bluuebunny/crossref_metadata_2025 huggingface dataset:
A disjointed effort: paediatric musculoskeletal examination
Authors: Gill Irwin , Sharif Farhana
Published: February 2012

Background

Musculoskeletal (MSK) symptoms are a frequent cause of emergency department attendance for children, and while most often indicative of benign or self-limiting disease, such symptoms can occasionally be the first presentation of serious illness such as leukaemia or juvenile idiopathic arthritis. MSK examination, however, is often not included as part of the routine paediatric examination. The authors aimed to evaluate how often and how thoroughly MSK examination was performed during admissions to the paediatric ward and to compare it with the examination of other symptoms in relation to the presenting complaint and eventual diagnosis.

Results

Medical records for 100 consecutive patients were reviewed. A poster campaign to increase awareness was then commenced along with oral and written presentations to staff regarding MSK examination. A further 100 consecutive patients were then reviewed. Only 9% of children in the initial group had routine MSK examination, rising to 32% in the second group. Where performed, MSK examination was often incomplete. Frequent errors included only examining the reported site of injury and only examining a single limb or single joint when limpness/stiffness was the presenting complaint. Non-limb joints were very rarely examined.

Conclusions

MSK examination is not performed routinely during paediatric admissions in contrast to the examination of other symptoms regardless of the presenting complaint. This may need to be addressed by local audit and increased undergraduate teaching.
Eliciting views on antibiotic prescribing and resistance among hospital and outpatient care physicians in Berlin, Germany: results of a qualitative study
Authors: Velasco Edward , Ziegelmann Antina , Eckmanns Tim , Krause Gérard
Published: February 2012

Objective

To better understand physicians' views on factors of influence for the prescribing of antibiotics and on antibiotic resistance in the Berlin region, Germany.

Design

Qualitative study with focus groups.

Setting

Outpatient care and hospital care practice in the Berlin region, Germany.

Participants

7 General practitioners, two urologists, one paediatrician from outpatient care and eight internists, two paediatricians, two ear, nose and throat specialists and two urologists from hospital care.

Results

Physicians showed differential interest in topics related to antibiotic prescribing and antibiotic resistance. Outpatient care physicians were interested in topics around their own prescribing, such as being able to diagnose and prescribe precisely, and topics about patient demand and non-compliance. Hospital care physicians were interested in hygiene challenges, limited consult time and multi-resistant pathogens.

Conclusions

Physicians considered the development of resistance to be more in the domain of clinical treatment than that of the patient. Major challenges related to antibiotic resistance for this group of physicians are access to and clarity of treatment recommendations, implementation of hygienic measures, as well as increased outsourcing of laboratory services. Results raise questions about whether meeting physicians' expectations should be a focus when developing intervention that aims to influence antibiotic resistance in this and other areas of Germany.
Computerised lung sound analysis to improve the specificity of paediatric pneumonia diagnosis in resource-poor settings: protocol and methods for an observational study
Authors: Ellington Laura E , Gilman Robert H , Tielsch James M , Steinhoff Mark , Figueroa Dante , Rodriguez Shalim , Caffo Brian , Tracey Brian , Elhilali Mounya , West James , Checkley William
Published: February 2012

Introduction

WHO case management algorithm for paediatric pneumonia relies solely on symptoms of shortness of breath or cough and tachypnoea for treatment and has poor diagnostic specificity, tends to increase antibiotic resistance. Alternatives, including oxygen saturation measurement, chest ultrasound and chest auscultation, exist but with potential disadvantages. Electronic auscultation has potential for improved detection of paediatric pneumonia but has yet to be standardised. The authors aim to investigate the use of electronic auscultation to improve the specificity of the current WHO algorithm in developing countries.

Methods

This study is designed to test the hypothesis that pulmonary pathology can be differentiated from normal using computerised lung sound analysis (CLSA). The authors will record lung sounds from 600 children aged ≤5 years, 100 each with consolidative pneumonia, diffuse interstitial pneumonia, asthma, bronchiolitis, upper respiratory infections and normal lungs at a children's hospital in Lima, Peru. The authors will compare CLSA with the WHO algorithm and other detection approaches, including physical exam findings, chest ultrasound and microbiologic testing to construct an improved algorithm for pneumonia diagnosis.

Discussion

This study will develop standardised methods for electronic auscultation and chest ultrasound and compare their utility for detection of pneumonia to standard approaches. Utilising signal processing techniques, the authors aim to characterise lung sounds and through machine learning, develop a classification system to distinguish pathologic sounds. Data will allow a better understanding of the benefits and limitations of novel diagnostic techniques in paediatric pneumonia.
Anaemia and the development of depressive symptoms following acute coronary syndrome: longitudinal clinical observational study
Authors: Steptoe Andrew , Wikman Anna , Molloy Gerard J , Kaski Juan-Carlos
Published: February 2012

Objective

Depressive symptoms are common following acute coronary syndrome (ACS) and predict subsequent cardiovascular morbidity. Depression in acute cardiac patients appears to be independent of clinical disease severity and other cardiovascular measures. One factor that has not been considered previously is anaemia, which is associated with fatigue and adverse cardiac outcomes. This study assessed the relationship between anaemia on admission and depressive symptoms following ACS.

