bluuebunny/crossref_metadata_2025 huggingface dataset:
Concurrent analysis of choice and control in childbirth
Authors: Snowden Austyn , Martin Colin , Jomeen Julie , Martin Caroline Hollins
Published: June 2011

Background

This paper reports original research on choice and control in childbirth. Eight women were interviewed as part of a wider investigation into locus of control in women with pre-labour rupture of membranes at term (PROM) [1].

Methods

The following study uses concurrent analysis to sample and analyse narrative aspects of relevant literature along with these interviews in order to synthesise a generalisable analysis of the pertinent issues. The original PROM study had found that women experienced a higher degree of control in hospital, a finding that appeared at odds with contemporary notions of choice. However, this paper contextualises this finding by presenting narratives that lucidly subscribe to the dominant discourse of hospital as the safest place to give birth, under the premise of assuring a live healthy baby irrespective of their management type.

Results

This complex narrative is composed of the following themes: 'perceiving risk', 'being prepared', 'reflecting on experience', maintaining control' and relinquishing control'. These themes are constructed within and around the medical, foetocentric, risk averse cultural context. Primary data are presented throughout to show the origins and interconnected nature of these themes.

Conclusions

Within this context it is clear that there is a highly valued role for competent health professionals that respect, understand and are capable of facilitating genuine choice for women.
No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study
Authors: de Mey Christian , Nassr Nassr , Lahu Gezim
Published: June 2011

Background

Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast.

Methods

This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study.

Results

Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation.

Conclusions

No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.

Trial Registration

Clinicaltrials.gov NCT00940329
Variation in quality of preventive care for well adults in Indigenous community health centres in Australia
Authors: Bailie Ross S , Si Damin , Connors Christine M , Kwedza Ru , O'Donoghue Lynette , Kennedy Catherine , Cox Rhonda , Liddle Helen , Hains Jenny , Dowden Michelle C , Burke Hugh P , Brown Alex , Weeramanthri Tarun , Thompson Sandra
Published: June 2011

Background

Early onset and high prevalence of chronic disease among Indigenous Australians call for action on prevention. However, there is deficiency of information on the extent to which preventive services are delivered in Indigenous communities. This study examined the variation in quality of preventive care for well adults attending Indigenous community health centres in Australia.

Methods

During 2005-2009, clinical audits were conducted on a random sample (stratified by age and sex) of records of adults with no known chronic disease in 62 Indigenous community health centres in four Australian States/Territories (sample size 1839). Main outcome measures: i) adherence to delivery of guideline-scheduled services within the previous 24 months, including basic measurements, laboratory investigations, oral health checks, and brief intervention on lifestyle modification; and ii) follow-up of abnormal findings.

Results

Overall delivery of guideline-scheduled preventive services varied widely between health centres (range 5-74%). Documentation of abnormal blood pressure reading ([greater than or equal to]140/90 mmHg), proteinuria and abnormal blood glucose ([greater than or equal to]5.5 mmol/L) was found to range between 0 and > 90% at the health centre level. A similarly wide range was found between health centres for documented follow up check/test or management plan for people documented to have an abnormal clinical finding. Health centre level characteristics explained 13-47% of variation in documented preventive care, and the remaining variation was explained by client level characteristics.

Conclusions

There is substantial room to improve preventive care for well adults in Indigenous primary care settings. Understanding of health centre and client level factors affecting variation in the care should assist clinicians, managers and policy makers to develop strategies to improve quality of preventive care in Indigenous communities.
Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia
Authors: Ceulemans An-Gaëlle , Zgavc Tine , Kooijman Ron , Hachimi-Idrissi Said , Sarre Sophie , Michotte Yvette
Published: June 2011

Background

Stroke is an important cause of morbidity and mortality and few therapies exist thus far. Mild hypothermia (33°C) is a promising neuroprotective strategy to improve outcome after ischemic stroke. However, its complete mechanism of action has not yet been fully elaborated. This study is the first to investigate whether this neuroprotection occurs through modulation of the neuroinflammatory response after stroke in a time-dependent manner.

Methods

The Endothelin-1 (Et-1) model was used to elicit a transient focal cerebral ischemia in male Wistar rats. In this model, the core and penumbra of the insult are represented by the striatum and the cortex respectively. We assessed the effects of 2 hours of hypothermia, started 20 minutes after Et-1 injection on neurological outcome and infarct volume. Furthermore, pro- and anti-inflammatory cytokine expression was determined using ELISA. Microgliosis and astrogliosis were investigated using CD-68 and GFAP staining respectively. All parameters were determined 8, 24, 72 hours and 1 week after the administration of Et-1.

