bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC
Authors: Fenouille Nina , Puissant Alexandre , Dufies Maeva , Robert Guillaume , Jacquel Arnaud , Ohanna Mickaël , Deckert Marcel , Pasquet Jean-Max , Mahon François-Xavier , Cassuto Jill-Patrice , Raynaud Sophie , Tartare-Deckert Sophie , Auberger Patrick
Published: November 2010

SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)–resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC. Cancer Res; 70(23); 9659–70. ©2010 AACR.
An Ex(o)citing Machinery for Invasive Tumor Growth
Authors: Hendrix An , Westbroek Wendy , Bracke Marc , De Wever Olivier
Published: November 2010

Cancer cells communicate with the environment through delivery of surface proteins, release of soluble factors (growth factors and cytokines), and sophisticated nanovehicles (exosomes) for establishment of invasive tumor growth. This communication occurs in part through constitutive exocytosis, regulated exocytosis, or release of intraluminal vesicles, and is modulated by small Rab GTPases, the master regulators of vesicle traffic. We studied Rab GTPases implicated in regulated exocytosis and showed a unique role for Rab27B in invasive tumor growth. Emerging evidence indicates that various exocytic routes are implemented by cancer cells to relay crucial information for fostering growth, migration, and matrix degradation. Cancer Res; 70(23); 9533–7. ©2010 AACR.
Plectin-1 as a Novel Biomarker for Pancreatic Cancer
Authors: Bausch Dirk , Thomas Stephanie , Mino-Kenudson Mari , Fernández-del Castillo Carlos , Bauer Todd W. , Williams Mark , Warshaw Andrew L. , Thayer Sarah P. , Kelly Kimberly A.
Published: November 2010

Purpose: We are in great need of specific biomarkers to detect pancreatic ductal adenocarcinoma (PDAC) at an early stage, ideally before invasion. Plectin-1 (Plec1) was recently identified as one such biomarker. However, its suitability as a specific biomarker for human pancreatic cancer, and its usability as an imaging target, remain to be assessed.

Experimental Design: Specimens of human PDAC, chronic pancreatitis, and normal pancreata were evaluated by immunohistochemistry and Western blot analysis. To validate Plec1 as an imaging target, Plec1-targeting peptides (tPTP) were used as a contrast agent for single photon emission computed tomography in an orthotopic and liver metastasis murine model of PDAC.

Results: Plec1 expression was noted to be positive in all PDACs but negative in benign tissues. Plec1 expression increases during pancreatic carcinogenesis. It was found to be misexpressed in only 0% to 3.85% of early PDAC precursor lesions (PanIN I/II) but in 60% of PanIN III lesions. Plec1 expression was further noted to be retained in all metastatic foci assayed and clearly highlighted these metastatic deposits in lymph nodes, liver, and peritoneum. In vivo imaging using tPTP specifically highlighted the primary and metastatic tumors. Biodistribution studies performed after imaging show that the primary pancreatic tumors and liver metastases retained 1.9- to 2.9-fold of tPTP over normal pancreas and 1.7-fold over normal liver.

Conclusions: Plec1 is the first biomarker to identify primary and metastatic PDAC by imaging and may also detect preinvasive PanIN III lesions. Strategies designed to image Plec1 could therefore improve detection and staging. Clin Cancer Res; 17(2); 302–9. ©2010 AACR.
Caveolin-1 Modulates the Ability of Ewing's Sarcoma to Metastasize
Authors: Sáinz-Jaspeado Miguel , Lagares-Tena Laura , Lasheras Jaime , Navid Fariba , Rodriguez-Galindo Carlos , Mateo-Lozano Silvia , Notario Vicente , Sanjuan Xavier , Garcia del Muro Xavier , Fabra Àngels , Tirado Oscar M.
Published: November 2010

Metastasis is the final stage of tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors. Caveolin-1 (CAV1) regulates multiple cancer-associated processes related to malignant tumor progression. In the present study, we tested the hypothesis that CAV1 modulates the metastatic ability of cells from the Ewing's sarcoma family of tumors (ESFT). First, we analyzed the expression of CAV1 by immunostaining a tissue microarray containing 43 paraffin-embedded ESFT tumors with known EWS translocations. Even though no evidence was found for a significant association between CAV1 expression and stage, size or tumor site, all metastatic samples (10 of 10) had significantly high CAV1 expression, suggesting that high CAV1 content could positively contribute to enhance ESFT metastasis. To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct. In vitro, migration and invasion assays showed that for both cell lines, CAV1 knocked-down cells migrated and invaded significantly less (P ≤ 0.01) than control cells. Moreover, control A673 cells introduced into BALB/c nude mice by tail vein injection strongly colonized the lungs. In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P < 0.0001). Finally, we show that the molecular mechanisms by which CAV1 carries out its key role in regulating ESFT metastasis involve matrix metalloproteinase production and activation as well as the control of the expression of SPARC, a known determinant of lung colonization. Mol Cancer Res; 8(11); 1489–500. ©2010 AACR.
Non-Diagnostic Rates for Thyroid Fine Needle Aspiration Are Negatively Correlated with Positive for Malignancy Rates
Authors: Renshaw Andrew A.
Published: November 2010

