Esfahani Somayeh , Tan Chun H , O'Brien Kate , Howard Jane L , Jans David A , Purcell Damian FJ , Stoltzfus C Martin , Sonza Secondo
Published: February 2008

Background

Macrophages are important targets and long-lived reservoirs of HIV-1, which are not cleared of infection by currently available treatments. In the primary monocyte-derived macrophage model of infection, replication is initially productive followed by a decline in virion output over ensuing weeks, coincident with a decrease in the levels of the essential viral transactivator protein Tat. We investigated two possible mechanisms in macrophages for regulation of viral replication, which appears to be primarily regulated at the level oftatmRNA: 1) differential mRNA stability, used by cells and some viruses for the rapid regulation of gene expression and 2) control of HIV-1 alternative splicing, which is essential for optimal viral replication.

Results

Following termination of transcription at increasing times after infection in macrophages, we found thattatmRNA did indeed decay more rapidly thanrevornefmRNA, but with similar kinetics throughout infection. In addition,tatmRNA decayed at least as rapidly in peripheral blood lymphocytes. Expression of cellular splicing factors in uninfected and infected macrophage cultures from the same donor showed an inverse pattern over time between enhancing factors (members of the SR family of RNA binding proteins) and inhibitory factors (members of the hnRNP family). While levels of the SR protein SC35 were greatly up-regulated in the first week or two after infection, hnRNPs of the A/B and H groups were down-regulated. Around the peak of virus production in each culture, SC35 expression declined to levels in uninfected cells or lower, while the hnRNPs increased to control levels or above. We also found evidence for increased cytoplasmic expression of SC35 following long-term infection.

Conclusion

While no evidence of differential regulation oftatmRNA decay was found in macrophages following HIV-1 infection, changes in the balance of cellular splicing factors which regulate alternative viral pre-mRNA splicing were observed. These changes correlated with changes in Tat expression and virus production and could play an important role in viral persistence in macrophages. This mechanism could provide a novel target for control of infection in this critical cell type, which would be necessary for eventual eradication of the virus from infected individuals.
What is the clinical and ethical importance of incidental abnormalities found by knee MRI?
Authors: Grainger Rebecca , Stuckey Stephen , O'Sullivan Richard , Davis Susan R , Ebeling Peter R , Wluka Anita E
Published: February 2008

Introduction

Magnetic resonance imaging (MRI) is increasingly used to examine joints for research purposes. It may detect both suspected and unsuspected abnormalities. This raises both clinical and ethical issues, especially when incidental abnormalities are detected. The prevalence of incidental, potentially clinically significant abnormalities identified by MRI and their clinical significance in a population undergoing knee MRI in research studies are unknown.

Methods

We examined the prevalence of such lesions in healthy asymptomatic adults and those with symptomatic knee osteoarthritis (OA) undergoing knee MRI with limited sequences for the purpose of research. The MRI findings in 601 asymptomatic subjects and 132 with knee OA who underwent at least one limited knee MRI scan for cartilage volume measurement were examined by an MRI radiologist for the presence of potentially clinically significant abnormalities.

Results

These were present in 2.3% of healthy and 2.3% of OA subjects. All required further investigation to exclude non-benign disease, including four with bone marrow expansion (0.7%), requiring further investigation and management. A single potentially life-threatening lesion, a myeloma lesion, was identified in a subject with symptomatic knee OA on their second MRI scan in a longitudinal study.

Conclusion

As musculoskeletal MRI is increasingly used clinically and for research purposes, the potential for detecting unsuspected abnormalities that require further investigation should be recognized. Incorporating a system to detect these, to characterize unexpected findings, and to facilitate appropriate medical follow-up when designing studies using this technology should be considered ethical research practice.
Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer
Authors: Wu Yanyuan , Mohamed Hezla , Chillar Ram , Ali Ishrat , Clayton Sheila , Slamon Dennis , Vadgama Jaydutt V
Published: February 2008

Introduction

Breast cancer patients with HER2/neu overexpression have poor outcomes with a decrease in disease-free survival (DFS) and overall survival. The biology of HER2/neu overexpression in breast tumors in African-American and Latina women is poorly understood. The purpose of this study is to understand the clinical significance of activated Akt (phospho-Akt or pAkt) expression in breast tumors from African-American and Latina patients with corresponding tissue HER2/neu overexpression. Cellular and molecular studies have shown that activation of the cell signaling phosphatidylinositol-3-kinase/Akt cascade via the HER2/neu and other receptor tyrosine kinases induces cell proliferation.

