bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambivalent or indifferent? Reconsidering the structure of EU public opinion
Authors: Stoeckel Florian
Published: November 2012

In the US context, research on ambivalence has established that individuals often simultaneously possess positive and negative considerations on a political object. Yet little is known about ambivalence in support for European integration. This article proposes a measure that distinguishes ambivalence from indifference in attitudes towards the European Union (EU). Using data from Eurobarometer wave 63.4 and the Chapel Hill expert survey I find that the causal logics of ambivalence and indifference are sharply different. Multinomial regression analysis reveals that levels of ambivalence towards the EU increase with political sophistication. Also, citizens are more ambivalent, less indifferent, and less positive about the EU when elite division on European integration is more pronounced. Finally, trust in EU institutions and attachment to Europe decrease indifference and ambivalence about the EU.
Volitional pursed lips breathing in patients with stable chronic obstructive pulmonary disease improves exercise capacity
Authors: Bhatt Surya P. , Luqman-Arafath T.K. , Gupta Arun K. , Mohan Anant , Stoltzfus Jill C. , Dey Tanujit , Nanda Sudip , Guleria Randeep
Published: November 2012

Pursed lips breathing (PLB) is used by a proportion of patients with chronic obstructive pulmonary disease (COPD) to alleviate dyspnea. It is also commonly used in pulmonary rehabilitation. Data to support its use in patients who do not spontaneously adopt PLB are limited. We performed this study to assess the acute effects of PLB on exercise capacity in nonspontaneously PLB patients with stable COPD. We performed a randomized crossover study comparing 6-min walk test (6MWT) at baseline without PLB with 6WMT using volitional PLB. Spirometry, maximal inspiratory and expiratory mouth pressures, and diaphragmatic excursion during tidal and vital capacity breathing using B-mode ultrasonography were measured at baseline and after 10 min of PLB. A Visual Analog Scale (VAS) assessed subjective breathlessness at rest, after 6MWT and after 6MWT with PLB. p ≤ 0.01 was considered significant. Mean ± SD age of patients was 53.1 ± 7.4 years. Forced expiratory volume in 1second was 1.1 ± 0.4 L/min (38.4 ± 13.2% predicted). Compared with spontaneous breathing, all but one patient with PLB showed a significant increment in 6MW distance (+34.9 ± 26.4 m; p = 0.002). There was a significant reduction in respiratory rate post 6MWT with PLB compared with spontaneous breathing (−4.4 ± 2.8 per minute; p = 0.003). There was no difference in VAS scores. There was a significant correlation between improvement in 6MWT distance and increase in diaphragmatic excursion during forced breathing. The improvement was greater in patients who had poorer baseline exercise performance. PLB has an acute benefit on exercise capacity. Sustained PLB or short bursts of PLB may improve exercise capacity in stable COPD.
Factors associated with early adherence to tiotropium in chronic obstructive pulmonary disease
Authors: Laforest Laurent , Licaj Idlir , Devouassoux Gilles , Hartwig Susanne , Marvalin Serge , Van Ganse Eric
Published: November 2012

Tiotropium is an innovative intervention in chronic obstructive pulmonary disease (COPD). Early adherence to tiotropium remains inadequately explored, notably time from initiation to discontinuation (persistence). In patients with COPD, the factors associated with the risk of discontinuing the treatment with tiotropium within 12 months following initiation were identified (12-month persistence). Claim databases from the French Social Security were used. A random sample of patients (aged 50–80 years) who initiated tiotropium soon after launch was selected. Factors associated with the persistence were investigated (Log-rank test and multivariate Cox model). Of the 1147 newly treated patients (mean age 68 years, 33% women), 64% remained in the treatment of tiotropium for over a period of 12 months following initiation. More than 10% of the patients interrupted therapy after a single dispensing, most often those with mild COPD. Lower risks of discontinuing tiotropium within 12 months following initiation were observed when it was initiated by a private sector specialist (hazard ratio (HR) = 0.65, 95% confidence interval (CI) = (0.52–0.82)), by hospital-based physician (HR = 0.58, 95% CI =  (0.42–0.78)), when ≥ 2 other respiratory drugs were associated (HR = 0.74, 95% CI = (0.58–0.95)) and in case of long-term disease status (HR = 0.78, 95% CI = (0.63–0.97)). Conversely, no clear effect appeared according to age or gender. In this population of patients with COPD, fewer early discontinuations of tiotropium were observed in patients having a severe condition.
Preliminary Experience With Option Inferior Vena Cava Filter
Authors: Iqbal Shams I. , Elmi Azadeh , Hedgire Sandeep , Yeddula Kalpana , Ganguli Suvranu , Walker T. Gregory , Salazar Gloria M. , Wicky Stephan , Kalva Sanjeeva P.
Published: November 2012

Objectives:

To evaluate the safety and efficacy of Option inferior vena cava (IVC) filter during placement and short-term follow-up.