Design

Longitudinal clinical observational study.

Setting

Coronary care unit.

Patients

223 patients with documented ACS.

Main outcome measures

Depressive symptoms measured with the Beck Depression Inventory 3 weeks after admission.

Results

Anaemia was defined with WHO criteria and was present in 30 (13.5%) patients. Anaemia predicted raised depression scores 3 weeks later independently of age, gender, marital status, educational attainment, smoking, Global Registry of Acute Cardiac Events (GRACE) risk scores, negative mood in hospital and history of depression (p=0.003). The odds of a Beck Depression Inventory score ≥10 among anaemic patients were 4.03 (95% CIs 1.48 to 11.00), adjusted for covariates. Sensitivity analyses indicated that effects were also present when haemoglobin was analysed as a continuous measure. Anaemia also predicted major adverse cardiac events over the subsequent 12 months.

Conclusions

Anaemia appears to contribute to depression following ACS and is associated with future cardiac morbidity. Studies evaluating the effects of anaemia management will help delineate the role of this pathway more precisely.
Empirical evidence that disease prevalence may affect the performance of diagnostic tests with an implicit threshold: a cross-sectional study
Authors: Willis Brian H
Published: February 2012

Objective

To investigate the effects that prevalence has on the diagnostic performance of junior doctors in interpreting x-rays.

Design

Two-armed cross-sectional design using systematic sampling.

Setting

Emergency department in the UK.

Participants

From a sample of 2593 patients (1434 men and 1159 women) taken from an unselected attending cohort between January and April 2002, 967 x-rays were analysed. The sex distribution was 558 men and 409 women, and the mean age of those receiving an x-ray was 34.6.

Interventions

The interpretation of x-rays by junior doctors after their triage into high- and low-prevalence populations by radiographers.

Main outcome measures

Sensitivity, specificity, likelihood ratios, diagnostic odds ratios and receiver operator characteristic curve.

Results

There were statistically significant differences in the performance characteristics of junior doctors when interpreting high-probability and low-probability x-rays. For the high- and low-probability populations, respectively, the sensitivities were 95.8% (95% CI 91.1% to 98.1%) and 78.3% (95% CI 65.7% to 87.2%) and the specificities were 56.0% (95% CI 41.9% to 69.2%) and 92.3% (95% CI 90.0% to 94.2%). Hierarchical logistic regression showed that the sensitivity did depend on the type of x-ray being interpreted but the diagnostic odds ratios did not vary significantly with prevalence, suggesting that doctors were changing their implicit threshold between the two populations along a common receiver operator characteristic curve.

Conclusions

This study provides evidence on how the prevalence may affect the performance of diagnostic tests with an implicit threshold and potentially includes the clinical history and examination. This has implications both for clinicians applying research findings to their practice and the design of future studies.
Utility of routine follow-up head CT scanning after mild traumatic brain injury: a systematic review of the literature
Authors: Stippler Martina , Smith Carl , McLean A Robb , Carlson Andrew , Morley Sarah , Murray-Krezan Cristina , Kraynik Jessica , Kennedy George
Published: February 2012

Objective

To evaluate the efficacy of routine follow-up CT scans of the head after complicated mild traumatic brain injury (TBI).

Methods

74 English language studies published from 1999 to February 2011 were reviewed. The papers were found by searching the PubMed database using a combination of keywords according to Cochrane guidelines. Excluding studies with missing or inappropriate data, 1630 patients in 19 studies met the inclusion criteria: complicated mild TBI, defined as a GCS score 13–15 with abnormal initial CT findings and the presence of follow-up CT scans. For these studies, the progression and type of intracranial haemorrhage, time from trauma to first scan, time between first and second scans, whether second scans were obtained routinely or for neurological decline and the number of patients who had a neurosurgical intervention were recorded.

Results

Routine follow-up CT scans showed hemorrhagic progression in 324 patients (19.9%). Routine follow-up head CT scans did not predict the need for neurosurgical intervention (p=0.10) but a CT scan of the head performed for decline in status did (p=0.00046). For the 56 patients (3.4%) who declined neurologically, findings on the second CT scan were worse in 38 subjects (67%) and unchanged in the rest. Overall, 39 patients (2.4%) underwent neurosurgical intervention.

Conclusion

Routine follow-up CT scans rarely alter treatment for patients with complicated mild TBI. Follow-up CT scans based on neurological decline alter treatment five times more often than routine follow-up CT scans.
School dropout: a major public health challenge: a 10-year prospective study on medical and non-medical social insurance benefits in young adulthood, the Young-HUNT 1 Study (Norway)
Authors: De Ridder Karin A A , Pape Kristine , Johnsen Roar , Westin Steinar , Holmen Turid Lingaas , Bjørngaard Johan Håkon
Published: February 2012

Background

School and work participation in adolescence and young adulthood are important for future health and socioeconomic status. The authors studied the association between self-rated health in adolescents, high school dropout and long-term receipt of medical and non-medical social insurance benefits in young adulthood.