Methods

A total of 234 African-American and Latina patients were selected retrospectively. From this group, 141 tumor tissue samples were analyzed for tissue pAkt by immunohistochemistry (IHC). This cohort consisted of 46 HER2/neu-positive (3+ by IHC) and 95 HER2/neu-negative tumors. The prognostic value of activated tissue Akt in relation to HER2/neu overexpression for DFS was determined.

Results

Patients with low pAkt and HER2-negative tumors had the best DFS. As expected, HER2/neu-overexpressing tumors with low pAkt had a decrease in DFS. Similarly, those with high pAkt and HER2-negative tumors also had poor DFS. However, those with an increase in both HER2 and pAkt had the worst DFS. An increase in pAkt was significantly associated with HER2/neu-positive and lymph node-positive breast tumors. Tumors with high HER2 and high pAkt were metastatic. Multivariate analysis demonstrated that, in addition to the common risk factors such as larger tumor size, lymph node involvement, estrogen receptor/progesterone receptor-negative tumors, and HER2/neu-positive tumors, overexpression of pAkt significantly was associated with a decrease in 5-year DFS. A decrease in DFS with an increase in pAkt was observed in both HER2/neu-positive and -negative groups. However, the DFS was similar between HER2/neu-positive/pAkt-negative and HER2/neu-negative/pAkt-positive groups.

Conclusion

Our data suggest that there may be differences in tumor phenotypes within the HER2/neu-overexpressing breast cancer patients. The overexpression of pAkt may be a powerful prognostic marker for predicting DFS and overall survival of breast cancer patients.
Oral Contraceptives, Postmenopausal Hormones, and Risk of Asynchronous Bilateral Breast Cancer: The WECARE Study Group
Authors: Figueiredo Jane C. , Bernstein Leslie , Capanu Marinela , Malone Kathleen E. , Lynch Charles F. , Anton-Culver Hoda , Stovall Marilyn , Bertelsen Lisbeth , Haile Robert W. , Bernstein Jonine L.
Published: February 2008

Purpose

To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years.

Patients and Methods

The WECARE (Women's Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs.

Results

OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results.

Conclusion

This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.
Ovarian Steroids Stimulate Adenosine Triphosphate-Sensitive Potassium (KATP) Channel Subunit Gene Expression and Confer Responsiveness of the Gonadotropin-Releasing Hormone Pulse Generator to KATP Channel Modulation
Authors: Huang Wenyu , Acosta-Martínez Maricedes , Levine Jon E.
Published: February 2008

The ATP-sensitive potassium (KATP) channels couple intracellular metabolism to membrane potential. They are composed of Kir6.x and sulfonylurea receptor (SUR) subunits and are expressed in hypothalamic neurons that project to GnRH neurons. However, their roles in regulating GnRH secretion have not been determined. The present study first tested whether KATP channels regulate pulsatile GnRH secretion, as indirectly reflected by pulsatile LH secretion. Ovariectomized rats received sc capsules containing oil, 17β-estradiol (E2), progesterone (P), or E2+P at 24 h before blood sampling. Infusion of the KATP channel blocker tolbutamide into the third ventricle resulted in increased LH pulse frequency in animals treated with E2+P but was without effect in all other groups. Coinfusion of tulbutamide and the KATP channel opener diazoxide blocked this effect, whereas diazoxide alone suppressed LH. Effects of steroids on Kir6.2 and SUR1 mRNA expression were then evaluated. After 24hr treatment, E2+P produced a modest but significant increase in Kir6.2 expression in the preoptic area (POA), which was reversed by P receptor antagonism with RU486. Neither SUR1 in the POA nor both subunits in the mediobasal hypothalamus were altered by any steroid treatment. After 8 d treatment, Kir6.2 mRNA levels were again enhanced by E2+P but to a greater extent in the POA. Our findings demonstrate that 1) blockade of preoptic/hypothalamic KATP channels produces an acceleration of the GnRH pulse generator in a steroid-dependent manner and 2) E2+P stimulate Kir6.2 gene expression in the POA. These observations are consistent with the hypothesis that the negative feedback actions of ovarian steroids on the GnRH pulse generator are mediated, in part, by their ability to up-regulate KATP channel subunit expression in the POA.
Paralogous Vitamin D Receptors in Teleosts: Transition of Nuclear Receptor Function
Authors: Howarth Deanna L. , Law Sheran H. W. , Barnes Benjamin , Hall Julie M. , Hinton David E. , Moore Linda , Maglich Jodi M. , Moore John T. , Kullman Seth W.
Published: February 2008