Methods:

A total of 165 patients (mean age: 60-years) who received Option IVC filter from June 2009 to July 2011 were included. In all, 42 patients presented with deep vein thrombosis (DVT), 26 with pulmonary embolism (PE), and 17 with both. All outcomes were examined until April 30, 2012.

Results:

The filters were successfully deployed in 161patients. During follow-up (mean, 9.5 ± 0.68months), 10 patients were diagnosed with post-filter PE and 13 patients with DVT. There were no instances of fatal PE. Follow-up abdominal computed tomography was available in 60 patients and demonstrated filter-related problems in 8 patients (2: penetration of filter legs, 5:  asymptomatic nonocclusive thrombus, and 1: caval occlusion). There were no instances of filter migration or fracture. In total, 27 filters were successfully retrieved after a mean of 5.27 ± 0.76 months.

Conclusion:

The Option filter was effective and safe during implantation and short-term follow-up and associated with high technical success at retrieval.
Validating Measures of Leader Authenticity
Authors: Randolph-Seng Brandon , Gardner William L.
Published: November 2012

Using a student sample in a lab setting, we examined the relationships between explicit and implicit self-esteem and two measures of leader authenticity: self-reported authentic leadership as measured by the Authentic Leadership Questionnaire (ALQ) and perceived leader authenticity as reflected in leadership speeches. In addition, we explored the influence of situational cues for an internal versus external focus on measures of leadership authenticity. Explicit and implicit self-esteem related to authentic leadership in predicted directions, but not perceived leader authenticity. ALQ scores were also positively related to perceived leader authenticity and were significantly affected by the situational cues. Results provide support for the construct validity of the ALQ, while also showing that ALQ scores can be influenced by situational cues promoting an internal versus external focus.
He’s a Real Man
Authors: Shih Grace , Dubé Kate , Sheinbein Miriam , Borrero Sonya , Dehlendorf Christine
Published: November 2012

Vasectomy has advantages with respect to safety and cost when compared with female sterilization. The reasons underlying the overall low use of vasectomy, particularly among Black and Latinos, have not been adequately explored. The goals of this study were to (a) explore the social context of vasectomy decisions and (b) generate hypotheses about the social factors contributing to differences in vasectomy use by race/ethnicity. Fourteen group and nine couples interviews were conducted. Participants were 37 heterosexual couples aged 25 to 55 years who had reached their desired family size and self-identified as Black, Latino, or White. Participants discussed reasons that men and women would or would not select male sterilization. Reasons to select vasectomy included a desire to care for their current family, sharing contraceptive responsibility, and infidelity. Reasons not to select vasectomy included negative associations with the term sterilization, loss of manhood, and permanence. Misconceptions about vasectomy included misunderstandings about the vasectomy procedure and adverse postvasectomy sexual function. In addition, Black and Latino participants cited perceived ease of reversibility of female sterilization and lack of support around vasectomy as reasons not to choose it. Improving communication and social support for vasectomy, particularly among Black and Latino communities, may improve vasectomy utilization. Misconceptions regarding female and male sterilization should be targeted in counseling sessions to ensure men, women, and couples are making informed contraceptive decisions.
Comparative mapping in intraspecific populations uncovers a high degree of macrosynteny between A- and B-genome diploid species of peanut
Authors: Guo Yufang , Khanal Sameer , Tang Shunxue , Bowers John E , Heesacker Adam F , Khalilian Nelly , Nagy Ervin D , Zhang Dong , Taylor Christopher A , Stalker H Thomas , Ozias-Akins Peggy , Knapp Steven J
Published: November 2012

Background

Cultivated peanut or groundnut (Arachis hypogaeaL.) is an important oilseed crop with an allotetraploid genome (AABB, 2n = 4x = 40). Both the low level of genetic variation within the cultivated gene pool and its polyploid nature limit the utilization of molecular markers to explore genome structure and facilitate genetic improvement. Nevertheless, a wealth of genetic diversity exists in diploidArachisspecies (2n = 2x = 20), which represent a valuable gene pool for cultivated peanut improvement. Interspecific populations have been used widely for genetic mapping in diploid species ofArachis. However, an intraspecific mapping strategy was essential to detect chromosomal rearrangements among species that could be obscured by mapping in interspecific populations. To develop intraspecific reference linkage maps and gain insights into karyotypic evolution within the genus, we comparatively mapped the A- and B-genome diploid species using intraspecific F2populations. Exploring genome organization among diploid peanut species by comparative mapping will enhance our understanding of the cultivated tetraploid peanut genome. Moreover, new sources of molecular markers that are highly transferable between species and developed from expressed genes will be required to construct saturated genetic maps for peanut.