Methods

Self-rated health in adolescence was assessed in 8795 adolescents participating in the Norwegian Young-HUNT Study (1995–1997). Linkages to the National Education Database and the National Insurance Administration allowed identification of school dropout and receipt of long-term medical and non-medical benefits during a 10-year follow-up (1998–2007). The data were explored by descriptive statistics and by multinomial logistic regression.

Results

A total of 17% was registered as being high school dropouts at age 24. The predicted 5-year risk of receiving benefits between ages 24–28 was 21% (95% CI 20% to 23%). High school dropouts had a 5-year risk of receiving benefits of 44% (95% CI 41 to 48) compared with 16% (95% CI 15 to 17) in those who completed high school (adjusted for self-rated health, parental education and sex). There was a 27% school dropout rate in adolescents who reported poor health compared with 16% in those who reported good health. The predicted 5-year risk of receiving any long-term social insurance benefits in adolescents who reported poor health was 33% (95% CI 30 to 37) compared with 20% (95% CI 19 to 21) in those who reported good health.

Conclusion

The strong association between poor self-rated health in adolescence, high school dropout and reduced work integration needs attention and suggests preventive measures on an individual as well as on a societal level.
Mechanical embolectomy for treatment of large vessel acute ischemic stroke in children
Authors: Tatum James , Farid Hamed , Cooke Daniel , Fullerton Heather , Smith Wade , Higashida Randall , Halbach Van V , Dowd Christopher
Published: February 2012

Background and purpose

The three largest adult stroke trials investigating mechanical embolectomy retrieval devices in acute stroke (the Merci, Multi Merci and Penumbra Pivotal Stroke Trials) excluded children. There is a need to expand the literature on mechanical embolectomy in large vessel pediatric arterial ischemic stroke. This paper reports the use of two mechanical embolectomy devices cleared by the Federal Drug Administration (FDA) in four consecutive cases.

Methods

Our pediatric stroke database from 2002 to the present was reviewed retrospectively. Patients were included if they were diagnosed with an acute large vessel occlusion, were <18 years of age and underwent recanalization with a device cleared by the FDA. Clinical and radiographic results were abstracted from medical record review. The Pediatric National Institutes of Health Stroke Scale (PedNIHSS) score at presentation and at discharge and a pediatric-modified Rankin Scale (Ped-mRS) at approximately 90 days were scored retrospectively based on documented examinations.

Results

Four patients aged 4–17 years with a PedNIHSS score at presentation ranging from 2 to 17 points underwent mechanical embolectomy for reperfusion of the basilar artery (n=3), M1 segment of the right middle cerebral artery (n=1) and right internal carotid artery terminus (n=1). Thrombolysis in cerebral infarction (TICI) grade 3 was achieved in four vessels and TICI grade 2A was achieved in one vessel; there was one asymptomatic intraparenchymal hemorrhage. Intra-arterial tissue plasminogen activator was administered in two vessels. The PedNIHSS score at discharge ranged from 0 to 16 points and the Ped-mRS score at approximately 90 days ranged from 0 to 3 with 75% achieving a Ped-mRS score of ≤2.

Conclusion

Mechanical embolectomy using the Merci and Penumbra systems may be a feasible therapeutic option in the treatment of large vessel pediatric arterial ischemic stroke.
ENTROPY STRUCTURE OF A CROSS-DIFFUSION TUMOR-GROWTH MODEL
Authors: JÜNGEL ANSGAR , STELZER INES VIKTORIA
Published: February 2012

The mechanical tumor-growth model of Jackson and Byrne is analyzed. The model consists of nonlinear parabolic cross-diffusion equations in one space dimension for the volume fractions of the tumor cells and the extracellular matrix (ECM). It describes tumor encapsulation influenced by a cell-induced pressure coefficient. The global-in-time existence of bounded weak solutions to the initial-boundary-value problem is proved when the cell-induced pressure coefficient is smaller than a certain explicit critical value. Moreover, when the production rates vanish, the volume fractions converge exponentially fast to the homogeneous steady state. The proofs are based on the existence of entropy variables, which allows for a proof of the non-negativity and boundedness of the volume fractions, and of an entropy functional, which yields gradient estimates and provides a new thermodynamic structure. Numerical experiments using the entropy formulation of the model indicate that the solutions exist globally in time also for cell-induced pressure coefficients larger than the critical value. For such coefficients, a peak in the ECM volume fraction forms and the entropy production density can be locally negative.
Robofest kick-off for CSED week at Lawrence Tech
Authors: Chung Chan Jin
Published: February 2012