Results

Et-1 infusion caused neurological deficit and a reproducible infarct size which increased up to 3 days after the insult. Both parameters were significantly reduced by hypothermia. The strongest reduction in infarct volume with hypothermia, at 3 days, corresponded with increased microglial activation. Reducing the brain temperature affected the stroke induced increase in interleukin-1β and tumor necrosis factor α in the striatum, 8 hours after its induction, but not at later time points. Transforming growth factor β increased as a function of time after the Et-1-induced insult and was not influenced by cooling. Hypothermia reduced astrogliosis at 1 and 3 days after stroke onset.

Conclusions

The beneficial effects of hypothermia after stroke on infarct volume and functional outcome coincide with a time-dependent modulation of the cytokine expression and gliosis.
A dual role for microglia in promoting tissue inhibitor of metalloproteinase (TIMP) expression in glial cells in response to neuroinflammatory stimuli
Authors: Welser-Alves Jennifer V , Crocker Stephen J , Milner Richard
Published: June 2011

Background

By neutralizing the effect of the matrix metalloproteinases (MMPs), the tissue inhibitors of matrix metalloproteinases (TIMPs) play a critical role in maintaining tissue proteolysis in balance. As the major reactive glial cell types in the central nervous system (CNS), microglia and astrocytes play fundamental roles in mediating tissue breakdown and repair. As such, it is important to define the TIMP expression profile in these cells, as well as the mechanisms of regulation by neuroinflammatory stimuli.

Methods

Primary mixed glial cultures (MGC), pure microglia, and pure astrocytes were used in this study. To study astrocytes, we employed a recently described pure astrocyte culture system, which has the major advantage of totally lacking microglia. The three different types of culture were treated with lipopolysaccharide (LPS) or individual cytokines, and cell culture supernatants assayed for TIMP-1 or TIMP-2 protein expression by western blot.

Results

LPS induced TIMP-1 expression in MGC, but not in pure astrocyte or microglial cultures. When pure astrocytes were treated with the cytokines IL-1β, IFN-γ, TNF or TGF-β1, only IL-1β induced TIMP-1 expression. Significantly, astrocyte TIMP-1 expression was restored in LPS-treated astrocyte cultures after the addition of microglia, or conditioned medium taken from LPS-activated microglia (MG-CM). Furthermore, this effect was lost after depletion of IL-1β from MG-CM. By contrast, TIMP-2 was constitutively expressed by astrocytes, whereas microglia expressed TIMP-2 only after exposure to serum.

Conclusions

Taken together, these results demonstrate an important concept in glial interactions, by showing that microglia play a central role in regulating glial cell expression of TIMPs, and identify microglial IL-1β as playing a key role in mediating microglial-astrocyte communication.
Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons
Authors: Liang Qiuli , Ouyang Xiaosen , Schneider Lonnie , Zhang Jianhua
Published: June 2011

Background

Huntington's disease is caused by aggregation of mutant huntingtin (mHtt) protein containing more than a 36 polyQ repeat. Upregulation of macroautophagy was suggested as a neuroprotective strategy to degrade mutant huntingtin. However, macroautophagy initiation has been shown to be highly efficient in neurons whereas lysosomal activities are rate limiting. The role of the lysosomal and other proteases in Huntington is not clear. Some studies suggest that certain protease activities may contribute to toxicity whereas others are consistent with protection. These discrepancies may be due to a number of mechanisms including distinct effects of the specific intermediate digestion products of mutant huntingtin generated by different proteases. These observations suggested a critical need to investigate the consequence of upregulation of individual lysosomal enzyme in mutant huntingtin accumulation and toxicity.

Results

In this study, we used molecular approaches to enhance lysosomal protease activities and examined their effects on mutant huntingtin level and toxicity. We found that enhanced expression of lysosomal cathepsins D and B resulted in their increased enzymatic activities and reduced both full-length and fragmented huntingtin in transfected HEK cells. Furthermore, enhanced expression of cathepsin D or B protected against mutant huntingtin toxicity in primary neurons, and their neuroprotection is dependent on macroautophagy.

Conclusions

These observations demonstrate a neuroprotective effect of enhancing lysosomal cathepsins in reducing mutant huntingtin level and toxicity in transfected cells. They highlight the potential importance of neuroprotection mediated by cathepsin D or B through macroautophagy.
Multiple Sox genes are expressed in stem cells or in differentiating neuro-sensory cells in the hydrozoan Clytia hemisphaerica
Authors: Jager Muriel , Quéinnec Eric , Le Guyader Hervé , Manuel Michaël
Published: June 2011

Background

The Sox genes are important regulators of animal development belonging to the HMG domain-containing class of transcription factors. Studies in bilaterian models have notably highlighted their pivotal role in controlling progression along cell lineages, various Sox family members being involved at one side or the other of the critical balance between self-renewing stem cells/proliferating progenitors, and cells undergoing differentiation.