Results

A total of 2,138 EST-SSR (expressed sequence tag-simple sequence repeat) markers were developed by mining a tetraploid peanut EST assembly including 101,132 unigenes (37,916 contigs and 63,216 singletons) derived from 70,771 long-read (Sanger) and 270,957 short-read (454) sequences. A set of 97 SSR markers were also developed by mining 9,517 genomic survey sequences ofArachis. An SSR-based intraspecific linkage map was constructed using an F2population derived from a cross between K 9484 (PI 298639) and GKBSPSc 30081 (PI 468327) in the B-genome speciesA.batizocoi. A high degree of macrosynteny was observed when comparing the homoeologous linkage groups between A (A.duranensis) and B (A.batizocoi) genomes. Comparison of the A- and B-genome genetic linkage maps also showed a total of five inversions and one major reciprocal translocation between two pairs of chromosomes under our current mapping resolution.

Conclusions

Our findings will contribute to understanding tetraploid peanut genome origin and evolution and eventually promote its genetic improvement. The newly developed EST-SSR markers will enrich current molecular marker resources in peanut.
A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death
Authors: Teirlinck Carolien H , Senni Faïza , Malti Rajae El , Majoor-Krakauer Danielle , Fellmann Florence , Millat Gilles , André-Fouët Xavier , Pernot François , Stumpf Michaël , Boutarin Jean , Bouvagnet Patrice
Published: November 2012

Background

Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation.

Methods

HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test.

Results

Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.

We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups.

Conclusion

A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations.
Effects of cardiovascular exercise early after stroke: systematic review and meta-analysis
Authors: Stoller Oliver , de Bruin Eling D , Knols Ruud H , Hunt Kenneth J
Published: November 2012

Background

Previous studies have shown the beneficial effects of aerobic exercise in chronic stroke. Most motor and functional recovery occurs in the first months after stroke. Improving cardiovascular capacity may have potential to precipitate recovery during early stroke rehabilitation. Currently, little is known about the effects of early cardiovascular exercise in stroke survivors. The aim of this systematic review was to evaluate the effectiveness of cardiovascular exercise early after stroke.

Methods

A systematic literature search was performed. For this review, randomized and non-randomized prospective controlled cohort studies using a cardiovascular, cardiopulmonary or aerobic training intervention starting within 6 months post stroke were considered. The PEDro scale was used to detect risk of bias in individual studies. Inter-rater agreement was calculated (kappa). Meta-analysis was performed using a random-effects model.

Results

A total of 11 trials were identified for inclusion. Inter-rater agreement was considered to be “very good” (Kappa: 0.81, Standard Error: 0.06, CI95%: 0.70–0.92), and the methodological quality was “good” (7 studies) to “fair” (4 studies). Peak oxygen uptake data were available for 155 participants. Pooled analysis yielded homogenous effects favouring the intervention group (standardised mean difference (SMD) = 0.83, CI95% = 0.50–1.16, Z = 4.93, P < 0.01). Walking endurance assessed with the 6 Minute Walk Test comprised 278 participants. Pooled analysis revealed homogenous effects favouring the cardiovascular training intervention group (SMD = 0.69, CI95% = 0.45–0.94, Z = 5.58, P < 0.01). Gait speed, measured in 243 participants, did not show significant results (SMD = 0.51, CI95% = −0.25–1.26, Z = 1.31, P = 0.19) in favour of early cardiovascular exercise.

Conclusion

This meta-analysis shows that stroke survivors may benefit from cardiovascular exercise during sub-acute stages to improve peak oxygen uptake and walking distance. Thus, cardiovascular exercise should be considered in sub-acute stroke rehabilitation. However, concepts to influence and evaluate aerobic capacity in severely affected individuals with sub-acute stroke, as well as in the very early period after stroke, are lacking.