Robofest 2012 kick-off informational meeting was held during the CS Ed week on Dec 5, 2011, at Lawrence Technological University in Southfield, Michigan. The meeting was also joined by several people across the nation via Webinar.
Non-sequential decomposition, composition and presentation of multimedia content
Authors: del Fabro Manfred
Published: February 2012

This thesis discusses three major issues that arise in the context of non-sequential usage of multimedia content, i.e. a usage, where users only access content that is interesting for them. These issues are (1) semantically meaningful segmentation of videos, (2) composition of new video streams with content from different sources and (3) non-sequential presentation of multimedia content.
Bariatric surgery to unload the stressed heart: a metabolic hypothesis
Authors: Algahim Mohamed F. , Sen Shiraj , Taegtmeyer Heinrich
Published: February 2012

Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.
Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms
Authors: Stenberg Thor Allan , Kildal Anders Benjamin , How Ole-Jakob , Myrmel Truls
Published: February 2012

Adrenomedullin (AM) used therapeutically reduces mortality in the acute phase of experimental myocardial infarction. However, AM is potentially deleterious in acute heart failure as it is vasodilative and inotropically neutral. AM and epinephrine (EPI) are cosecreted from chromaffin cells, indicating a physiological interaction. We assessed the hemodynamic and energetic profile of AM-EPI cotreatment, exploring whether drug interaction improves cardiac function. Left ventricular (LV) mechanoenergetics were evaluated in 14 open-chest pigs using pressure-volume analysis and the pressure-volume area-myocardial O2 consumption (PVA-MV˙o2) framework. AM (15 ng·kg−1·min−1, n = 8) or saline (controls, n = 6) was infused for 120 min. Subsequently, a concurrent infusion of EPI (50 ng·kg−1·min−1) was added in both groups (AM-EPI vs. EPI). AM increased cardiac output (CO) and coronary blood flow by 20 ± 10% and 39 ± 14% (means ± SD, P < 0.05 vs. baseline), whereas controls were unaffected. AM-EPI increased CO and coronary blood flow by 55 ± 17% and 75 ± 16% ( P < 0.05, AM-EPI interaction) compared with 13 ± 12% ( P < 0.05 vs. baseline) and 18 ± 31% ( P = not significant) with EPI. LV systolic capacitance decreased by −37 ± 22% and peak positive derivative of LV pressure (dP/d tmax) increased by 32 ± 7% with AM-EPI ( P < 0.05, AM-EPI interaction), whereas no significant effects were observed with EPI. Mean arterial pressure was maintained by AM-EPI and tended to decrease with EPI (+2 ± 13% vs. −11 ± 10%, P = not significant). PVA-MV˙o2 relationships were unaffected by all treatments. In conclusion, AM-EPI cotreatment has an inodilator profile with CO and LV function augmented beyond individual drug effects and is not associated with relative increases in energetic cost. This can possibly take the inodilator treatment strategy beyond hemodynamic goals and exploit the cardioprotective effects of AM in acute heart failure.
Electromechanical and structural alterations in the aging rabbit heart and aorta
Authors: Cooper Leroy L. , Odening Katja E. , Hwang Min-Sig , Chaves Leonard , Schofield Lorraine , Taylor Chantel A. , Gemignani Anthony S. , Mitchell Gary F. , Forder John R. , Choi Bum-Rak , Koren Gideon
Published: February 2012

Aging increases the risk for arrhythmias and sudden cardiac death (SCD). We aimed at elucidating aging-related electrical, functional, and structural changes in the heart and vasculature that account for this heightened arrhythmogenic risk. Young (5–9 mo) and old (3.5–6 yr) female New Zealand White (NZW) rabbits were subjected to in vivo hemodynamic, electrophysiological, and echocardiographic studies as well as ex vivo optical mapping, high-field magnetic resonance imaging (MRI), and histochemical experiments. Aging increased aortic stiffness (baseline pulse wave velocity: young, 3.54 ± 0.36 vs. old, 4.35 ± 0.28 m/s, P < 0.002) and diastolic (end diastolic pressure-volume relations: 3.28 ± 0.5 vs. 4.95 ± 1.5 mmHg/ml, P < 0.05) and systolic (end systolic pressure-volume relations: 20.56 ± 4.2 vs. 33.14 ± 8.4 mmHg/ml, P < 0.01) myocardial elastances in old rabbits. Electrophysiological and optical mapping studies revealed age-related slowing of ventricular and His-Purkinje conduction (His-to-ventricle interval: 23 ± 2.5 vs. 31.9 ± 2.9 ms, P < 0.0001), altered conduction anisotropy, and a greater inducibility of ventricular fibrillation (VF, 3/12 vs. 7/9, P < 0.05) in old rabbits. Histochemical studies confirmed an aging-related increased fibrosis in the ventricles. MRI showed a deterioration of the free-running Purkinje fiber network in ventricular and septal walls in old hearts as well as aging-related alterations of the myofibrillar orientation and myocardial sheet structure that may account for this slowed conduction velocity. Aging leads to parallel stiffening of the aorta and the heart, including an increase in systolic stiffness and contractility and diastolic stiffness. Increasingly, anisotropic conduction velocity due to fibrosis and altered myofibrillar orientation and myocardial sheet structure may contribute to the pathogenesis of VF in old hearts. The aging rabbit model represents a useful tool for elucidating age-related changes that predispose the aging heart to arrhythmias and SCD.
Aspirin Prophylaxis for the Prevention of Thrombosis: Expectations and Limitations
Authors: Rao Gundu H. R. , Fareed Jawad
Published: February 2012