Introduction: Non-diagnostic rates for thyroid fine needle aspiration vary considerably, but reasons for this variation are poorly understood. Methods: Our group reviewed the results of all thyroid aspirations with surgical resection for the last 13 years at our institutions, combined these with those in the literature, and correlated non-diagnostic rates with positivity rates. Results: Non-diagnostic rates were negatively correlated with positivity rates (R2 = 0.55). Studies that had significantly lower non-diagnostic rates than the rest of the literature (2 vs. 15%, p = 0.002) had different or undefined adequacy criteria or used core biopsies in addition to fine needle aspiration. Conclusions: Non-diagnostic rates for thyroid fine needle aspirations are negatively correlated with positivity rates. These data provide more realistic estimates of achievable adequacy rates.
The Glasgow Prognostic Score Is a Good Predictor of Treatment Outcome in Patients with Unresectable Pancreatic Cancer
Authors: Shimoda Mitsugi , Katoh Masato , Kita Junji , Sawada Tokihiko , Kubota Keiichi
Published: November 2010

Background: We analyzed the outcome of patients with advanced unresectable pancreatic cancer treated in our department from 2001 to 2008. Methods: Of the 83 patients included in this study, 50 patients received single-agent treatment with gemcitabine (GEM), 9 patients GEM combined with radiotherapy (GEM+R) and 24 patients had best supportive care (BSC). We analyzed survival rates among the groups and risk factors for each group. Results: The 3-year survival rates were dismal: GEM group 2.9%, GEM+R group 0% and BSC group 0%. Significant prognostic factors of the study were: performance status (PS), response rate and decrease in the CA19-9 level. Significant prognostic factors by the Cox proportional hazard model were the albumin level prior to treatment, CA19-9 levels before treatment, decrease in CA19-9 and response rate. Albumin levels and the Glasgow Prognostic Score (GPS) were found to be factors affecting survival in the GEM group. Conclusion: In this series of patients with unresectable pancreatic cancer, good PS, decrease in CA19-9 after treatment and good GPS determined prior to treatment were independent prognostic factors for better overall survival.
Alopecic and Aseptic Nodules of the Scalp (Pseudocyst of the Scalp): A Prospective Clinicopathological Study of 15 Cases
Authors: Abdennader Sami , Vignon-Pennamen Marie-Dominique , Hatchuel Jean , Reygagne Pascal
Published: November 2010

Background: Alopecic and aseptic nodules of the scalp (AANS) is a new entity reported first in Japan as ‘pseudocyst of the scalp’. Only retrospective studies have been published. Objectives: To describe the clinicopathological features of AANS (pseudocyst), to evaluate the response to doxycycline and to compare the results to those obtained from patients with dissecting cellulitis of the scalp (DCS). Methods: Fifteen patients with AANS and 7 with DCS were prospectively included. A puncture and a biopsy were made. Patients were treated with doxycycline (100 mg/day) for 3 months. Results: AANS affects predominantly young (mean age 29.7 years), Caucasian (11/15), male (14/15) patients. The main location of the nodules was the occiput. The associated alopecia was nonscarring. Material from the puncture was aseptic. The histopathology showed a deep granuloma in 7 of 14 patients and a nonspecific inflammation in 7 patients. After 3 months, 8 patients were cured and 3 had a good response. Conclusions: The singular aspect of the nodules, the nonscarring alopecia, the deep inflammatory infiltrate and the efficacy of doxycycline confer specificity to AANS.
Detection of Merkel Cell Polyomavirus in Epidermodysplasia-Verruciformis-Associated Skin Neoplasms
Authors: Mertz K.D. , Schmid M. , Burger B. , Itin P. , Palmedo G. , Schärer L. , Kutzner H. , Fernández Figueras M.T. , Cribier B. , Pfaltz M. , Kempf W.
Published: November 2010

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis that is characterized by susceptibility to infection with specific human papillomavirus (HPV) genotypes. Among polyomaviruses, the novel Merkel cell polyomavirus (MCPyV) has been found in different epithelial skin neoplasias. Objective: To examine whether EV is associated with cutaneous MCPyV infection. Methods: We used MCPyV-specific PCR to study skin neoplasms of 6 congenital EV patients and of 1 patient with acquired EV. Results: In all congenital EV patients, MCPyV DNA was found in carcinomas in situ, in invasive squamous cell carcinomas and in common warts. In 4 of these patients, the MCPyV-positive skin lesions were from different anatomic locations. In addition, 1 immunosuppressed patient suffering from acquired EV harbored MCPyV DNA in 2 common warts. In contrast, 7 normal skin samples tested negative for MCPyV DNA. Only 2 out of 24 carcinomas in situ (8.3%) and 2 out of 30 common warts (6.7%) from immunocompetent individuals were positive for MCPyV DNA. Conclusions: The strong association of EV-associated skin neoplasms with MCPyV suggests a unique susceptibility of EV patients to infections with MCPyV. Both MCPyV and EV-HPV may act as synergistic oncogenic cofactors in the development of EV-associated skin neoplasms.
Hypothalamic Sites of Leptin Action Linking Metabolism and Reproduction
Authors: Donato, Jr. José , Cravo Roberta M. , Frazão Renata , Elias Carol F.
Published: November 2010