Further research is needed to develop appropriate methods for cardiovascular rehabilitation early after stroke and to evaluate long-term effects of cardiovascular exercise on aerobic capacity, physical functioning, and quality-of-life.
Evaluating patient values and preferences for thromboprophylaxis decision making during pregnancy: a study protocol
Authors: Alonso-Coello Pablo , Ebrahim Shanil , Guyatt Gordon H , Tikkinen Kari AO , Eckman Mark H , Neumann Ignacio , McDonald Sarah D , Akl Elie A , Bates Shannon M
Published: November 2012

Background

Pregnant women with prior venous thromboembolism (VTE) are at risk of recurrence. Low molecular weight heparin (LWMH) reduces the risk of pregnancy-related VTE. LMWH prophylaxis is, however, inconvenient, uncomfortable, costly, medicalizes pregnancy, and may be associated with increased risks of obstetrical bleeding. Further, there is uncertainty in the estimates of both the baseline risk of pregnancy-related recurrent VTE and the effects of antepartum LMWH prophylaxis. The values and treatment preferences of pregnant women, crucial when making recommendations for prophylaxis, are currently unknown. The objective of this study is to address this gap in knowledge.

Methods

We will perform a multi-center cross-sectional interview study in Canada, USA, Norway and Finland. The study population will consist of 100 women with a history of lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and who are either pregnant, planning pregnancy, or may in the future consider pregnancy (women between 18 and 45 years). We will exclude individuals who are on full dose anticoagulation or thromboprophylaxis, who have undergone surgical sterilization, or whose partners have undergone vasectomy. We will determine each participant's willingness to receive LMWH prophylaxis during pregnancy through direct choice exercises based on real life and hypothetical scenarios, preference-elicitation using a visual analog scale (“feeling thermometer”), and a probability trade-off exercise. The primary outcome will be the minimum reduction (threshold) in VTE risk at which women change from declining to accepting LMWH prophylaxis. We will explore possible determinants of this choice, including educational attainment, the characteristics of the women’s prior VTE, and prior experience with LMWH. We will determine the utilities that women place on the burden of LMWH prophylaxis, pregnancy-related DVT, pregnancy-related PE and pregnancy-related hemorrhage. We will generate a “personalized decision analysis” using participants’ utilities and their personalized risk of recurrent VTE as inputs to a decision analytic model. We will compare the personalized decision analysis to the participant’s stated choice.

Discussion

The preferences of pregnant women at risk of VTE with respect to the use of antithrombotic therapy remain unexplored. This research will provide explicit, quantitative expressions of women's valuations of health states related to recurrent VTE and its prevention with LMWH. This information will be crucial for both guideline developers and for clinicians.
Treatment actions and treatment failure: case studies in the response to severe childhood febrile illness in Mali
Authors: Ellis Amy A , Traore Sidy , Doumbia Seydou , Dalglish Sarah L , Winch Peter J
Published: November 2012

Background

Appropriate home management of illness is vital to efforts to control malaria. The strategy of home management relies on caregivers to recognize malaria symptoms, assess severity and promptly seek appropriate care at a health facility if necessary. This paper examines the management of severe febrile illness (presumed malaria) among children under the age of five in rural Koulikoro Region, Mali.

Methods

This research examines in-depth case studies of twenty-five households in which a child recently experienced a severe febrile illness, as well as key informant interviews and focus group discussions with community members. These techniques were used to explore the sequence of treatment steps taken during a severe illness episode and the context in which decisions were made pertaining to pursing treatments and sources of care, while incorporating the perspective and input of the mother as well as the larger household.

Results

Eighty-one participants were recruited in 25 households meeting inclusion criteria. Children's illness episodes involved multiple treatment steps, with an average of 4.4 treatment steps per episode (range: 2–10). For 76% of children, treatment began in the home, but 80% were treated outside the home as a second recourse. Most families used both traditional and modern treatments, administered either inside the home by family members, or by traditional or modern healers. Participants’ stated preference was for modern care, despite high rates of reported treatment failure (52%, n=12), however, traditional treatments were also often deemed appropriate and effective. The most commonly cited barrier to seeking care at health facilities was cost, especially during the rainy season. Financial constraints often led families to use traditional treatments.

Conclusions

Households have few options available to them in moments of overlapping health and economic crises. Public health research and policy should focus on the reducing barriers that inhibit poor households from promptly seeking appropriate health care. Enhancing the quality of care provided at community health facilities and supporting mechanisms by which treatment failures are quickly identified and addressed can contribute to reducing subsequent treatment delays and avoid inappropriate recourse to traditional treatments.
Stochastic amplitude-modulated stretching of rabbit flexor digitorum profundus tendons reduces stiffness compared to cyclic loading but does not affect tenocyte metabolism
Authors: Steiner Thomas H , Bürki Alexander , Ferguson Stephen J , Gantenbein-Ritter Benjamin
Published: November 2012

Background

It has been demonstrated that frequency modulation of loading influences cellular response and metabolism in 3D tissues such as cartilage, bone and intervertebral disc. However, the mechano-sensitivity of cells in linear tissues such as tendons or ligaments might be more sensitive to changes in strain amplitude than frequency. Here, we hypothesized that tenocytes in situ are mechano-responsive to random amplitude modulation of strain.