Platelets play a very important role in the pathogenesis of acute vascular events leading to thrombosis of the coronary and cerebral arteries. Blockage of these arteries leading to regional ischemia of heart and brain tissues precipitate heart attacks and stroke. Acetyl salicylic acid (Aspirin) has been the drug of choice for over half a century for the primary and secondary prophylaxis of thrombotic events. In spite of its extensive use as an antiplatelet drug for the prevention of vascular thrombosis, there is considerable concern about the degree of protection it offers, to patients under aspirin therapy. In this paper, we explain the phenomenon of aspirin resistance, discuss the limitations of aspirin therapy, and suggest methods to monitor “at-risk” individuals. Ability to monitor and determine at risk patients will provide opportunities for the clinicians to customize antiplatelet therapies.
Reprogramming Tumor-Associated Dendritic Cells In Vivo Using miRNA Mimetics Triggers Protective Immunity against Ovarian Cancer
Authors: Cubillos-Ruiz Juan R. , Baird Jason R. , Tesone Amelia J. , Rutkowski Melanie R. , Scarlett Uciane K. , Camposeco-Jacobs Ana L. , Anadon-Arnillas Jorge , Harwood Noah M. , Korc Murray , Fiering Steven N. , Sempere Lorenzo F. , Conejo-Garcia Jose R.
Published: February 2012

Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics. Cancer Res; 72(7); 1683–93. ©2012 AACR.
Mammary Tumor Regression Elicited by Wnt Signaling Inhibitor Requires IGFBP5
Authors: Liu Bob Y. , Soloviev Irina , Huang XiaoDong , Chang Peter , Ernst James A. , Polakis Paul , Sakanaka Chie
Published: February 2012

Wnt ligand–driven tumor growth is inhibited by the soluble Wnt inhibitor Fzd8CRD, but the mechanism through which this effect is mediated is unknown. In the MMTV-Wnt1 mouse model, regression of mammary tumors by Fzd8CRD treatment coincides with an acute and strong induction of insulin-like growth factor (IGF)–binding protein IGFBP5, an antagonist of IGF signaling that mediates involution of mammary gland in females after offspring are weaned. In this study, we show that repression of this IGF inhibitory pathway is crucial for Wnt-driven growth of mammary tumors. We found that IGFBP5 regulation was mediated by the β-catenin–dependent Wnt pathway. Wnt, in addition to IGF ligands, facilitated tumor growth by paracrine communication among tumor cells. In addition, Fzd8CRD caused precocious induction of IGFBP5 in normal mammary glands undergoing involution, implying an acceleration of the involution process by inhibition of Wnt signaling. The molecular and phenotypic parallel between tumor regression and mammary gland involution suggests that Wnt-driven mammary tumors use the same growth mechanism as proliferating normal mammary glands. Cancer Res; 72(6); 1568–78. ©2012 AACR.
A Population-Based Study of Prevalence and Adherence Trends in Average Risk Colorectal Cancer Screening, 1997 to 2008
Authors: Sinicrope Pamela S. , Goode Ellen L. , Limburg Paul J. , Vernon Sally W. , Wick Joseph B. , Patten Christi A. , Decker Paul A. , Hanson Andrew C. , Smith Christina M. , Beebe Timothy J. , Sinicrope Frank A. , Lindor Noralane M. , Brockman Tabetha A. , Melton L. Joseph , Petersen Gloria M.
Published: February 2012

Background: Increasing colorectal cancer screening (CRCS) is important for attaining the Healthy People 2020 goal of reducing CRC-related morbidity and mortality. Evaluating CRCS trends can help identify shifts in CRCS, and specific groups that might be targeted for CRCS.

Methods: We utilized medical records to describe population-based adherence to average-risk CRCS guidelines from 1997 to 2008 in Olmsted County, MN. CRCS trends were analyzed overall and by gender, age, and adherence to screening mammography (women only). We also carried out an analysis to examine whether CRCS is being initiated at the recommended age of 50.

Results: From 1997 to 2008, the size of the total eligible sample ranged from 20,585 to 21,468 people. CRCS increased from 22% to 65% for women and from 17% to 59% for men (P < 0.001 for both) between 1997 and 2008. CRCS among women current with mammography screening increased from 26% to 74%, and this group was more likely to be adherent to CRCS than all other subgroups analyzed (P < 0.001).The mean ages of screening initiation were stable throughout the study period, with a mean age of 55 years among both men and women in 2008.