A critical amount of energy reserve is necessary for puberty initiation, for normal sexual maturation and maintenance of cyclicity and fertility in females of most species. Therefore, the existence of circulating metabolic cues which directly modulate the hypothalamus-pituitary-gonad axis is predictable. The adipocyte-derived hormone leptin is one of these cues having been studied extensively in the context of regulating the reproductive physiology. Humans and mice lacking leptin (ob/ob) or leptin receptor (LepR, db/db) are infertile. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility. LepR is expressed in brain, pituitary gland and gonads, but studies using genetically engineered mouse models determined that the brain plays a major role. Recently, it has been made clear that leptin acts indirectly on gonadotropin-releasing hormone (GnRH)-secreting cells via actions on interneurons. However, the exact site(s) of leptin action has been difficult to determine. In this review, we discuss the recent advances in the field focused on the identification of potential site(s) or specific neuronal populations involved in leptin’s effects in the neuroendocrine reproductive axis.
Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays
Authors: Baghaei Fariba , Blixter Inger Fagerberg , Gustafsson Kerstin , Stigendal Lennart , Sten-Linder Margareta , Strandberg Karin , Hillarp Andreas , Lindahl Tomas ,   and from the expert group on coagulation of the External Quality Assurance in Laboratory Medicine in Sweden
Published: November 2010

Dabigatran is an oral, reversible thrombin inhibitor that has shown promising results in large clinical trials. Laboratory monitoring is not needed but the effects on common coagulation assays are incompletely known. Dabigatran was added to plasma from healthy subjects in the concentration range 0–1,000 μg/l and analysed using several reagents for activated thromboplastin time (APTT), prothrombin time (PT), fibrinogen, antithrombin, and activated protein C resistance. Typical trough concentrations are about 50 μg/l, peak concentrations 100–300 μg/l. At 100 μg/l all APTT-results were prolonged. The concentration required to double APTT ranged between 227 and 286 μg/l, the responses for all five reagents were similar. PT-reagents were much less affected with almost no samples above INR 1.2 at 100 μg/l. The effect was sample dilution dependent with PT Quick type more sensitive than PT Owren type methods. If a patient on dabigatran has prolonged APTT, >90 seconds, and Quick PT INR>2 or Owren PT INR>1.5 over-dosing or accumulation of dabigatran should be considered. Two of four fibrinogen reagents underestimated the fibrinogen concentration considerably at expected peak concentration. Methods based on inhibition of thrombin over-estimated the antithrombin concentration, but not Xa-based. The APC-resistance methods over-estimated the APC-ratio, which may lead to miss-classification of factor V Leiden patients as being normal. Different coagulation assays, and even different reagents within an assay group, display variable effects at therapeutic concentrations of dabigatran. Some of these assay variations are of clinical importance, thus knowledge is needed for a correct interpretation of results.
Inflammation, oxidative stress and platelet activation in aspirin-treated critical limb ischaemia: Beneficial effects of iloprost
Authors: Cuccurullo Chiara , Di Michele Dario , Laurora Giuseppe , Sgrò Giuseppe , Di Ruscio Paolo , Simeone Emilio , Di Iorio Pierangelo , Lattanzio Stefano , Liani Rossella , Ferrante Elisabetta , Lessiani Gianfranco , Vazzana Natale , Davì Giovanni
Published: November 2010

Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB2 and 8-iso-PGF2α excretion rate, as in vivoindexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB2 [499 (277 – 807) vs. 380 (189 – 560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF2α [533 (316 – 842) vs. 334 (196 – 540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005 – 3015) vs. 948 (845 – 2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8 – 35.9) vs. 43.7 (33.0 – 75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.
Drug-Eluting or Bare Metal Stents for the Treatment of Saphenous Vein Graft Disease
Authors: Paradis Jean-Michel , Bélisle Patrick , Joseph Lawrence , Bertrand Olivier F. , DeLarochellière Robert , Déry Jean-Pierre , Larose Éric , Rodés-Cabau Josep , Rinfret Stéphane
Published: November 2010

Background—

Observational studies and randomized, controlled trials have yielded uncertain results regarding the benefits of drug-eluting stents (DES) for the treatment of saphenous vein graft (SVG) disease. The objective of this meta-analysis was to assess the cumulative evidence regarding the efficacy and effectiveness of DES to treat SVG compared with bare metal stent (BMS).