Methods

We compared stochastic amplitude-modulated versus sinusoidal cyclic stretching. Rabbit tendon were kept in tissue-culture medium for twelve days and were loaded for 1h/day for six of the total twelve culture days. The tendons were randomly subjected to one of three different loading regimes: i) stochastic (2 – 7% random strain amplitudes), ii) cyclic_RMS (2–4.42% strain) and iii) cyclic_high (2 - 7% strain), all at 1 Hz and for 3,600 cycles, and one unloaded control.

Results

At the end of the culture period, the stiffness of the “stochastic” group was significantly lower than that of the cyclic_RMS and cyclic_high groups (both, p < 0.0001). Gene expression of eleven anabolic, catabolic and inflammatory genes revealed no significant differences between the loading groups.

Conclusions

We conclude that, despite an equivalent metabolic response, stochastically stretched tendons suffer most likely from increased mechanical microdamage, relative to cyclically loaded ones, which is relevant for tendon regeneration therapies in clinical practice.
Human conditions of insulin-like growth factor-I (IGF-I) deficiency
Authors: Puche Juan E , Castilla-Cortázar Inma
Published: November 2012

Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions).

IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction.

The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.
O6-methylguanine-DNA methyltransferase in equine sarcoids: molecular and epigenetic analysis
Authors: Altamura Gennaro , Strazzullo Maria , Corteggio Annunziata , Francioso Romina , Roperto Franco , D'Esposito Maurizio , Borzacchiello Giuseppe
Published: November 2012

Background

Bovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species. In fact, BPVs 1/2 induce neoplasia in their natural bovine host but infection is also associated to neoplastic skin lesions in equids termed sarcoids. The equine sarcoid is considered to be the most common equine cutaneous tumour worldwide for which no effective therapy is available. Very little is known about the molecular mechanisms underlying tumourigenesis, although genes contributing to sarcoid development have been identified. Several studies associate the development of cancer to the loss of function of a number of oncosuppressor genes. In this study the putative role of O6-methylguanine-DNA methyltrasferase (MGMT) was investigated for sarcoids. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissues. In addition, the DNA methylation profile was analysed to assess the role of epigenetic mechanism in regulation of MGMT expression.

Results

A group of 15 equine sarcoids and two primary sarcoid cell lines (fibroblasts) were analyzed for the expression of MGMT protein by immunohistochemistry, immunofluorescence and Western blotting techniques. The sarcoid cell line EqSO4b and the tumour samples showed a reduction or absence of MGMT expression. To investigate the causes of deregulated MGMT expression, ten samples were analyzed for the DNA methylation profile of the CpG island associated to the MGMT promoter. The analysis of 73 CpGs encompassing the region of interest showed in 1 out of 10 (10%) sarcoids a pronouncedly altered methylation profile when compared to the control epidermal sample. Similarily the EqSO4b cell line showed an altered MGMT methylation pattern in comparison to normal fibroblasts.

Conclusion

As previously demonstrated for the oncosuppressor gene FHIT, analysis of MGMT expression in sarcoid tissues and a sarcoid-derived fibroblast cell line further suggests that oncosuppressor silencing may be also involved in BPV-induced equine tumours. Abnormal DNA methylation seems to be one of the possible molecular mechanisms involved in the alteration of MGMT expression. Further studies are required to address other basic molecular mechanisms involved in reduced MGMT expression. This study underlines the possible role of DNA methylation in oncosuppressor inactivation in equine sarcoids.
RETRACTED ARTICLE: Loss of pigment epithelium-derived factor: a novel mechanism for the development of endocrine resistance in breast cancer
Authors: Jan Rifat , Huang Min , Lewis-Wambi Joan
Published: November 2012

Introduction

Despite the benefits of endocrine therapies such as tamoxifen and aromatase inhibitors in treating estrogen receptor (ER) alpha-positive breast cancer, many tumors eventually become resistant. The molecular mechanisms governing resistance remain largely unknown. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Recent studies indicate that PEDF expression is significantly reduced in several tumor types, including breast cancer, and that its reduction is associated with disease progression and poor patient outcome. In the current study, we investigated the role of PEDF in the development of endocrine resistance in breast cancer.