The availability of multiple teleost (bony fish) genomes is providing unprecedented opportunities to understand the diversity and function of gene duplication events using comparative genomics. Here we describe the cloning and functional characterization of two novel vitamin D receptor (VDR) paralogs from the freshwater teleost medaka (Oryzias latipes). VDR sequences were identified through mining of the medaka genome database in which gene organization and structure was determined. Two distinct VDR genes were identified in the medaka genome and mapped to defined loci. Each VDR sequence exhibits unique intronic organization and dissimilar 5′ untranslated regions, suggesting they are not isoforms of the same gene locus. Phylogenetic comparison with additional teleosts and mammalian VDR sequences illustrate that two distinct clusters are formed separating aquatic and terrestrial species. Nested within the teleost cluster are two separate clades for VDRα and VDRβ. The topology of teleost VDR sequences is consistent with the notion of paralogous genes arising from a whole genome duplication event prior to teleost radiation. Functional characterization was conducted through the development of VDR expression vectors including Gal4 chimeras containing the yeast Gal4 DNA binding domain fused to the medaka VDR ligand binding domain and full-length protein. The common VDR ligand 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] resulted in significant transactivation activity with both the Gal4 and full-length constructs of medaka (m) VDRβ. Comparatively, transactivation of mVDRα with 1α,25(OH)2D3 was highly attenuated, suggesting a functional divergence between these two nuclear receptor paralogs. We additionally demonstrate through coactivator studies that mVDRα is still functional; however, it exhibits a different sensitivity to 1α,25(OH)2D3, compared with VDRβ. These results suggest that in mVDRα and VDRβ have undergone a functional divergence through a process of sub- and/or neofunctionalization of VDR nuclear receptor gene pairs.
Insulin-Like Growth Factor (IGF) Binding Protein-4 Is Both a Positive and Negative Regulator of IGF Activity in Vivo
Authors: Ning Yun , Schuller Alwin G. P. , Conover Cheryl A. , Pintar John E.
Published: February 2008

IGFs are required for normal prenatal and postnatal growth. Although actions of IGFs can be modulated by a family of IGF-binding proteins (IGFBPs) in vitro, these studies have identified a complicated pattern of stimulatory and inhibitory IGFBP effects, so that understanding relevant aspects of IGFBP action in vivo has been limited. Here we have produced a null mutation of one specific IGFBP, IGFBP-4, which is coexpressed with IGF-II early in development. Surprisingly, mutation of IGFBP-4, believed from in vitro studies to be exclusively inhibitory, leads to a prenatal growth deficit that is apparent from the time that the IGF-II growth deficit first arises, which strongly suggests that IGFBP-4 is required for optimal IGF-II-promoted growth during fetal development. Mice encoding a mutant IGFBP-4 protease (pregnancy-associated plasma protein-A), which facilitates IGF-II release from an inactive IGF-II/IGFBP-4 complex in vitro, are even smaller than IGFBP-4 mutant mice. However, the more modest IGFBP-4 growth deficit is completely restored in double IGFBP-4/pregnancy-associated plasma protein-A-deficient mice. Taken together these results indicate not only that IGFBP-4 functions as a local reservoir to optimize IGF-II actions needed for normal embryogenesis, but also establish that IGFBP-4 proteolysis is required to activate most, if not all, IGF-II mediated growth-promoting activity.
Preemptive Public Policy for Genomics
Authors: Carlson Rick J.
Published: February 2008

To many, genomics is merely exploitable technology for the leviathan of biotechnology. This is both shallow and short sighted. Genomics is applied knowledge based on profound and evolving science about how living things develop, how healthy or sick we are, and what our future will be like. In health care, genomics technologies are disruptive yet potentially cost-effective because they enable primary prevention, the antidote to runaway costs and declining productivity. The challenges to integration are great, however, and many bioethical and social-policy implications are alarming. Because it is poorly understood today, we must debate genomics vigorously if we are to act wisely. Public policy must lead.
A Temporal Analytical Approach to Decentralization: Lessons from Brazil's Health Sector
Authors: Gómez Eduardo J.
Published: February 2008

This article introduces a new concept to the study of decentralization processes: policy dynamism. At its core is the notion that the sequential and temporal process of health decentralization affect the nature of intergovernmental relationships and municipal bureaucratic capacity. Examining the case of Brazil, I argue that the rush to decentralize health services to municipalities has, in the absence of sufficient financial and technical assistance from the federal and state governments, increased state-municipal conflict over the management of health policy, limiting municipalities' ability to increase bureaucratic capacity. Consequently, some states have attempted to recentralize reforms, generating further conflict between both subnational levels of government. While some municipalities have tried to overcome these problems by creating associations and working with international organizations, several bureaucratic obstacles remain. This article attributes these outcomes not to federal institutions and economic constraints (the traditional approach in the literature) but rather to the noninstitutional, temporal policy dynamics of decentralization.
Prudence and Experience: Ambassadors and Political Culture in Early Modern Italy
Authors: Frigo Daniela
Published: February 2008