Methods and Results—

We conducted a bayesian hierarchical meta-analysis of all randomized, controlled trials and observational studies that compared clinical outcomes after DES or BMS placement in SVG disease. Our search resulted in 25 studies, cumulating 5755 patients. DES implantation was not associated with an increased risk of death (odds ratio [OR], 0.85; 95% credible intervals (CrI) [CrI], 0.62 to 1.21) or myocardial infarction (OR, 0.83; 95% CrI, 0.56 to 1.32), but wide CrIs preclude definitive conclusions. Target vessel revascularization (OR, 0.55; 95% CrI, 0.39 to 0.76) and target lesion revascularization (OR, 0.58; 95% CrI, 0.37 to 0.87) were both reduced by approximately 45% with DES. When combining these outcomes, the OR for major adverse cardiac events was reduced in patients treated with DES (OR, 0.62; 95% CrI, 0.46 to 0.81). Finally, the relative risk of stent thrombosis appeared lower with DES, although again the CrIs were very wide (OR, 0.54; 95% CrI, 0.13 to 1.39).

Conclusions—

In this study-level meta-analysis, the largest ever reported and the first using bayesian methods, the use of DES for the treatment of SVG disease reduces target vessel revascularization and target lesion revascularization procedures compared with BMS. Although there is no evidence to date to suggest increased rates of mortality, myocardial infarction, or stent thrombosis, further data are needed to address this safety issue.
Predictors of Neurological Events Associated With Carotid Artery Stenting in High-Surgical-Risk Patients
Authors: Aronow Herbert D. , Gray William A. , Ramee Stephen R. , Mishkel Gregory J. , Schreiber Theodore J. , Wang Hong
Published: November 2010

Background—

Comorbid and anatomic characteristics that portend higher procedural risk are well defined for carotid endarterectomy but less so for carotid artery stenting.

Methods and Results—

We pooled carotid stent data from 4 Cordis-sponsored trials (n=2104) with similar patient cohorts and end point determination to identify predictors of neurological death or stroke within 30 days of the procedure. Median age was 74 years (24% >80 years), 36% were women, and 24.2% were symptomatic in the previous 6 months. There were 88 (4.2%) neurological deaths or strokes at 30 days. Among symptomatic patients, the risk of adverse neurological outcome declined with increasing time between the incident neurological event and carotid stent procedure. In a logistic regression model that included preprocedural and procedural variables, significant multivariable predictors of 30-day neurological death or stroke were older age (continuous), black race, angiographically visible thrombus in symptomatic patients, procedural use of glycoprotein IIb/IIIa inhibitors, procedural transient ischemic attack, final residual stenosis >30%, and periprocedural use of protamine or vasopressors.

Conclusions—

In this pooled analysis, a number of preprocedural and procedural factors predicted higher risk of stroke and neurological death within 30 days of a carotid stent procedure. Identification of such predictors may help to guide patient selection and further refine procedural technique.
Use of Antithrombotic Medications Among Elderly Ischemic Stroke Patients
Authors: Lichtman Judith H. , Naert Lisa , Allen Norrina B. , Watanabe Emi , Jones Sara B. , Barry Lisa C. , Bravata Dawn M. , Goldstein Larry B.
Published: November 2010

Background—

The use of antithrombotic medications after ischemic stroke is recommended for deep vein thrombosis prophylaxis and secondary stroke prevention. We assessed the rate of receipt of these therapies among eligible ischemic stroke patients age ≥65 years and determined the effects of age and other patient characteristics on treatment.

Methods and Results—

The analysis included Medicare fee-for-service beneficiaries discharged with ischemic stroke (ICD 433.x1, 434.x1, 436) randomly selected for inclusion in the Medicare Health Care Quality Improvement Program's National Stroke Project 1998 to 1999, 2000 to 2001. Patients discharged from nonacute facilities, transferred, or terminally ill were excluded. Receipt of in-hospital pharmacological deep vein thrombosis prophylaxis, antiplatelet medication, anticoagulants for atrial fibrillation, and antithrombotic medications at discharge were assessed in eligible patients, stratified by age (65 to 74, 75 to 84, and 85+ years). Descriptive models identified characteristics associated with treatment. Among 31 554 patients, 14.9% of those eligible received pharmacological deep vein thrombosis prophylaxis, 83.9% antiplatelet drugs, 82.8% anticoagulants for atrial fibrillation, and 74.2% were discharged on an antithrombotic medication. Rates of treatment decreased with age and were lowest for patients ages 85 years or older. Admission from a skilled nursing facility and functional dependence were associated with lower treatment rates.

Conclusions—

There was substantial underutilization of antithrombotic therapies among elderly ischemic stroke patients, particularly among the very elderly, those admitted from skilled nursing facilities, and patients with functional dependence. The reasons for low use of antithrombotic therapies, including the apparent underutilization of deep vein thrombosis prophylaxis in otherwise eligible patients, require further investigation.
Risk-Adjusted Percent Time in Therapeutic Range as a Quality Indicator for Outpatient Oral Anticoagulation
Authors: Rose Adam J. , Hylek Elaine M. , Ozonoff Al , Ash Arlene S. , Reisman Joel I. , Berlowitz Dan R.
Published: November 2010

Background—

Oral anticoagulation is safer and more effective when patients receive high-quality care. However, there have been no prior efforts to measure quality of oral anticoagulation care or to risk adjust it to ensure credible comparisons. Our objective was to profile site performance in the Veterans Health Administration (VA) using risk-adjusted percent time in therapeutic range (TTR).