Methods

PEDF mRNA and protein levels were measured in several endocrine-resistant breast cancer cell lines including MCF-7:5C, MCF-7:2A, and BT474 and in endocrine-sensitive cell lines MCF-7, T47D, and ZR-75-1 using real-time PCR and western blot analyses. Tissue microarray analysis and immunohistochemistry were used to assess the PEDF protein level in tamoxifen-resistant breast tumors versus primary tumors. Lentiviruses were used to stably express PEDF in endocrine-resistant breast cancer cell lines to determine their sensitivity to tamoxifen following PEDF re-expression.

Results

We found that PEDF mRNA and protein levels were dramatically reduced in endocrine-resistant MCF-7:5C, MCF-7:2A, and BT474 breast cancer cells compared with endocrine-sensitive MCF-7, T47D, and ZR-75-1 cells, and that loss of PEDF was associated with enhanced expression of pSer167ERα and the receptor tyrosine kinase rearranged during transfection (RET). Importantly, we found that silencing endogenous PEDF in tamoxifen-sensitive MCF-7 and T47D breast cancer cells conferred tamoxifen resistance whereas re-expression of PEDF in endocrine-resistant MCF-7:5C and MCF-7:2A cells restored their sensitivity to tamoxifen in vitro and in vivo through suppression of RET. Lastly, tissue microarray studies revealed that PEDF protein was reduced in ~52.4% of recurrence tumors (31 out of 59 samples) and loss of PEDF was associated with disease progression and poor patient outcome.

Conclusion

Overall, these findings suggest that PEDF silencing might be a novel mechanism for the development of endocrine resistance in breast cancer and that PEDF expression might be a predictive marker of endocrine sensitivity.
Routine Bone Marrow Biopsy Has Little or No Therapeutic Consequence for Positron Emission Tomography/Computed Tomography–Staged Treatment-Naive Patients With Hodgkin Lymphoma
Authors: El-Galaly Tarec Christoffer , d'Amore Francesco , Mylam Karen Juul , de Nully Brown Peter , Bøgsted Martin , Bukh Anne , Specht Lena , Loft Annika , Iyer Victor , Hjorthaug Karin , Nielsen Anne Lerberg , Christiansen Ilse , Madsen Charlotte , Johnsen Hans-Erik , Hutchings Martin
Published: November 2012

Purpose

To investigate whether bone marrow biopsy (BMB) adds useful information to [18F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) staging in patients with Hodgkin lymphoma (HL).

Patients and Methods

Newly diagnosed patients with HL undergoing a pretherapeutic staging that encompasses both PET/CT and BMB were included in this retrospective study. The pattern of skeletal FDG uptake was categorized as uni-, bi-, or multifocal (≥ three lesions). Clinical stage, risk assessment, and treatment plan were determined with and without the contribution of BMB results according to the Ann Arbor classification and the guidelines from the German Hodgkin Study Group.

Results

A total of 454 patients with HL were included of whom 82 (18%) had focal skeletal PET/CT lesions and 27 (6%) had positive BMB. No patients with positive BMB were assessed as having stage I to II disease by PET/CT staging. BMB upstaged five patients, assessed as being stage III before BMB; none of the 454 patients would have been allocated to another treatment on the basis of BMB results. Focal skeletal PET/CT lesions identified positive and negative BMBs with a sensitivity and specificity of 85% and 86%, respectively. The positive and negative predictive values of focal skeletal PET/CT lesions for BMB results were 28% and 99%, respectively.

Conclusion

A consistent finding of this study was the absence of positive BMBs in PET/CT-assessed stage I to II disease. The omission of staging BMB would not have changed the risk assessment or treatment strategy in this cohort of 454 newly diagnosed patients with HL.
Rules for abbreviation of protecting groups (IUPAC Technical
Report)
Authors: Brimble Margaret A. , Black David StC. , Hartshorn Richard , Rauter Amélia P. , Sha Chin-Kang , Sydnes Leiv K.
Published: November 2012

With the goal of presenting information in the scientific literature clearly and
unambiguously, a set of rules for the abbreviation of protecting groups has been
developed. It is based on principles designed to be as descriptive and
systematic as possible, but also sufficiently pragmatic and flexible so as to
accommodate the most important current abbreviations.
Melanoma resistance to photodynamic therapy: new insights
Authors: Huang Ying-Ying , Vecchio Daniela , Avci Pinar , Yin Rui , Garcia-Diaz Maria , Hamblin Michael R.
Published: November 2012