Translated by John Watkins

University of Minnesota, Minneapolis, Minnesota
Identification and characterization of subpopulations in undifferentiated ES cell culture
Authors: Toyooka Yayoi , Shimosato Daisuke , Murakami Kazuhiro , Takahashi Kadue , Niwa Hitoshi
Published: February 2008

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass (ICM) and the epiblast, and have been suggested to be a homogeneous population with characteristics intermediate between them. These cells express Oct3/4 and Rex1 genes, which have been used as markers to indicate the undifferentiated state of ES cells. Whereas Oct3/4 is expressed in totipotent and pluripotent cells in the mouse life cycle, Rex1 expression is restricted to the ICM, and is downregulated in pluripotent cell populations in the later stages, i.e. the epiblast and primitive ectoderm (PrE). To address whether ES cells comprise a homogeneous population equivalent to a certain developmental stage of pluripotent cells or a heterogeneous population composed of cells corresponding to various stages of differentiation, we established knock-in ES cell lines in which genes for fluorescent proteins were inserted into the Rex1 and Oct3/4gene loci to visualize the expression of these genes. We found that undifferentiated ES cells included at least two different populations, Rex1+/Oct3/4+ cells and Rex1-/Oct3/4+ cells. The Rex1-/Oct3/4+ and Rex1+/Oct3/4+ populations could convert into each other in the presence of LIF. In accordance with our assumption that Rex1+/Oct3/4+ cells and Rex1-/Oct3/4+ cells have characteristics similar to those of ICM and early-PrE cells, Rex1+/Oct3/4+ cells predominantly differentiated into primitive ectoderm and contributed to chimera formation,whereas Rex1-/Oct3/4+ cells differentiated into cells of the somatic lineage more efficiently than non-fractionated ES cells in vitro and showed poor ability to contribute to chimera formation. These results confirmed that undifferentiated ES cell culture contains subpopulations corresponding to ICM, epiblast and PrE.
Reduction of Indium(III) Oxide to Indium through Mechanochemical Route
Authors: Kano Junya , Kobayashi Eiko , Tongamp William , Saito Fumio
Published: February 2008

A nonthermal reduction of indium(III) oxide (In2O3) to metallic indium (In) was achieved through mechanochemical route in this work. A mixture of In2O3 and lithium nitride (Li3N) under ammonia (NH3) and/or nitrogen (N2) gas environments was milled in a planetary ball mill with uni-size ZrO2 balls to induce mechanochemical reaction between the starting materials. Metallic indium was obtained after milling for 120 min, and the results are confirmed by X-ray diffraction (XRD) analysis. Washing of the milled product with water to remove by-products using the planetary ball mill for a further 10 min resulted in formation of pellets which were analyzed by EPMA, results clearly show that high purity indium metal was obtained.
Long-Term Cognitive Effects of Music as Loud Noise
Authors: Yule Valerie
Published: February 2008

Many of the effects of very loud music are now known, but not the long-term cognitive effects. This is an important question, since loud music is now ubiquitous. Investigation is called for, including the collation of research that is currently hard to find. Two hundred teenagers aged 12–19 completed a questionnaire on ‘Very Loud Music’ and their responses are discussed.
RANKL Inhibition with Osteoprotegerin Increases Bone Strength by Improving Cortical and Trabecular bone Architecture in Ovariectomized Rats
Authors: Ominsky Michael S , Li Xiaodong , Asuncion Frank J , Barrero Mauricio , Warmington Kelly S , Dwyer Denise , Stolina Marina , Geng Zhaopo , Grisanti Mario , Tan Hong-Lin , Corbin Timothy , McCabe James , Simonet William S , Ke Hua Z , Kostenuik Paul J
Published: February 2008

Introduction: Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats.

Materials and Methods: Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L1–L5) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L5) were analyzed by μCT and biomechanical testing, and L6 was analyzed for ash weight.

Results: OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. μCT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p < 0.05 versus OVX-Veh). OPG improved cortical area in L5 and the femur neck to levels that were significantly greater than OVX or sham controls (p < 0.05). Biomechanical testing of L5 and femur necks showed significantly greater maximum load values in the OVX-OPG group (p < 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r2 = 0.54–0.74, p < 0.0001), which was also significantly increased by OPG (p < 0.05 versus OVX).