Methods and Results—

We included 124 551 patients who received outpatient oral anticoagulation from 100 VA sites of care for indications other than valvular heart disease from October 1, 2006, to September 30, 2008. We calculated TTR for each patient and mean TTR for each site of care. Expected TTR was calculated for each patient and each site based on the variables in the risk adjustment model, which included demographics, comorbid conditions, medications, and hospitalizations. Mean TTR for the entire sample was 58%. Site-observed TTR varied from 38% to 69% or from poor to excellent. Site-expected TTR varied from 54% to 62%. Site risk-adjusted performance ranged from 18% below expected to 12% above expected. Risk adjustment did not alter performance rankings for many sites, but for other sites, it made an important difference. For example, the site ranked 27th of 100 before risk adjustment was one of the best (risk-adjusted rank, 7). Risk-adjusted site rankings were consistent from year to year (correlation between years, 0.89).

Conclusions—

Risk-adjusted TTR can be used to profile the quality of outpatient oral anticoagulation in a large, integrated health system. This measure can serve as the basis for quality measurement and quality improvement efforts.
A Theory of Slow Feature Analysis for Transformation-Based Input Signals with an Application to Complex Cells
Authors: Sprekeler Henning , Wiskott Laurenz
Published: November 2010

We develop a group-theoretical analysis of slow feature analysis for the case where the input data are generated by applying a set of continuous transformations to static templates. As an application of the theory, we analytically derive nonlinear visual receptive fields and show that their optimal stimuli, as well as the orientation and frequency tuning, are in good agreement with previous simulations of complex cells in primary visual cortex (Berkes and Wiskott, 2005 ). The theory suggests that side and end stopping can be interpreted as a weak breaking of translation invariance. Direction selectivity is also discussed.
Bayes-Optimal Chemotaxis
Authors: Mortimer Duncan , Dayan Peter , Burrage Kevin , Goodhill Geoffrey J.
Published: November 2010

Chemotaxis plays a crucial role in many biological processes, including nervous system development. However, fundamental physical constraints limit the ability of a small sensing device such as a cell or growth cone to detect an external chemical gradient. One of these is the stochastic nature of receptor binding, leading to a constantly fluctuating binding pattern across the cell's array of receptors. This is analogous to the uncertainty in sensory information often encountered by the brain at the systems level. Here we derive analytically the Bayes-optimal strategy for combining information from a spatial array of receptors in both one and two dimensions to determine gradient direction. We also show how information from more than one receptor species can be optimally integrated, derive the gradient shapes that are optimal for guiding cells or growth cones over the longest possible distances, and illustrate that polarized cell behavior might arise as an adaptation to slowly varying environments. Together our results provide closed-form predictions for variations in chemotactic performance over a wide range of gradient conditions.
Learning Active Fusion of Multiple Experts' Decisions: An Attention-Based Approach
Authors: Mirian Maryam S. , Ahmadabadi Majid Nili , Araabi Babak N. , Siegwart Roland R.
Published: November 2010

In this letter, we propose a learning system, active decision fusion learning (ADFL), for active fusion of decisions. Each decision maker, referred to as a local decision maker, provides its suggestion in the form of a probability distribution over all possible decisions. The goal of the system is to learn the active sequential selection of the local decision makers in order to consult with and thus learn the final decision based on the consultations. These two learning tasks are formulated as learning a single sequential decision-making problem in the form of a Markov decision process (MDP), and a continuous reinforcement learning method is employed to solve it. The states of this MDP are decisions of the attended local decision makers, and the actions are either attending to a local decision maker or declaring final decisions. The learning system is punished for each consultation and wrong final decision and rewarded for correct final decisions. This results in minimizing the consultation and decision-making costs through learning a sequential consultation policy where the most informative local decision makers are consulted and the least informative, misleading, and redundant ones are left unattended. An important property of this policy is that it acts locally. This means that the system handles any nonuniformity in the local decision maker's expertise over the state space. This property has been exploited in the design of local experts. ADFL is tested on a set of classification tasks, where it outperforms two well-known classification methods, Adaboost and bagging, as well as three benchmark fusion algorithms: OWA, Borda count, and majority voting. In addition, the effect of local experts design strategy on the performance of ADFL is studied, and some guidelines for the design of local experts are provided. Moreover, evaluating ADFL in some special cases proves that it is able to derive the maximum benefit from the informative local decision makers and to minimize attending to redundant ones.
Letters from the Mackinaw Mission School
Authors: De Rosa Marla
Published: November 2010

Young Native American women from the Mackinaw Mission write to Mary Lyon and Zilpah Grant at the Ipswich Female Seminary. The 1829 letters reflect the progressive education offered to the students as well as the pressures they were under to forsake their language and culture and embrace evangelical Protestant Christianity
The Taming of God: Revealed Religion and Natural Religion in the Eighteenth-Century Harvard Dudleian Lectures
Authors: Lee Michael Jeehoon
Published: November 2010