Melanoma is the most dangerous form of skin cancer, with a steeply rising incidence and a poor prognosis in its advanced stages. Melanoma is highly resistant to traditional chemotherapy and radiotherapy, although modern targeted therapies such as BRAF inhibitors are showing some promise. Photodynamic therapy (PDT, the combination of photosensitizing dyes and visible light) has been tested in the treatment of melanoma with some promising results, but melanoma is generally considered to be resistant to it. Optical interference by the highly-pigmented melanin, the antioxidant effect of melanin, the sequestration of photosensitizers inside melanosomes, defects in apoptotic pathways, and the efflux of photosensitizers by ATP-binding cassette transporters have all been implicated in melanoma resistance to PDT. Approaches to overcoming melanoma resistance to PDT include: the discovery of highly active photosensitizers absorbing in the 700–800-nm near infrared spectral region; interventions that can temporarily reduce the amount or pigmentation of the melanin; compounds that can reverse apoptotic defects or inhibit drug-efflux of photosensitizers; and immunotherapy approaches that can take advantage of the ability of PDT to activate the host immune system against the tumor being treated.
Development and Characterization of a New Parkinson's Disease Model Resulting from Impaired Autophagy
Authors: Ahmed Ishrat , Liang Yideng , Schools Sabitha , Dawson Valina L. , Dawson Ted M. , Savitt Joseph M.
Published: November 2012

Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the interaction of genetic and environmental factors. However, the etiology of PD remains largely unknown. Macroautophagy is known to play an essential role in the degradation of abnormal proteins and organelles. Furthermore, the loss of autophagy-related (Atg) genes results in neurodegeneration and abnormal protein accumulation. Since these are also pathologic features of Parkinson's disease, the conditional impairment of autophagy may lead to improved animal models for the study of PD. Using transgenic mice expressing Cre recombinase under the control of either the dopamine transporter or the engrailed-1 promoters, we generated mice with the conditional deletion of Atg7 in the dopamine neurons of the substantia nigra pars compacta, other regions of the midbrain, and also the hindbrain. This conditional impairment of autophagy results in the age-related loss of dopaminergic neurons and corresponding loss of striatal dopamine, the accumulation of low-molecular-weight α-synuclein, and the presence of ubiquitinated protein aggregates, recapitulating many of the pathologic features of PD. These conditional knock-out animals provide insight into the process of autophagy in Parkinson's disease pathology.
In VivoFunctional and Myeloarchitectonic Mapping of Human Primary Auditory Areas
Authors: Dick Frederic , Taylor Tierney Adam , Lutti Antoine , Josephs Oliver , Sereno Martin I. , Weiskopf Nikolaus
Published: November 2012

In contrast to vision, where retinotopic mapping alone can define areal borders, primary auditory areas such as A1 are best delineated by combiningin vivotonotopic mapping with postmortem cyto- or myeloarchitectonics from the same individual. We combined high-resolution (800 μm) quantitative T1mapping with phase-encoded tonotopic methods to map primary auditory areas (A1 and R) within the “auditory core” of human volunteers. We first quantitatively characterize the highly myelinated auditory core in terms of shape, area, cortical depth profile, and position, with our data showing considerable correspondence to postmortem myeloarchitectonic studies, both in cross-participant averages and in individuals. The core region contains two “mirror-image” tonotopic maps oriented along the same axis as observed in macaque and owl monkey. We suggest that these two maps within the core are the human analogs of primate auditory areas A1 and R. The core occupies a much smaller portion of tonotopically organized cortex on the superior temporal plane and gyrus than is generally supposed. The multimodal approach to defining the auditory core will facilitate investigations of structure–function relationships, comparative neuroanatomical studies, and promises new biomarkers for diagnosis and clinical studies.
Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer's Disease
Authors: Furman Jennifer L. , Sama Diana M. , Gant John C. , Beckett Tina L. , Murphy M. Paul , Bachstetter Adam D. , Van Eldik Linda J. , Norris Christopher M.
Published: November 2012

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically “activated” phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV–Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2–VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies.
Oxytocin Modulates Social Distance between Males and Females
Authors: Scheele Dirk , Striepens Nadine , Güntürkün Onur , Deutschländer Sandra , Maier Wolfgang , Kendrick Keith M. , Hurlemann René
Published: November 2012