Conclusion: Although overall CRCS tripled during the study period, there is still room for improvement.

Impact: Working to decrease the age at first screening, exploration of gender differences in screening behavior, and targeting women adherent to mammography but not to CRCS seem warranted. Cancer Epidemiol Biomarkers Prev; 21(2); 347–50. ©2011 AACR.
ω-3 and ω-6 Polyunsaturated Fatty Acid Intakes and the Risk of Breast Cancer in Mexican Women: Impact of Obesity Status
Authors: Chajès Véronique , Torres-Mejía Gabriela , Biessy Carine , Ortega-Olvera Carolina , Angeles-Llerenas Angélica , Ferrari Pietro , Lazcano-Ponce Eduardo , Romieu Isabelle
Published: February 2012

Background: ω-3 polyunsaturated fatty acids (PUFA) could play a protective role on the risk of breast cancer; however, little is known about this relation among Mexican women. We evaluated the association between ω-3 and ω-6 PUFA intake and breast cancer risk by obesity status in Mexican women.

Methods: A population-based case–control study was conducted in Mexico, including 1,000 incident breast cancer cases and 1,074 controls matched to cases by age, health care system, and region. Women provided information on health and diet by in-person interview. Body mass index (BMI) measures were used to define overall obesity. Obesity status was categorized as normal weight (18.5 < BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). A conditional logistic regression model was used to assess the association between PUFA and breast cancer risk.

Results: Overall, there was no significant association between ω-3 PUFA intake and breast cancer risk (P = 0.31). An increased risk of breast cancer was associated with increasing ω-6 PUFA intake in premenopausal women [OR = 1.92, 95% confidence interval (CI) = 1.13–3.26; P = 0.04]. A decreased risk of breast cancer was significantly associated with increasing ω-3 PUFA intake in obese women (OR = 0.58, 95% CI = 0.39–0.87; P = 0.008) but not in normal weight nor in overweight women (Pheterogeneity = 0.017).

Conclusions: Obesity status may affect the association between ω-3 PUFA intake and breast cancer risk. The underlying mechanisms may be related to decreased inflammation and improved adipokin and estrogen levels induced by ω-3 PUFA in adipose tissue in obese women.

Impact: Increased intake of ω-3 PUFA should be recommended among Mexican women in particular in obese women. Cancer Epidemiol Biomarkers Prev; 21(2); 319–26. ©2011 AACR.
Coffee, Tea, and Sugar-Sweetened Carbonated Soft Drink Intake and Pancreatic Cancer Risk: A Pooled Analysis of 14 Cohort Studies
Authors: Genkinger Jeanine M. , Li Ruifeng , Spiegelman Donna , Anderson Kristin E. , Albanes Demetrius , Bergkvist Leif , Bernstein Leslie , Black Amanda , van den Brandt Piet A. , English Dallas R. , Freudenheim Jo L. , Fuchs Charles S. , Giles Graham G. , Giovannucci Edward , Goldbohm R. Alexandra , Horn-Ross Pamela L. , Jacobs Eric J. , Koushik Anita , Männistö Satu , Marshall James R. , Miller Anthony B. , Patel Alpa V. , Robien Kim , Rohan Thomas E. , Schairer Catherine , Stolzenberg-Solomon Rachael , Wolk Alicja , Ziegler Regina G. , Smith-Warner Stephanie A.
Published: February 2012

Background: Coffee has been hypothesized to have pro- and anticarcinogenic properties, whereas tea may contain anticarcinogenic compounds. Studies assessing coffee intake and pancreatic cancer risk have yielded mixed results, whereas findings for tea intake have mostly been null. Sugar-sweetened carbonated soft drink (SSB) intake has been associated with higher circulating levels of insulin, which may promote carcinogenesis. Few prospective studies have examined SSB intake and pancreatic cancer risk; results have been heterogeneous.

Methods: In this pooled analysis from 14 prospective cohort studies, 2,185 incident pancreatic cancer cases were identified among 853,894 individuals during follow-up. Multivariate (MV) study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and then pooled using a random-effects model.

Results: No statistically significant associations were observed between pancreatic cancer risk and intake of coffee (MVRR = 1.10; 95% CI, 0.81–1.48 comparing ≥900 to <0 g/d; 237g ≈ 8oz), tea (MVRR = 0.96; 95% CI, 0.78–1.16 comparing ≥400 to 0 g/d; 237g ≈ 8oz), or SSB (MVRR = 1.19; 95% CI, 0.98–1.46 comparing ≥250 to 0 g/d; 355g ≈ 12oz; P value, test for between-studies heterogeneity > 0.05). These associations were consistent across levels of sex, smoking status, and body mass index. When modeled as a continuous variable, a positive association was evident for SSB (MVRR = 1.06; 95% CI, 1.02–1.12).