Results

We have investigated the expression of 10 Sox genes in the cnidarian Clytia hemisphaerica. Our phylogenetic analyses allocated most of these Clytia genes to previously-identified Sox groups: SoxB (CheSox2, CheSox3, CheSox10, CheSox13, CheSox14), SoxC (CheSox12), SoxE (CheSox1, CheSox5) and SoxF (CheSox11), one gene (CheSox15) remaining unclassified. In the planula larva and in the medusa, the SoxF orthologue was expressed throughout the endoderm. The other genes were expressed either in stem cells/undifferentiated progenitors, or in differentiating (-ed) cells with a neuro-sensory identity (nematocytes or neurons). In addition, most of them were expressed in the female germline, with their maternal transcripts either localised to the animal region of the egg, or homogeneously distributed.

Conclusions

Comparison with other cnidarians, ctenophores and bilaterians suggest ancient evolutionary conservation of some aspects of gene expression/function at the Sox family level: (i) many Sox genes are expressed in stem cells and/or undifferentiated progenitors; (ii) other genes, or the same under different contexts, are associated with neuro-sensory cell differentiation; (iii) Sox genes are commonly expressed in the germline; (iv) SoxF group genes are associated with endodermal derivatives. Strikingly, total lack of correlation between a given Sox orthology group and expression/function in stem cells/progenitors vs. in differentiating cells implies that Sox genes can easily switch from one side to the other of the balance between these fundamental cellular states in the course of evolution.
Fukuyama-type congenital muscular dystrophy and defective glycosylation of α-dystroglycan
Authors: Saito Fumiaki , Matsumura Kiichiro
Published: June 2011

Fukuyama-type congenital muscular dystrophy (FCMD) is a severe form of muscular dystrophy accompanied by abnormalities in the eye and brain. The incidence of FCMD is particularly high in the Japanese population. Mutations in the fukutin gene have been identified in patients with FCMD. Fukutin is predicted to be a Golgi apparatus resident protein and to be involved in the post-translational modification of cell-surface proteins. Recently, progress has been made in our understanding of the molecular mechanisms by which the mutation of fukutin leads to the phenotype of FCMD. Loss of function of fukutin results in defective glycosylation of α-dystroglycan, a central component of the dystrophin-glycoprotein complex, leading to disruption of the linkage between basal lamina and cytoskeleton. This disruption is implicated in the pathogenesis of both the MD and brain anomalies in FCMD. Furthermore, genetic analyses have revealed that the spectrum of the FCMD phenotype is much wider than originally thought. In this review, we summarize the diverging clinical phenotype of FCMD and its molecular pathomechanisms.
Want to Improve Undergraduate Thesis Writing? Engage Students and Their Faculty Readers in Scientific Peer Review
Authors: Reynolds Julie A. , Thompson Robert J.
Published: June 2011

One of the best opportunities that undergraduates have to learn to write like a scientist is to write a thesis after participating in faculty-mentored undergraduate research. But developing writing skills doesn't happen automatically, and there are significant challenges associated with offering writing courses and with individualized mentoring. We present a hybrid model in which students have the structural support of a course plus the personalized benefits of working one-on-one with faculty. To optimize these one-on-one interactions, the course uses BioTAP, the Biology Thesis Assessment Protocol, to structure engagement in scientific peer review. By assessing theses written by students who took this course and comparable students who did not, we found that our approach not only improved student writing but also helped faculty members across the department—not only those teaching the course—to work more effectively and efficiently with student writers. Students who enrolled in this course were more likely to earn highest honors than students who only worked one-on-one with faculty. Further, students in the course scored significantly better on all higher-order writing and critical-thinking skills assessed.
Redesigning a Large-Enrollment Introductory Biology Course
Authors: Ueckert Catherine , Adams Alison , Lock Judith
Published: June 2011

Using an action research model, biology faculty examined, implemented, and evaluated learner-centered instructional strategies to reach the goal of increasing the level of student achievement in the introductory biology course BIO 181: Unity of Life I, which was characterized by both high enrollments and a high DFW rate. Outcomes included the creation and implementation of an assessment tool for biology content knowledge and attitudes, development and implementation of a common syllabus, modification of the course to include learner-centered instructional strategies, and the collection and analysis of data to evaluate the success of the modifications. The redesigned course resulted in greater student success, as measured by grades (reduced %DFW and increased %AB) as well as by achievement in the course assessment tool. In addition, the redesigned course led to increased student satisfaction and greater consistency among different sections. These findings have important implications for both students and institutions, as the significantly lower DFW rate means that fewer students have to retake the course.
Using Digital Images of the Zebra Finch Song System as a Tool to Teach Organizational Effects of Steroid Hormones: A Free Downloadable Module
Authors: Grisham William , Schottler Natalie A. , McCauley Lisa M. Beck , Pham Anh P. , Ruiz Maureen L. , Fong Michelle C. , Cui Xinran
Published: June 2011