In the mid–1700s, America's religious leaders feared deism, but by the early 1800s, it had faded from view. The death of its leaders and the rise of pietistic Christianity have been charged with its downfall. At one of its purported hotbeds—Harvard College—another possibility emerges: deism disappeared because, at least in some crucial arenas, it had triumphed, and thus deists were appeased.
Beyond Chapter VIII: Limits and Opportunities for Regional Representation at the UN security Council
Authors: Drieskens Edith
Published: November 2010

Zooming in on the serving European Union (EU) Member States and exploring the legal parameters defining regional actorness both directly and indirectly, this article analyzes the EU's representation at the United Nations (UN) Security Council. Looking at the theory and practice behind Articles 52, 23 and 103 of the UN Charter, we shed fresh light on the only provision in the European Treaties that explicitly referred to the UN Security Council, i.e. the former Article 19 of the EU Treaty. We define that provision as a regional interpretation of Article 103 of the UN Charter and discuss its implementation in day-to-day decision-making, especially as for economic and financial sanctions measures. Hereby, we focus on the negotiations leading to UN Security Council Resolution 1822(2008).
Aid or Assistance and Direction and Control between states and International Organizations in the Commission of Internationally Wrongful Acts
Authors: Reinisch August
Published: November 2010

Questions concerning the international responsibility of international organizations and/or their member States for internationally wrongful acts primarily raise important issues of attribution. In addition, a concurrent responsibility may arise from situations where international organizations aid or assist or direct and control the acts of States or other international organizations. This contribution intends to highlight some problems that stem from the fact that the current formulations of Articles 13 and 14 of the ILC Draft Articles on responsibility of international organizations are largely based on the corresponding provisions of the 2001 ILC Articles on State responsibility.
Daytime Heat Transfer Processes Related to Slope Flows and Turbulent Convection in an Idealized Mountain Valley
Authors: Serafin Stefano , Zardi Dino
Published: November 2010

The mechanisms governing the daytime development of thermally driven circulations along the transverse axis of idealized two-dimensional valleys are investigated by means of large-eddy simulations. In particular, the impact of slope winds and turbulent convection on the heat transfer from the vicinity of the ground surface to the core of the valley atmosphere is examined. The interaction between top-down heating produced by compensating subsidence in the valley core and bottom-up heating due to turbulent convection is described. Finally, an evaluation of the depth of the atmospheric layer affected by the slope wind system is provided.
The Resonant Interaction of a Tropical Cyclone and a Tropopause Front in a Barotropic Model. Part I: Zonally Oriented Front
Authors: Scheck Leonhard , Jones Sarah C. , Juckes Martin
Published: November 2010

The interaction of a tropical cyclone and a zonally aligned tropopause front is investigated in an idealized framework. A nondivergent barotropic model is used in which the front is represented by a vorticity step, giving a jetlike velocity profile. The excitation of frontal waves by a cyclone located south of the front and the impact of the wave flow on the cyclone motion is studied for different representations of the cyclone and the jet. The evolution from the initial wave excitation until after the cyclone has crossed the front is discussed. The interaction becomes stronger with increasing jet speed. For cyclone representations containing negative relative vorticity, anticyclones develop and can influence the excitation of frontal waves significantly. Resonant frontal waves propagating with a phase speed matching the zonal translation speed of the cyclone are decisive for the interaction. The frontal wave spectrum excited by a cyclone on the front is dominated by waves that are in resonance in the initial phase. These waves have the largest impact on the cyclone motion.
Pneumococcal Resistance and Serotype 19A in Pittsburgh-Area Children With Acute Otitis Media Before and After Introduction of 7-Valent Pneumococcal Polysaccharide Vaccine
Authors: Hoberman Alejandro , Paradise Jack L. , Shaikh Nader , Greenberg David P. , Kearney Diana H. , Colborn D. Kathleen , Rockette Howard E. , Kurs-Lasky Marcia , McEllistrem M. Catherine , Zoffel Lisa M. , Balentine Tracy L. , Barbadora Karen A. , Wald Ellen R.
Published: November 2010

Methods: Before and after introduction of pneumococcal conjugate vaccine (PCV7), the authors obtained nasopharyngeal (NP) specimens from 3 groups of children aged 6 to 23 months with acute otitis media (AOM): group 1 (pre-PCV7), group 2 (early post-PCV7), and group 3 (late post-PCV7). Results: Of the Streptococcus pneumoniae isolates, the proportion that were vaccine serotypes (VTs) declined progressively (60.4% vs 48.6% vs 5.2% in groups 1, 2, and 3, respectively; P < .001). Concurrently, increases occurred in the proportion of penicillin-nonsusceptible isolates (minimum inhibitory concentration >0.1 µg/mL; 26.7% vs 37.8% vs. 38.5%; P = .12); the proportion of isolates that were serotype 19A (4.0% vs 0% vs 25.9%; P < .001); and the proportion of 19A isolates that were penicillin-nonsusceptible (0% in group 1, 68.6% in group 3; P = .004). Conclusion: Shifts in pneumococcal serotype distribution and increases in penicillin nonsusceptibility among pneumococcal isolates from children with AOM underscore the need for continuing bacteriological surveillance for future vaccine development.
The Changing Clinical Presentation of Hypertrophic Pyloric Stenosis: The Experience of a Large, Tertiary Care Pediatric Hospital
Authors: Glatstein Miguel , Carbell Gary , Sirisha Kusuma Boddu  , Bernardini Annalucia , Scolnik Dennis
Published: November 2010