Conclusion and Impact: Overall, no associations were observed for intakes of coffee or tea during adulthood and pancreatic cancer risk. Although we were only able to examine modest intake of SSB, there was a suggestive, modest positive association for risk of pancreatic cancer for intakes of SSB. Cancer Epidemiol Biomarkers Prev; 21(2); 305–18. ©2011 AACR.
Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype
Authors: Wu Richard C. , Liu Shujuan , Chacon Jessica A. , Wu Sheng , Li Yufeng , Sukhumalchandra Pariya , Murray James L. , Molldrem Jeffrey J. , Hwu Patrick , Pircher Hanspeter , Lizée Gregory , Radvanyi Laszlo G.
Published: February 2012

Purpose: Tumor-specific T cells are frequently induced naturally in melanoma patients and infiltrate tumors. It is enigmatic why these patients fail to experience tumor regression. Given that CD8+ T cells mediate antigen-specific killing of tumor cells, the focus of this study was to identify alterations in the differentiation of CD8+ residing at the tumor site, with emphasis on a population expressing CD57, a marker for terminal differentiation.

Experimental Design: We conducted flow cytometric analysis of CD8+ tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases with known T-cell differentiation markers. For comparison, peripheral blood mononuclear cells were isolated from matched melanoma patients. We sorted different CD8+ subsets found in TIL and determined their effector functions. In addition, we carried out Vβ clonotype expression analysis of T-cell receptors to determine lineage relationship between the CD8+ TIL subsets.

Results: The majority of CD8+ TIL was in the early-effector memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells coexpressing CD27, CD28, CD57, and Granzyme B, with little or no perforin. These cells could be induced to proliferate, produce a high level of IFN-γ, and differentiate into CD27−CD57+, perforinhigh mature CTL in vitro. Addition of TGF-β1 prevented further differentiation.

Conclusions: Our studies identified a novel subset of incompletely differentiated CD8+ CTL coexpressing early effector memory and late CTL markers. This population resembles that found in patients with uncontrolled chronic viral infections. TGF-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting further maturation of this subset. Clin Cancer Res; 18(9); 2465–77. ©2012 AACR.
Sorafenib Is an Inhibitor of UGT1A1 but Is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia
Authors: Peer Cody J. , Sissung Tristan M. , Kim AeRang , Jain Lokesh , Woo Sukyung , Gardner Erin R. , Kirkland C. Tyler , Troutman Sarah M. , English Bevin C. , Richardson Emily D. , Federspiel Joel , Venzon David , Dahut William , Kohn Elise , Kummar Shivaani , Yarchoan Robert , Giaccone Giuseppe , Widemann Brigitte , Figg William D.
Published: February 2012

Purpose: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)5/6/7 repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.

Experimental Design: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.

Results: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC50 = 18 μmol/L; Ki = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R2 = 0.38 and R2 = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.

Conclusions: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. Clin Cancer Res; 18(7); 2099–107. ©2012 AACR.
Defeminization of Brain Functions by a Single Injection of Estrogen Receptor α or β Agonist in Neonatal Female Rats
Authors: Kanaya Moeko , Yamanouchi Korehito
Published: February 2012

Sexual differentiation of brain function is regulated by estrogen in the perinatal period of rodents. However, the role of the estrogen receptor subtypes ERα and ERβ is still in question. Accordingly, the effects of neonatal treatment with the ERα agonist propyl pyrazole triol (PPT) or the ERβ agonist diarylpropionitrile (DPN) on female reproductive functions were investigated in rats. Female rats were injected subcutaneously with 100–500 µg/10 g body weight (b.w.) PPT or DPN, 100 µg/10 g b.w. estradiol (E2), or saline at day 5 (birth day = day 1), and then vaginal opening and vaginal smears were examined. On day 60, their ovaries were removed and lordosis behavior was observed after subcutaneous implantation of a silicon tube containing E2. As a result, in most PPT and all E2 rats, vaginal opening was advanced and an irregular estrous cycle was observed. In contrast, in most rats of the DPN groups, vaginal opening was comparable to that of the control and there was a regular estrous cycle. Lordosis tests revealed that the mean lordosis quotients (LQs) in the 250- and 500-µg PPT groups was lower than in the saline group, but higher than in the E2 group. Mean LQs in all DPN groups were comparable to those in the saline group. These results suggest that ERα plays a major role in masculinization of the system regulating the estrous cycle in the rat brain. In behavioral defeminization of the lordosis-regulation system, ERα was also found to be the main target of estrogen.
The Novel WHO 2010 Classification for Gastrointestinal Neuroendocrine Tumours Correlates Well with the Metastatic Potential of Rectal Neuroendocrine Tumours
Authors: Jernman Juha , Välimäki Matti J. , Louhimo Johanna , Haglund Caj , Arola Johanna
Published: February 2012