Zebra finch song behavior is sexually dimorphic: males sing and females do not. The neural system underlying this behavior is sexually dimorphic, and this sex difference is easy to quantify. During development, the zebra finch song system can be altered by steroid hormones, specifically estradiol, which actually masculinizes it. Because of the ease of quantification and experimental manipulation, the zebra finch song system has great potential for use in undergraduate labs. Unfortunately, the underlying costs prohibit use of this system in undergraduate labs. Further, the time required to perform a developmental study renders such undertakings unrealistic within a single academic term. We have overcome these barriers by creating digital tools, including an image library of song nuclei from zebra finch brains. Students using this library replicate and extend a published experiment examining the dose of estradiol required to masculinize the female zebra finch brain. We have used this library for several terms, and students not only obtain significant experimental results but also make gains in understanding content, experimental controls, and inferential statistics (analysis of variance and post hoc tests). We have provided free access to these digital tools at the following website: http://mdcune.psych.ucla.edu/modules/birdsong .
Undergraduate Science Research: A Comparison of Influences and Experiences between Premed and Non–Premed Students
Authors: Pacifici Lara Brongo , Thomson Norman
Published: June 2011

Most students participating in science undergraduate research (UR) plan to attend either medical school or graduate school. This study examines possible differences between premed and non–premed students in their influences to do research and expectations of research. Questionnaire responses from 55 premed students and 80 non–premed students were analyzed. No differences existed in the expectations of research between the two groups, but attitudes toward science and intrinsic motivation to learn more about science were significantly higher for non–premed students. Follow-up interviews with 11 of the students, including a case study with one premed student, provided explanation for the observed differences. Premed students, while not motivated to learn more about science, were motivated to help people, which is why most of them are pursuing medicine. They viewed research as a way to help them become doctors and to rule out the possibility of research as a career. Non–premed students participated in research to learn more about a specific science topic and gain experience that may be helpful in graduate school research. The difference in the reasons students want to do UR may be used to tailor UR experiences for students planning to go to graduate school or medical school.
Harnessing Technology to Improve Formative Assessment of Student Conceptions in STEM: Forging a National Network
Authors: Haudek Kevin C. , Kaplan Jennifer J. , Knight Jennifer , Long Tammy , Merrill John , Munn Alan , Nehm Ross , Smith Michelle , Urban-Lurain Mark
Published: June 2011

Concept inventories, consisting of multiple-choice questions designed around common student misconceptions, are designed to reveal student thinking. However, students often have complex, heterogeneous ideas about scientific concepts. Constructed-response assessments, in which students must create their own answer, may better reveal students’ thinking, but are time- and resource-intensive to evaluate. This report describes the initial meeting of a National Science Foundation–funded cross-institutional collaboration of interdisciplinary science, technology, engineering, and mathematics (STEM) education researchers interested in exploring the use of automated text analysis to evaluate constructed-response assessments. Participants at the meeting shared existing work on lexical analysis and concept inventories, participated in technology demonstrations and workshops, and discussed research goals. We are seeking interested collaborators to join our research community.
Reciprocal regulation of CXCR4 and CXCR7 in intestinal mucosal homeostasis and inflammatory bowel disease
Authors: Werner Lael , Elad Hofit , Brazowski Eli , Tulchinsky Hagit , Vigodman Sharon , Kopylov Uri , Halpern Zamir , Guzner-Gur Hanan , Dotan Iris
Published: June 2011

IBDs are characterized by increased influx of immune cells to the mucosa of genetically susceptible persons. Cellular migration to injury sites is mediated by chemokines. CXCL12 is a ubiquitous, constitutive chemokine that participates in stem cell proliferation and migration and mediates T lymphocyte migration to inflamed tissues. We have recently reported that CXCL12 and its receptor, CXCR4, are expressed in normal and more prominently, inflamed human intestinal mucosa. However, the interactions and roles of CXCL12 and its receptors, CXCR4 and the recently discovered CXCR7, in intestinal inflammation have not been defined. In the present study, we further dissected the effects of CXCL12 on lymphocytes in intestinal homeostasis and inflammation and delineated the interplay between CXCL12 and its receptors CXCR4 and CXCR7. To that end, fresh mononuclear cells were isolated from mucosa and PB of healthy or IBD patients. Phenotypical and functional assays were conducted using flow cytometry, Transwell migration chambers, and ELISA. The data show that CXCL12-mediated migration of T cells is CXCR4- but not CXCR7-dependent. T cell activation reciprocally regulates CXCR7 and CXCR4 expression and migratory capacity. IBD PBTs expressed more CXCR7 than normal PBTs. Finally, T cells attracted by CXCL12 are mostly of a memory phenotype. In conclusion, the present study suggests that the interplay between CXCL12 and its receptors affects homeostasis and inflammation in the intestinal mucosa.
Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System
Authors: Röllig Christoph , Bornhäuser Martin , Thiede Christian , Taube Franziska , Kramer Michael , Mohr Brigitte , Aulitzky Walter , Bodenstein Heinrich , Tischler Hans-Joachim , Stuhlmann Reingard , Schuler Ulrich , Stölzel Friedrich , von Bonin Malte , Wandt Hannes , Schäfer-Eckart Kerstin , Schaich Markus , Ehninger Gerhard
Published: June 2011