The authors reviewed the clinical and laboratory data from cases of hypertrophic pyloric stenosis (HPS) diagnosed at their institution from 2006 to 2008. They assessed and compared presentation of patients with HPS over time at their institution. A total of 118 patients were included in this study. An “olive” was palpated in only 13.6% of cases. This is in contrast to older studies, where more than 50% of the patients were reported to have a palpable “olive” depending on when the study was conducted. In patients from this institution, hypochloremia was present in 23% and alkalosis in 14.4%, which are less frequent than the incidence of these abnormalities in older studies. There was a change in the additional “classical” symptoms, represented by the lower percentage of infants in whom an “olive” was palpated and the lower numbers of patients with severe electrolyte imbalances. The reason for this change appears to be the frequent use of ultrasound.
5-4-3-2-1 Go! Coordinating Pediatric Resident Education and Community Health Promotion to Address the Obesity Epidemic in Children and Youth
Authors: Stahl Christiane Ellen , Necheles Jonathan Wolf , Mayefsky Jay Hirsh , Wright Lydia Katherine , Rankin Kristin Michele
Published: November 2010

This study investigated the feasibility and effectiveness of training pediatric residents to conduct a brief clinic-based behavioral intervention in coordination with community dissemination of a health promotion message developed by the Consortium for Lowering Obesity in Chicago Children. A total of 113 residents completed a short (<60 minutes) online training program. Some (64) residents distributed interview contact cards to patients they saw in their continuity of care clinics after training; others (45) distributed cards before training. A researcher interviewed 75% of the 509 patients 4 weeks after the visit. More patients of trained residents reported positive changes in behaviors which have been associated with lower obesity rates: increased intake of fruits and vegetables (28% vs 16%, P < .01), increased intake of water (30% vs 19%, P < .01), increased physical activity (40% vs 29%, P < .03), and decreased television time (36% vs 24%, P < .01). Brief training using the 5-4-3-2-1-Go! message seems to be feasible and effective.
Thrombocytopenic Syndromes Masquerading as Childhood Immune Thrombocytopenic Purpura
Authors: Bryant Nichole , Watts Raymond
Published: November 2010

Immune thrombocytopenic purpura (ITP) is the most common cause of thrombocytopenia in children and adolescents. However, there are a number of other diagnoses that are often mistaken for ITP. A 10-year retrospective chart review was performed at the Children’s Hospital of Alabama to characterize ITP. Initially, 492 patients who had the coded diagnosis of ITP (ICD 287.3) were identified. However, 83 (17%) of patients were found to have alternative diagnoses on chart review. Of the 83 patients, 13 patients (3%) represented coding errors or study classification errors. The 70 remaining patients (14%) had an alternative explanation for their thrombocytopenia, consisting of 31 different diagnoses. The most common diagnoses were familial thrombocytopenia (10%), systemic lupus erythematosus (9%), hypersplenism (9%), neonatal alloimmune thrombocytopenia (7%), Wiskott—Aldrich syndrome (7%), or systemic infection (6%). In total, 16 of the patients (23%) were ultimately diagnosed with one of a number of congenital syndromes with concurrent thrombocytopenia. Although this review confirms that most children with thrombocytopenia are diagnosed with ITP, 14% of the study population manifested other diagnoses. The clinician evaluating a child with thrombocytopenia must keep an open mind about the possible diagnosis and perform a comprehensive and thoughtful evaluation based on the clinical picture. ITP must be a diagnosis of exclusion as misdiagnosis in a child with thrombocytopenia may have a significant impact on morbidity and mortality.
The Foundations of Complexity, the Complexity of Foundations
Authors: Cudworth Erika , Hobden Stephen
Published: November 2010

A debate over the possibilities for foundations of knowledge has been a key feature of theoretical discussions in the discipline of International Relations. A number of recent contributions suggest that this debate is still active. This article offers a contribution to this debate by suggesting that the study of complexity may provide a contingent foundation for the study of international relations. We examine the grounds on which such a claim might be made, and examine the implications for taking complexity as a foundational claim.
Small-City Management Experience
Authors: Thurmond James
Published: November 2010

Does small-city management experience (<50,000 population) help city managers get large-city management jobs (>100,000 population), and does it help them to keep the large-city jobs? The answers to these questions are important for city managers planning a move to a larger city and for young professionals planning a career in city management. This study indicates that the large-city assistant city manager (ACM) position is the prevalent route for getting a large-city manager’s position, while small-city experience by itself may have a negative influence on managers' job tenure in large cities. A career path combining both large-city ACM and small-city management experiences helps large-city managers keep their jobs.
A Prospective Randomized Study Comparing Arthroscopic Single-Bundle and Double-Bundle Posterior Cruciate Ligament Reconstructions Preserving Remnant Fibers
Authors: Yoon Kyoung Ho , Bae Dae Kyung , Song Sang Jun , Cho Hyung Jun , Lee Jung Hwan
Published: November 2010

Background: Several controversies exist regarding the superiority of double-bundle (DB) posterior cruciate ligament (PCL) reconstruction versus single-bundle (SB) reconstruction, although DB reconstruction has been shown to restore the intact knee kinematics more closely than SB reconstruction.

