bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue Factor and Cancer Stem Cells
Authors: Milsom Chloe , Magnus Nathalie , Meehan Brian , Al-Nedawi Khalid , Garnier Delphine , Rak Janusz
Published: July 2009

A common feature in the progression of multiple human malignancies is the protracted deregulation of the coagulation system, often referred to as cancer coagulopathy. Indeed, cancer cells and their vascular stroma often exhibit procoagulant properties, of which deregulation of tissue factor (TF) expression is a notable, although not the sole example. These changes can be traced to oncogenic influences affecting epidermal growth factor receptor (EGFR), EGFRvIII, K-ras, p53, PTEN, and probably many other proto-oncogenes and tumor suppressors in tumor parenchyma. Cancer stem cells (CSCs)/tumor initiating cells (TICs) are thought to represent the primary target and the main cellular effector through which oncogenic mutations exert their tumor-inducing effects. In so doing, CSCs/TICs depend on interactions with the tumor vasculature, which forms supportive niches for their clonal growth. We postulate that TF contributes to these interactions (directly or indirectly) through procoagulant and signaling effects, the latter executed in concert with juxtaposed protease activated receptors (mainly PAR-1 and PAR-2). TF/PAR system acts as a “blood sensing” mechanism, whereby cancer cells, including CSCs/TICs, may respond to plasma proteases (Factors VIIa, Xa, and IIa) and their related microenvironmental changes (fibrin deposition, activation of platelets). A growing body of still largely circumstantial evidence suggests that these events may contribute to the CSC/TIC niche, which could influence tumor initiation, metastasis, recurrence, and therapeutic intractability. Indeed, certain types of cancer cells harboring markers of CSCs (CD133) exhibit elevated TF expression and depend on this receptor to efficiently initiate tumor growth. We propose that both tumor cell–associated and host-related TF could influence the properties of CSCs, and that agents targeting the TF/PAR system may represent a hitherto unappreciated therapeutic opportunity to control cancer progression by influencing the CSC/TIC compartment.
Angiotensin II–Inducible Smooth Muscle Cell Apoptosis Involves the Angiotensin II Type 2 Receptor, GATA-6 Activation, and FasL-Fas Engagement
Authors: Tan Nicole Y. , Li Jian-Mei , Stocker Roland , Khachigian Levon M.
Published: July 2009

Rationale
:

Fas ligand (FasL)-mediated smooth muscle cell (SMC) apoptosis within the vulnerable plaque may lead to plaque instability and rupture, events that underlie myocardial infarction and stroke.

Objective
:

The molecular mechanisms underlying FasL transcription and FasL-dependent SMC apoptosis were investigated in this study in vitro and in vivo.

Methods and Results
:

We demonstrate that GATA-6, the predominant GATA family member expressed in SMCs, stimulates SMC apoptosis in an extracellular FasL-dependent manner. Both GATA-6 and FasL were inducibly and transiently expressed following balloon injury to rat carotid arteries. We identified two potential GATA binding in the FasL promoter and demonstrated using DNA binding and chromatin immunoprecipitation assays that GATA-6 regulates FasL through one (
−298
TTATCA
−303
) but not both these elements. Angiotensin II (Ang II) stimulated expression of both GATA-6 and FasL. Ang II increased SMC apoptosis in an Ang II type 2 receptor–, caspase 8–, and FasL-dependent fashion. GATA-6 activation was MEK-ERK1/2– and JNK-dependent, and GATA-6 small interfering RNA blocked Ang II–inducible FasL expression and SMC apoptosis. Administration of Ang II to rats increased FasL expression and apoptosis in carotid artery SMCs in an Ang II type 2 receptor– and GATA-6–dependent manner.

Conclusions
:

This study provides new insights into the transcriptional events underpinning FasL-dependent SMC apoptosis after exposure to Ang II.
Cyclo-Oxygenase-2 Mediates Hyperbaric Oxygen Preconditioning-Induced Neuroprotection in the Mouse Model of Surgical Brain Injury
Authors: Jadhav Vikram , Ostrowski Robert P. , Tong Wenni , Matus Brenden , Jesunathadas Rachel , Zhang John H.
Published: July 2009

Background and Purpose—

We investigated the role of cyclo-oxygenase-2 (COX-2) in mechanisms of hyperbaric oxygen preconditioning (HBO-PC) in the mouse model of surgical brain injury (SBI).

Methods—

C57BL mice were administered 100% oxygen for 1 hour at 2.5 atmosphere absolute for 5 consecutive days and subjected to SBI. Neurological status and brain edema were evaluated at 24 hours and 72 hours after the brain insult. Fluorescent immunostaining and Western blotting were performed to study hypoxia-inducible factor-1α and COX-2, respectively. Two doses of COX-2 inhibitor, NS398 (3 mg/kg and 10 mg/kg) were used to verify the role of COX-2 signaling pathway in the mechanism of HBO-PC.