Background: Approximately 10–15% of gastroenteropancreatic neuroendocrine tumours (NETs, carcinoids) occur in the rectum, some of which are potentially able to metastasize. The new WHO 2010 classification of NETs applies to all gastroenteropancreatic NETs, but no reports have studied its correlation with the prognosis of rectal NETs. Patients and Methods: We retrospectively classified 73 rectal NETs according to the novel WHO 2010 and the previous WHO 2000 classifications. The aim was to assess the validity of the classifications in distinguishing indolent rectal NETs from metastasising tumours. Results: Using the WHO 2010 criteria, we identified 61 G1 tumours, none of which had metastasised during follow-up. Of 11 G2 tumours, 9 had shown distant metastases. The only G3 neuroendocrine carcinoma that occurred had been disseminated at initial presentation. Conclusion: Our results show that rectal NETs classified as G1 according to the WHO 2010 classification have an indolent clinical course, whereas G2 NETs often metastasise. The WHO 2010 classification of NETs predicts the metastatic potential of rectal NETs better than the WHO 2000 classification.
Differential Ontogenetic Patterns of in vitro Desensitization to GHRH in Fetal and Neonatal Anterior Pituitary
Authors: Torronteras R. , Canalejo A. , Elsaesser F.
Published: February 2012

The aim of this study was to assess the ontogenetic changes in vitro in both the responsiveness of anterior pituitary tissue to growth hormone-releasing hormone (GHRH) and the critical role of GHRH in the long-term regulation of pulsatile GH secretion during perinatal porcine life. A superfusion system was used to apply three consecutive 10-min pulses of GHRH (the first of 1 nM and the other two of 10 nM) for 3 consecutive days in pituitary glands isolated from fetal (95- and 110-day) and neonatal (12-day) male pigs. In fetuses, total GHRH-induced GH release decreased progressively over the 3 days. However, in neonates, GH did not decrease until day 3, but remained higher than in fetuses. When each GH pulse was assessed individually, fetuses showed a similar pattern. GH secretion induced by the first GHRH pulse on days 1 and 2 was lower than that induced by the second and third pulses. By day 3, GH release lowered dramatically after all pulses. In contrast, in neonates no differences were observed among the GH levels induced by the three GHRH pulses at any day, although day 3 showed lower GH rates. In conclusion, during perinatal development, a desensitizing effect to long-term repetitive GHRH pulses was observed in both fetuses and neonates, but this effect was delayed in neonates. Thus, the capacity of somatotrope cells to maintain GH response to GHRH seems to be developmentally regulated during perinatal stages. Furthermore, the frequency of GHRH pulses, rather than the concentrations, might be a key factor to elicit desensitization.
45,X Maleness: Clinical and Cytogenetic Features in Two Patients
Authors: Dati E. , Valetto A. , Bertini V. , Chiocca E. , Baroncelli G.I. , Battini R. , Bertelloni S.
Published: February 2012

45,X maleness is a very rare disorder. We report on 2 new 45,X males aged 9 10/12 and 39 years, respectively. The boy presented for developmental delay, while the man was referred to us because of infertility. Both patients showed short stature (boy –2.29 SDS, man –4.05 SDS) and an unbalanced translocation of Yp, including SRY, onto the long arm of chromosome 10 and short arm of chromosome 14, respectively. The growth pattern of the 2 patients and literature data suggest the presence of a specific growth gene in the pericentrometric region of Yq. In addition, developmental delay in some 45,X males may be related to specific deletion of telomeric autosome regions, but involvement of gene(s) on the Y chromosome may play a role as well. Albeit in the boy inhibin B levels were in the normal range for age, azoospermia was demonstrated in the adult, supporting that infertility is a feature of adult 45,X men with AZFa–c deletion.
Pneumatic Ureteroscopic Lithotripsy: Is It Still a Reasonable Treatment Option for Multiple Ureteric Stones?
Authors: Isen Kenan
Published: February 2012

Objectives: To assess the efficacy and safety of ureteroscopic pneumatic lithotripsy for multiple ureteric stones. Materials and Methods: 36 patients with multiple ureteric stones were treated with ureteroscopic lithotripsy (URSL). A 8/9.8-Fr Wolf semirigid ureteroscope and pneumatic lithotripter were used for stone fragmentation. Results: 87 stones were treated with URSL. Successful fragmentation was achieved in 77 (88.5%) of the stones. The retreatment rate was 11.5%. The stone-free rate (SFR) of lower ureteric stones (93.3%) and middle ureteric stones (87.5%) was significantly higher compared with upper (73.3%) ureteric stones (p < 0.05). For patients with stones less than 1 cm and greater than 1 cm, the SFR was 91.5 and 75.0%, respectively (p < 0.05). Perforation occurred in 1 patient, mucosal injury occurred in 5 and stone migration in 5. No long-term complication was observed in any patient. Conclusions: Ureteroscopic pneumatic lithotripsy is still a reasonable treatment option for multiple ureteric stones. The procedure has high success rates with minimal morbidity. However, success rate can be affected by stone size and ureteric location.