In humans, interpersonal romantic attraction and the subsequent development of monogamous pair-bonds is substantially predicted by influential impressions formed during first encounters. The prosocial neuropeptide oxytocin (OXT) has been identified as a key facilitator of both interpersonal attraction and the formation of parental attachment. However, whether OXT contributes to the maintenance of monogamous bonds after they have been formed is unclear. In this randomized placebo-controlled trial, we provide the first behavioral evidence that the intranasal administration of OXT stimulates men in a monogamous relationship, but not single ones, to keep a much greater distance (∼10–15 cm) between themselves and an attractive woman during a first encounter. This avoidance of close personal proximity occurred in the physical presence of female but not male experimenters and was independent of gaze direction and whether the female experimenter or the subject was moving. We further confirmed this unexpected finding using a photograph-based approach/avoidance task that showed again that OXT only stimulated men in a monogamous relationship to approach pictures of attractive women more slowly. Importantly, these changes cannot be attributed to OXT altering the attitude of monogamous men toward attractive women or their judgments of and arousal by pictures of them. Together, our results suggest that where OXT release is stimulated during a monogamous relationship, it may additionally promote its maintenance by making men avoid signaling romantic interest to other women through close-approach behavior during social encounters. In this way, OXT may help to promote fidelity within monogamous human relationships.
Human Immunodeficiency Virus Type 1 (HIV-1) Transactivator of Transcription through Its Intact Core and Cysteine-Rich Domains Inhibits Wnt/β-Catenin Signaling in Astrocytes: Relevance to HIV Neuropathogenesis
Authors: Henderson Lisa J. , Sharma Amit , Monaco Maria Chiara G. , Major Eugene O. , Al-Harthi Lena
Published: November 2012

Wnt/β-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/β-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/β-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/β-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/β-catenin signaling as demonstrated by its inhibition of active β-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/β-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit β-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter β-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of β-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with β-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of β-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV long terminal repeat. These findings highlight a bidirectional interference between Tat and Wnt/β-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/β-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.
Mechanistic Basis and Functional Roles of Long-Term Plasticity in Auditory Neurons Induced by a Brain-Generated Estrogen
Authors: Tremere Liisa A. , Kovaleski Ryan F. , Burrows Kaiping , Jeong Jin Kwon , Pinaud Raphael
Published: November 2012

The classic estrogen 17β-estradiol (E2) was recently identified as a novel modulator of hearing function. It is produced rapidly, in an experience-dependent fashion, by auditory cortical neurons of both males and females. This brain-generated E2 enhances the efficiency of auditory coding and improves the neural and behavioral discrimination of auditory cues. Remarkably, the effects of E2 are long-lasting and persist for hours after local rises in hormone levels have subsided. The mechanisms and functional consequences of this E2-induced plasticity of auditory responses are unknown. Here, we addressed these issues in the zebra finch model by combining intracerebral pharmacology, biochemical assays,in vivoneurophysiology in awake animals, and computational and information theoretical approaches. We show that auditory experience activates the MAPK pathway in an E2-dependent manner. This effect is mediated by estrogen receptor β (ERβ), which directly associates with MEKK1 to sequentially modulate MEK and ERK activation, where the latter is required for the engagement of downstream molecular targets. We further show that E2-mediated activation of the MAPK cascade is required for the long-lasting enhancement of auditory-evoked responses in the awake brain. Moreover, a functional consequence of this E2/MAPK activation is to sustain enhanced information handling and neural discrimination by auditory neurons for several hours following hormonal challenge. Our results demonstrate that brain-generated E2 engages, via a nongenomic interaction between an estrogen receptor and a kinase, a persistent form of experience-dependent plasticity that enhances the neural coding and discrimination of behaviorally relevant sensory signals in the adult vertebrate brain.
Temporal Dynamics of Parvalbumin-Expressing Axo-axonic and Basket Cells in the Rat Medial Prefrontal CortexIn Vivo
Authors: Massi Lema , Lagler Michael , Hartwich Katja , Borhegyi Zsolt , Somogyi Peter , Klausberger Thomas
Published: November 2012

Axo-axonic interneurons, innervating exclusively axon initial segments, and parvalbumin-expressing basket interneurons, targeting somata, dendrites, and spines of pyramidal cells, have been proposed to control neuronal activity in prefrontal circuits. We recorded the spike-timing of identified neurons in the prelimbic cortex of anesthetized rats, and show that axo-axonic cells increase their firing during tail pinch-induced brain state-activation. In addition, axo-axonic cells differ from other GABAergic parvalbumin-expressing cells in their spike timing during DOWN- to UP-state transitions of slow oscillations and in their coupling to gamma and spindle oscillations. The distinct firing dynamics and synaptic targets of axo-axonic and other parvalbumin-expressing cells provide differential contributions to the temporal organization of prefrontal networks.