Results—

HBO-PC improved neurological status and decreased brain edema at 24 hours and 72 hours after SBI. HBO-PC by itself and SBI independently increased COX-2 levels by 2-fold and 4-fold, respectively. HBO-PC, however, reduced increase in hypoxia-inducible factor-1α and COX-2 expression after SBI. The HBO-PC-induced improvement in neurological status and brain edema was reversed by a suboptimal dose of the COX-2 inhibitor, NS398 (10 mg/kg intraperitoneally; 1/4th of dose shown to provide neuroprotection), which itself had no effect on investigated end points.

Conclusions—

HBO-PC attenuates postoperative brain edema and improves neurological outcomes after SBI. The HBO-PC-induced neuroprotection is mediated through COX-2 signaling pathways.
Early Diffusion Weighted MRI as a Negative Predictor for Disabling Stroke After ABCD
2
Score Risk Categorization in Transient Ischemic Attack Patients
Authors: Asimos Andrew W. , Rosamond Wayne D. , Johnson Anna M. , Price Marlow F. , Rose Kathryn M. , Murphy Carol V. , Tegeler Charles H. , Felix Ana
Published: July 2009

Background and Purpose—

The prognostic value early diffusion-weighted magnetic resonance imaging (DWMRI) adds in the setting of transient ischemic attack (TIA), after risk stratification by a clinical score, is unclear. The purpose of this study is to evaluate, after ABCD
2
score risk categorization in admitted TIA patients, whether negative DWMRI performed within 24 hours of symptom onset improves on the identification of patients at low risk for experiencing a disabling stroke within 90 days.

Methods—

At 15 North Carolina hospitals, we enrolled a prospective nonconsecutive sample of admitted TIA patients. We excluded patients not undergoing a DWMRI within 24 hours of admission and patients for whom a dichotomized (≤ or >3) ABCD
2
score could not be calculated. We conducted a medical record review to determine disabling ischemic stroke outcomes within 90 days.

Results—

Over 35 months, 944 TIA patients met inclusion criteria, of whom 4% (n=41) had a disabling ischemic stroke within 90 days. In analyses stratified by low versus moderate/high ABCD
2
score, the combination of a low risk ABCD
2
score and a negative early DWMRI had excellent sensitivity (100%, 95% CI 34 to 100) for identifying low-risk patients. In patients classified as moderate to high risk, a negative early DWMRI predicted a low risk of disabling ischemic stroke within 90 days (sensitivity 92%, 95% CI 80 to 97; NLR 0.11, 95% CI 0.04 to 0.32).

Conclusions—

After risk stratification by the ABCD
2
score, early DWMRI enhances the prediction of a low risk for disabling ischemic stroke within 90 days. Further study is warranted in a large, consecutive TIA population of early DWMRI as a sensitive negative predictor for disabling stroke within 90 days.
Red Blood Cell Transfusion Increases Cerebral Oxygen Delivery in Anemic Patients With Subarachnoid Hemorrhage
Authors: Dhar Rajat , Zazulia Allyson R. , Videen Tom O. , Zipfel Gregory J. , Derdeyn Colin P. , Diringer Michael N.
Published: July 2009

Background and Purpose—

Anemia is common after subarachnoid hemorrhage and may exacerbate the reduction in oxygen delivery (DO
2
) underlying delayed cerebral ischemia. The association between lower hemoglobin and worse outcome, including more cerebral infarcts, supports a role for red blood cell transfusion to correct anemia. However, the cerebral response to transfusion remains uncertain, because higher hemoglobin may increase viscosity and further impair cerebral blood flow (CBF) in the setting of vasospasm.

Methods—

Eight patients with aneurysmal subarachnoid hemorrhage and hemoglobin <10 g/dL were studied with
15
O-positron emission tomography before and after transfusion of 1 U red blood cells. Paired
t
tests were used to analyze the change in global and regional CBF, oxygen extraction fraction, and oxygen metabolism after transfusion. DO
2
was calculated from CBF and arterial oxygen content. CBF, oxygen metabolism, and DO
2
are reported in mL/100 g/min.

Results—

Transfusion resulted in a 15% rise in hemoglobin (8.7±0.8 to 10.0±1.0 g/dL) and arterial oxygen content (11.8±1.0 to 13.6±1.1 mL/dL; both
P
<0.001). Global CBF remained stable (40.5±8.1 to 41.6±9.9), resulting in an 18% rise in DO
2
from 4.8±1.1 to 5.7±1.4 (
P
=0.017). This was associated with a fall in oxygen extraction fraction from 0.49±0.11 to 0.41±0.11 (
P
=0.11) and stable oxygen metabolism. Rise in DO
2
was greater (28%) in regions with oligemia (low DO
2
and oxygen extraction fraction ≥0.5) at baseline but was attenuated (10%) within territories exhibiting angiographic vasospasm, where CBF fell 7%.