Purpose

The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients.

Patients and Methods

Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing.

Results

The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II.

Conclusion

In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.
Randomized Phase III Trial of Paclitaxel/Carboplatin With or Without PF-3512676 (Toll-Like Receptor 9 Agonist) As First-Line Treatment for Advanced Non–Small-Cell Lung Cancer
Authors: Hirsh Vera , Paz-Ares Luis , Boyer Michael , Rosell Rafael , Middleton Gary , Eberhardt Wilfried E.E. , Szczesna Aleksandra , Reiterer Pavel , Saleh Mansoor , Arrieta Oscar , Bajetta Emilio , Webb Roy T. , Raats Johannes , Benner Rebecca J. , Fowst Camilla , Meech Sandra J. , Readett David , Schiller Joan H.
Published: June 2011

Purpose

This phase III study examined efficacy of the synthetic Toll-like receptor 9–activating oligodeoxynucleotide PF-3512676 in combination with standard paclitaxel/carboplatin chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned (1:1) to receive up to six courses of paclitaxel/carboplatin (intravenous paclitaxel 200 mg/m2 and carboplatin at area under the [concentration-time] curve 6 on day 1 of a 3-week cycle) alone (control arm) or in combination with 0.2 mg/kg subcutaneous PF-3512676 on days 8 and 15 (investigational arm). Primary end point was overall survival (OS).

Results

Baseline demographics were similar across arms (N = 828). Most patients (88%) had stage IV disease. Median OS and median progression-free survival (PFS) were similar (OS: investigational arm, 10.0 months v control arm, 9.8 months; P = .56; PFS: investigational arm, 4.8 months v control arm, 4.7 months; P = .79). Most commonly reported PF-3512676–related adverse events (AEs) were mild-to-moderate local injection site reactions, pyrexia, and flu-like symptoms. In the investigational arm, grades 3 to 4 AEs, including neutropenia, thrombocytopenia, and anemia, were more frequent, and more patients had one or more sepsis-related AEs versus controls (17 v 3). At first interim analysis, the Data Safety Monitoring Committee recommended study discontinuation because of lack of incremental efficacy and more sepsis-related serious AEs in the PF-3512676 arm. Administration of PF-3512676, but not chemotherapy, was halted.

Conclusion

Addition of PF-3512676 to paclitaxel/carboplatin did not improve OS or PFS versus paclitaxel/carboplatin alone for first-line treatment of patients with advanced NSCLC but did increase toxicity. This regimen cannot be recommended for treating patients with advanced NSCLC.
Changes in Prostate Cancer Grade on Serial Biopsy in Men Undergoing Active Surveillance
Authors: Porten Sima P. , Whitson Jared M. , Cowan Janet E. , Cooperberg Matthew R. , Shinohara Katsuto , Perez Nannette , Greene Kirsten L. , Meng Maxwell V. , Carroll Peter R.
Published: June 2011

Purpose

Active surveillance is now considered a viable treatment option for men with low-risk prostate cancer. However, little is known regarding changes in Gleason grade on serial biopsies over an extended period of time.

Patients and Methods

Men diagnosed with prostate cancer between 1998 and 2009 who elected active surveillance as initial treatment, with 6 or more months of follow-up and a minimum of six cores at biopsy, were included in analysis. Upgrading and downgrading were defined as an increase or decrease in primary or secondary Gleason score. Means and frequency tables were used to describe patient characteristics, and treatment-free survival rates were determined by life-table product limit estimates.

Results

Three hundred seventy-seven men met inclusion criteria. Mean age at diagnosis was 61.9 years. Fifty-three percent of men had prostate-specific antigen of 6 ng/mL or less, and 94% had Gleason score of 6 or less. A majority of men were cT1 (62%), had less than 33% of biopsy cores involved (80%), and were low risk (77%) at diagnosis. Median number of cores taken at diagnostic biopsy was 13, mean time to follow-up was 18.5 months, and 29% of men had three or more repeat biopsies. Overall, 34% (129 men) were found to have an increase in Gleason grade. The majority of men who experienced an upgrade (81%) did so by their second repeat biopsy.