Hypothesis: Double-bundle PCL reconstruction will present better results than SB reconstruction in postoperative outcomes.

Study Design: Randomized controlled trial; Level of evidence, 2.

Methods: The authors prospectively analyzed 25 cases of SB reconstruction and 28 cases of DB reconstruction using Achilles tendon allograft with a minimum 2-year follow-up. They compared preoperative and postoperative range of motion, posterior stability by posterior stress radiography, Tegner activity score, Lysholm score, and International Knee Documentation Committee (IKDC) subjective knee evaluation form and knee examination form between the 2 groups.

Results: There was no difference in range of motion, Tegner activity score, Lysholm score, and IKDC subjective knee evaluation form between the 2 groups at last follow-up. The side-to-side difference in posterior translation significantly improved in both groups. There was no preoperative difference in posterior instability between the groups but a significant difference at last follow-up. On the IKDC knee examination form, the DB reconstruction group presented better results in grade distribution.

Conclusion: The DB reconstruction for PCL ruptures using the Achilles allograft showed better results in posterior stability and IKDC knee examination form than the SB reconstruction did. Although the difference of 1.4 mm in posterior stability was statistically significant, it is unclear that DB reconstruction is definitely superior to SB reconstruction clinically and functionally because there was no difference in the subjective scores.
Risk of Serious Injury for Young Baseball Pitchers
Authors: Fleisig Glenn S. , Andrews James R. , Cutter Gary R. , Weber Adam , Loftice Jeremy , McMichael Chris , Hassell Nina , Lyman Stephen
Published: November 2010

Background: The risk of elbow or shoulder injury for young baseball pitchers is unknown.

Purpose/Hypothesis: The purpose of this study was to quantify the cumulative incidence of throwing injuries in young baseball pitchers who were followed for 10 years. Three hypotheses were tested: Increased amount of pitching, throwing curveballs at a young age, and concomitantly playing catcher increase a young pitcher’s risk of injury.

Study Design: Cohort study; Level of evidence, 3.

Methods: In sum, 481 youth pitchers (aged 9 to 14 years) were enrolled in a 10-year follow-up study. Participants were interviewed annually. Injury was defined as elbow surgery, shoulder surgery, or retirement due to throwing injury. Fisher exact test compared the risk of injury between participants who pitched at least 4 years during the study and those who pitched less. Fisher exact tests were used to investigate risks of injury for pitching more than 100 innings in at least 1 calendar year, starting curveballs before age 13 years, and playing catcher for at least 3 years.

Results: The cumulative incidence of injury was 5.0%. Participants who pitched more than 100 innings in a year were 3.5 times more likely to be injured (95% confidence interval = 1.16 to 10.44). Pitchers who concomitantly played catcher seemed to be injured more frequently, but this trend was not significant with the study sample size.

Conclusion: Pitching more than 100 innings in a year significantly increases risk of injury. Playing catcher appears to increase a pitcher’s risk of injury, although this trend is not significant. The study was unable to demonstrate that curveballs before age 13 years increase risk of injury.

Clinical Relevance: The risk of a youth pitcher sustaining a serious throwing injury within 10 years is 5%. Limiting the number of innings pitched per year may reduce the risk of injury. Young baseball pitchers are encouraged to play other positions as well but might avoid playing catcher.
The Prevention of Depression and Anxiety in a Sample of High-Risk Adolescents: A Randomized Controlled Trial
Authors: Dobson Keith S. , Ahnberg Hopkins Jamie , Fata Ladan , Scherrer Martin , Allan Lauren C.
Published: November 2010

This study investigated the efficacy of cognitive behavioural therapy (CBT) techniques in preventing depression and anxiety in a group of adolescent high school students with elevated risk for developing emotional disorders. Students were screened using a measure of depression severity and clinical interview. Following screening procedures, students at risk for, but not currently diagnosed with, depression were randomly assigned to one of two intervention groups: a CBT ( n = 25) or an active control group ( n = 21). Assessment measures were administered before treatment, after treatment, and at 3- and 6-month follow-up. Both groups exhibited significant improvements in mood symptomatology and self-esteem outcomes over time. Significant differences between groups were not observed at posttreatment and two follow-up points of assessment. The efficacy of CBT techniques was also examined using a “benchmarking” strategy. The limitations of this study and future research directions are discussed.