Conclusions: OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats.
Osteoblast-Derived TGF-β1 Stimulates IL-8 Release Through AP-1 and NF-κB in Human Cancer Cells
Authors: Fong Yi-Chin , Maa Ming-Chei , Tsai Fuu-Jen , Chen Wen-Chi , Lin Jaung-Geng , Jeng Long-Bin , Yang Rong-Sen , Fu Wen-Mei , Tang Chih-Hsin
Published: February 2008

Introduction: The bone marrow microenvironment is further enriched by growth factors released during osteoclastic bone resorption. It has been reported that the chemokine interleukin (IL)-8 is a potent and direct activator of osteoclastic differentiation and bone resorption. However, the effect of bone-derived growth factors on the IL-8 production in human cancer cells and the promotion of osteoclastogenesis are largely unknown. The aim of this study was to investigate whether osteoblast-derived TGF-β1 is associated with osteolytic bone diseases.

Materials and Methods: IL-8 mRNA levels were measured using RT-PCR analysis. MAPK phosphorylation was examined using the Western blot method. siRNA was used to inhibit the expression of TGF-β1, BMP-2, and IGF-1. DNA affinity protein-binding assay and chromatin immunoprecipitation assays were used to study in vitro and in vivo binding of c-fos, c-jun, p65, and p50 to the IL-8 promoter. A transient transfection protocol was used to examine IL-8, NF-κB, and activator protein (AP)-1 activity.

Results: Osteoblast conditioned medium (OBCM) induced activation of IL-8, AP-1, and NF-κB promoter in human cancer cells. Osteoblasts were transfected with TGF-β1, BMP-2, or IGF-1 small interfering RNA, and the medium was collected after 48 h. TGF-β1 but not BMP-2 or IGF-1 siRNA inhibited OBCM-induced IL-8 release in human cancer cells. In addition, TGF-β1 also directly induced IL-8 release in human cancer cells. Activation of AP-1 and NF-κB DNA-protein binding and MAPKs after TGF-β1 treatment was shown, and TGF-β1–induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades.

Conclusions: In this study, we provide evidence to show that the osteoblasts release growth factors, including TGF-β1, BMP-2, and IGF-1. TGF-β1 is the major contributor to the activation of extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), leading to the activation of AP-1 and NF-κB on the IL-8 promoter and initiation of IL-8 mRNA and protein release, thereby promoting osteoclastogenesis.
ALK1 Opposes ALK5/Smad3 Signaling and Expression of Extracellular Matrix Components in Human Chondrocytes
Authors: Finnson Kenneth W , Parker Wendy L , ten Dijke Peter , Thorikay Midory , Philip Anie
Published: February 2008

Introduction: TGF-β is a multifunctional regulator of chondrocyte proliferation, differentiation, and extracellular matrix production. Dysregulation of TGF-β action has been implicated in cartilage diseases such as osteoarthritis. TGF-β signaling is transduced through a pair of transmembrane serine/threonine kinases, known as the type I (ALK5) and type II receptors. However, recent studies on endothelial cells have identified ALK1 as a second type I TGF-β receptor and have shown that ALK1 and ALK5 have opposing functions in these cells. Here we examined ALK1 expression and its regulation of TGF-β signaling and responses in human chondrocytes.

Materials and Methods: ALK1 expression in human chondrocytes was examined by RT-PCR and Western blot. The ability of ALK1 to form complexes with other TGF-β receptors was determined by affinity labeling/immunoprecipitation and by immunoprecipitation followed by Western blot. The effect of ALK1 on TGF-β1–induced signaling and responses was determined by varying ALK1 expression levels and measuring transcriptional activity using promoter/luciferase assays, Smad1/5 and Smad3 phosphorylation, and expression of type II collagen, PAI-1, and fibronectin.

Results: Our results indicate that ALK1 is expressed in human chondrocytes and that it is a component of the TGF-β receptor system, associating with ALK5, type II TGF-β receptor, endoglin, and betaglycan. Furthermore, we show that both ALK1 and ALK5 are needed for TGF-β–induced phosphorylation of intracellular mediators Smad1/5, whereas only ALK5 is essential for TGF-β1–induced phosphorylation of Smad3. In addition, our results show that ALK1 inhibits, whereas ALK5 potentiates, TGF-β–induced Smad3-driven transcriptional activity and the expression of PAI-1, fibronectin, and type II collagen in chondrocytes.

Conclusions: Our results suggest that ALK1 and ALK5 display opposing functions in human chondrocytes, implicating an essential role for ALK1 in the regulation of TGF-β signaling and function in these cells.