Conclusion

A proportion of men experience an upgrade in Gleason score while undergoing active surveillance. Men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation.
National Estimates of Out-of-Pocket Health Care Expenditure Burdens Among Nonelderly Adults With Cancer: 2001 to 2008
Authors: Bernard Didem S.M. , Farr Stacy L. , Fang Zhengyi
Published: June 2011

Purpose

To compare the prevalence of high out-of-pocket burdens among patients with cancer with other chronically ill and well patients, and to examine the sociodemographic characteristics associated with high burdens among patients with cancer.

Methods

The sample included persons 18 to 64 years of age who received treatment for cancer, taken from a nationally representative sample of the US population from the 2001 to 2008 Medical Expenditure Panel Survey. We examined the proportion of persons living in families with high out-of-pocket burdens associated with medical spending, including insurance premiums, relative to income, defining high health care (total) burden as spending more than 20% of income on health care (and premiums).

Results

The risk of high burdens is significantly greater for patients with cancer compared with other chronically ill and well patients. We find that 13.4% of patients with cancer had high total burdens, in contrast to 9.7% among those with other chronic conditions and 4.4% among those without chronic conditions. Among nonelderly persons with cancer, the following were associated with higher out-of-pocket burdens: private nongroup insurance, age 55 to 64 years, non-Hispanic black, never married or widowed, one child or no children, unemployed, lower income, lower education level, living in nonmetropolitan statistical areas, and having other chronic conditions.

Conclusion

High burdens may affect treatment choice and deter patients from getting care. Thus, although a detailed patient-physician discussion of costs of care may not be feasible, we believe that an awareness of out-of-pocket burdens among patients with cancer is useful for clinical oncologists.
Beta Blockers and Breast Cancer Mortality: A Population- Based Study
Authors: Barron Thomas I. , Connolly Roisin M. , Sharp Linda , Bennett Kathleen , Visvanathan Kala
Published: June 2011

Purpose

Preclinical studies have demonstrated that antagonism of β2-adrenergic signaling inhibits several pathways necessary for breast tumor progression and metastasis. A series of population-based observational studies were conducted to examine associations between beta blocker use and breast tumor characteristics at diagnosis or breast cancer–specific mortality.

Patients and Methods

Linked national cancer registry and prescription dispensing data were used to identify women with a diagnosis of stage I to IV invasive breast cancer between January 1, 2001, and December 31, 2006. Women taking propranolol (β1/β2 antagonist; n = 70) or atenolol (β1 antagonist; n = 525), in the year before breast cancer diagnosis were matched (1:2) to women not taking a beta blocker (n = 4,738). Associations between use of propranolol or atenolol and risk of local tumor invasion at diagnosis (T4 tumor), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumor), and time to breast cancer–specific mortality were assessed.

Results

Propranolol users were significantly less likely to present with a T4 (odds ratio [OR], 0.24, 95% CI, 0.07 to 0.85) or N2/N3/M1 (OR, 0.20; 95% CI, 0.04 to 0.88) tumor compared with matched nonusers. The cumulative probability of breast cancer–specific mortality was significantly lower for propranolol users compared with matched nonusers (hazard ratio, 0.19; 95% CI, 0.06 to 0.60). There was no difference in T4 or N2/N3/M1 tumor incidence or breast cancer–specific mortality between atenolol users and matched nonusers.

Conclusion

The results provide evidence in humans to support preclinical observations suggesting that inhibiting the β2-adrenergic signaling pathway can reduce breast cancer progression and mortality.
Pathology Review of Outside Material: When Does It Help and When Can It Hurt?
Authors: Smith Lauren B.
Published: June 2011

Purpose

Pathology review is performed for patients when care is transferred to a tertiary care center after diagnostic tissue has been obtained. While it has many benefits, this practice can lead to unforeseen difficulties in doctor-patient communication and patient well-being, especially if a diagnosis is overturned or modified years after treatment. The aim of this analysis is to identify clinical situations in which pathology review can result in challenging discussions between patients and oncologists.

Patients

Representative case scenarios are presented in the subspecialty area of hematopathology. Analysis of the clinical benefits and possible harm to patients, pathologists, and treating oncologists that may ensue from pathology review is performed.

Results

Pathology review may result in a valuable second opinion and expert subclassification. However, problematic situations may arise with pathology review, especially if the patient has already undergone definitive treatment and is referred to an academic institution in remission. Difficulties can also arise when patients do not understand the limitations of diagnosing disease on small biopsies. The patient may receive a different diagnosis or it may become apparent that the diagnosis could have been made more expeditiously. These discrepancies must be communicated to the patient and may cause confusion and distress.

Conclusion

Pathology review can be beneficial or potentially harmful depending on the clinical situation. Preliminary recommendations are provided for selecting patients for review. Limiting pathology review to certain clinical situations and encouraging patients to get second opinions before initial treatment at local referral centers may be helpful in minimizing reassignment of diagnoses after definitive treatment.
Adult Medulloblastoma Comprises Three Major Molecular Variants
Authors: Remke Marc , Hielscher Thomas , Northcott Paul A. , Witt Hendrik , Ryzhova Marina , Wittmann Andrea , Benner Axel , von Deimling Andreas , Scheurlen Wolfram , Perry Arie , Croul Sidney , Kulozik Andreas E. , Lichter Peter , Taylor Michael D. , Pfister Stefan M. , Korshunov Andrey
Published: June 2011

Purpose

Medulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood.

Patients and Methods

We combined transcriptome and DNA copy number analyses for 28 adult medulloblastomas. Statistical and bioinformatic tools were applied to discover distinct molecular variants. Clinical and molecular characteristics of each biologic subtype were validated using immunohistochemistry on a tissue microarray derived from an independent patient cohort of adult medulloblastomas (n = 103).

Results

Gene expression profiles revealed three distinct molecular variants with stable subtype separation using the 300 most varying transcripts. Distinct demographics, genetics, transcriptome, and prognosis were noted for each subtype of adult medulloblastoma. Immunohistochemistry revealed aberrant activation of the sonic hedgehog (SHH) pathway in over half of adult medulloblastomas constituting a promising molecular therapeutic target. In contrast, subtype C tumors, which comprise a robust subtype in childhood medulloblastoma are only exceptionally seen in adult cohorts. Notably, adult subtype D and Wnt/wingless tumors were associated with worse prognosis than pediatric cohorts, whereas survival for SHH tumors was similar for both age groups.

Conclusion

The transcriptome of adult medulloblastomas differs considerably from pediatric counterparts, both in terms of tumor biology and prognostic impact. Therefore, age-specific classification is required and must be adapted for use in clinical trials of adult medulloblastoma.
Identification of Novel TSH Interaction Sites by Systematic Binding Analysis of the TSHR Hinge Region
Authors: Mueller Sandra , Szkudlinski Mariusz W. , Schaarschmidt Jörg , Günther Robert , Paschke Ralf , Jaeschke Holger
Published: June 2011

In which ways the binding of the thyroid stimulating hormone to the extracellular domain of its receptor leads to activation of the thyroid-stimulating hormone receptor (TSHR) is currently only incompletely understood. It is known that TSH binding to the TSHR depends on the interaction with the leucine-rich repeat and sulfation at Y385 of the hinge region. Recently it was also shown that electrostatic interactions between positive charges of bovine (b) TSH and the residues E297, E303, and D382 of the hinge region contribute to hormone-TSHR binding. After the identification of these first TSH binding sites in the hinge region, it was apparent that multiple positions in this region remained to be characterized for their roles in hormone binding. The goal of this study was therefore to clarify whether further contact points of TSH exist in the structurally undefined hinge region. Therefore, we systematically analyzed 41 uncharacterized residues of the TSHR hinge region as single mutants regarding differences between cell surface expression and bTSH binding. Indeed, we identified further amino acids of the hinge region with influence on bTSH binding. Some of these contribute to a new binding domain from human TSHR position F381 to D386. These hinge mutants with influence on bTSH binding were also analyzed for binding of the superagonistic human TSH analog TR1401 demonstrating that these positions also have an impact on TR1401 binding. Moreover, side chain variations revealed that different amino acid properties like the negative charge, aromatic as well as hydrophilic characteristics, contribute to maintain the hormone-TSHR hinge interaction.
Colonial Beef and the Blackfeet Reservation Slaughterhouse, 1879–1895
Authors: Wise Michael
Published: June 2011

In 1884, the U.S. Office of Indian Affairs (OIA) built a slaughterhouse on the Blackfeet Reservation. Over the next decade, the slaughterhouse instituted profound changes in Blackfeet foodways. Trading work for prepared meat dissociated from its animal origins reoriented Blackfeet meat making from a process of collaborative hunting and butchering to an individuated procedure of exchanging labor for beef. This article explores how the slaughterhouse provided a potent force to colonize Blackfeet land and labor during the late nineteenth century.
“Chili Queens” and Checkered Tablecloths
Authors: Gabaccia Donna R. , Pilcher Jeffrey M.
Published: June 2011

This article examines the modernization of food retailing and the governance of urban space through a connected comparison of southern Italian migrants to New York City and Mexicans living in San Antonio, Texas. Street foods were common and restaurants scarce in the regions of Mexico and of southern Italy that either sent large numbers of migrants to the United States or were incorporated into its national territory. We ask why street foods became iconic symbols of ethnic Mexican food in the United States when ethnic Italian food became associated with restaurants. We consider a number of analytical themes in seeking to explain these divergent histories of street foods, including climate, gendered agency, and racial thinking. We conclude that histories of municipal governance, created through empire building and migration, had a determinant role in situating culinary niches within urban landscapes. As newcomers in a vast metropolis, southern Italians were readily confined to existing restaurant structures, whereas Mexicans in nineteenth-century San Antonio, despite their dwindling numbers and political influence, successfully preserved and expanded traditional patterns of street food retailing.
“Partaking of choice poultry cooked a la southern style”
Authors: Bégin Camille
Published: June 2011

This article discusses southern food on, across, and over the color line in 1930s United States. The aim of the article is to show how food was used to rhetorically reinforce and justify segregation while, in practice, foodways and taste preferences tended to sap it. My argument builds on the findings of cultural and social history scholars and the literature on the remaking of the categories of race and ethnicity in 1930s United States. Yet, my analysis is also informed by the field of sensory history and Mark Smith's remark that studying the senses as social constructs is a way to explain the “historically conditioned, visceral, emotional aspect of racial construction and racism.” My research goal is thus to highlight how taste, as a historically defined category of perception, was instrumental in the everyday making of race, gender, and class in the New Deal Era.
Fuel Economy, Car Class Mix, and Safety
Authors: Jacobsen Mark R
Published: June 2011

Fuel economy standards change the composition of the vehicle fleet, potentially influencing accident fatality risks. I estimate the direction and magnitude of this impact, introducing a correction for selection on driver behavior. A policy application using my new estimates shows that the present distinction between light trucks and cars in fuel economy rules has very negative consequences for overall safety: Each MPG increment to the standard results in an additional 150 fatalities per year in expectation. My correction for selection is pivotal in this finding. I then demonstrate a simple alternative regulation that can produce near-zero changes in accident fatalities.
Credit Ratings and Security Prices in the Subprime MBS Market
Authors: Ashcraft Adam , Goldsmith-Pinkham Paul , Hull Peter , Vickery James
Published: June 2011

We present and discuss preliminary evidence suggesting that credit ratings significantly influenced prices for subprime mortgage-backed securities issued in the period leading up to the recent financial crisis. Ratings are closely correlated with prices even controlling for a rich set of security- and loan-level controls. This incremental variation in ratings has much less predictive power for security defaults, however, based on findings to date from our ongoing research, suggesting prices were excessively sensitive to ratings relative to their informational content.
Credit Ratings and the Evolution of the Mortgage-Backed Securities Market
Authors: He Jie , Qian Jun , Strahan Philip E
Published: June 2011

We compare the structure and performance of private (non-GSE) mortgage-backed securities sold by large issuers vs. those sold by small issuers over the period 2000–2006. Securities sold by large issuers have less subordination—a greater fraction of the deal receiving AAA rating—than those sold by small issuers. Prices for AAA-rated and non-AAA rated tranches sold by large issuers fell more when the market turned down than those sold by small issuers, and this difference was concentrated among tranches issued between 2004 and 2006. These results suggest that rating agencies grant favorable ratings to large issuers, especially during market booms.
Wine Retail Price Dispersion in the United States: Searching for Expensive Wines?
Authors: Jaeger David A , Storchmann Karl
Published: June 2011

Similar to other markets in which deviations from Jevons' “law of one price” is the norm rather than the exception, the retail wine market in the United States is characterized by large price dispersions. Drawing on a large sample of retail prices from wine-searcher.com we find an average per-wine coefficient of variation of 23 percent. Some of this is due to differential market conditions, especially state regulations. Our evidence suggests that dispersion also depends positively on price levels, after controlling for consumer, market, and state heterogeneity.
Climate, Grapevine Phenology, Wine Production, and Prices: Pauillac (1800–2009)
Authors: Chevet Jean-Michel , Lecocq Sébastien , Visser Michael
Published: June 2011

This paper analyzes 19th and 20th century data from a well-known château in Bordeaux. The dataset includes information on weather conditions, starting dates of three phenological stages of grapevine, prices, and yields. We discuss how these variables have evolved over the last two centuries. We also study to what extent the impact of climate on yields and prices has changed over time. Our regression analysis suggests that the effect of temperature on yields has become weaker since the 19th century. The influence on prices has, on the contrary, become stronger.