Conclusions—

Transfusion of red blood cells to anemic patients with subarachnoid hemorrhage resulted in a significant rise in cerebral DO
2
without lowering global CBF. This was associated with reduced oxygen extraction fraction, which may improve tolerance of vulnerable brain regions to further impairments of CBF. Further studies are needed to confirm the benefit of transfusion on delayed cerebral ischemia and balance this against potential systemic and cerebral risks.
Risk Factors Associated With Injury Attributable to Falling Among Elderly Population With History of Stroke
Authors: Divani Afshin A. , Vazquez Gabriela , Barrett Anna M. , Asadollahi Marjan , Luft Andreas R.
Published: July 2009

Background and Purpose—

Stroke survivors are at high risk for falling. Identifying physical, clinical, and social factors that predispose stroke patients to falls may reduce further disability and life-threatening complications, and improve overall quality of life.

Methods—

We used 5 biennial waves (1998–2006) from the Health and Retirement Study to assess risk factors associated with falling accidents and fall-related injuries among stroke survivors. We abstracted demographic data, living status, self-evaluated general health, and comorbid conditions. We analyzed the rate ratio (RR) of falling and the OR of injury within 2 follow-up years using a multivariate random effects model.

Results—

We identified 1174 stroke survivors (mean age±SD, 74.4±7.2 years; 53% female). The 2-year risks of falling, subsequent injury, and broken hip attributable to fall were 46%, 15%, and 2.1% among the subjects, respectively. Factors associated with an increased frequency of falling were living with spouse as compared to living alone (RR, 1.4), poor general health (RR, 1.1), time from first stroke (RR, 1.2), psychiatric problems (RR, 1.7), urinary incontinence (RR, 1.4), pain (RR, 1.4), motor impairment (RR, 1.2), and past frequency of ≥3 falls (RR, 1.3). Risk factors associated with fall-related injury were female gender (OR, 1.5), poor general health (OR, 1.2), past injury from fall (OR, 3.2), past frequency of ≥3 falls (OR, 3.1), psychiatric problems (OR, 1.4), urinary incontinence (OR, 1.4), impaired hearing (OR, 1.6), pain (OR, 1.8), motor impairment (OR, 1.3), and presence of multiple strokes (OR, 3.2).

Conclusions—

This study demonstrates the high prevalence of falls and fall-related injuries in stroke survivors, and identifies factors that increase the risk. Modifying these factors may prevent falls, which could lead to improved quality of life and less caregiver burden and cost in this population.
Can the ABCD
2
Risk Score Predict Positive Diagnostic Testing for Emergency Department Patients Admitted for Transient Ischemic Attack?
Authors: Schrock Jon W. , Victor Aaron , Losey Theodore
Published: July 2009

Background and Purpose—

We sought to determine if the ABCD
2
score, typically used for risk stratification, could predict having a positive diagnostic test in patients evaluated acutely for transient ischemic attack.

Methods—

We performed a retrospective cohort study for patients admitted from our emergency department with a new diagnosis of transient ischemic attack confirmed by a neurologist. ABCD
2
scores were calculated and patients with a score of ≥4 were placed in the high-risk cohort. Tests evaluated included electrocardiogram, CT, MRI, MR angiography, carotid ultrasonography, and echocardiography. Specific test findings considered to signify positive diagnostic tests were created a priori.

Results—

We identified 256 patients with transient ischemic attack for inclusion; 167 (61%) were female, the median age was 60 years (interquartile range, 50 to 72), and 162 (63%) patients had an ABCD
2
score of ≥4. Rates of completion of diagnostic testing were electrocardiogram, 270 (100%); CT, 224 (88%); MRI, 89 (35%); MR angiography, 68 (27%); carotid ultrasonography, 125 (49%); and echocardiography, 135 (53%). Univariate analysis found a significant association only with elevated ABCD
2
score and carotid duplex testing (
P
<0.05).

Conclusion—

An elevated ABCD
2
score may help predict patients with severe carotid occlusive disease but does not predict positive outcome in other commonly ordered tests for patients being evaluated for transient ischemic attack. An elevated ABCD
2
score cannot be recommended as a tool to guide diagnostic testing in patients presenting acutely with transient ischemic attack.
Lifetime Learning as a Factor in Life History Evolution
Authors: Bullinaria John A.
Published: July 2009

An artificial life approach is taken to explore the effect that lifetime learning can have on the evolution of certain life history traits, in particular the periods of protection that parents offer their young, and the age at first reproduction of those young. The study begins by simulating the evolution of simple artificial neural network systems that must learn quickly to perform well on simple classification tasks, and determining if and when extended periods of parental protection emerge. It is concluded that longer periods of parental protection of children do offer clear learning advantages and better adult performance, but only if procreation is not allowed during the protection period. In this case, a compromise protection period evolves that balances the improved learning performance against reduced procreation period. The crucial properties of the neural learning processes are then abstracted out to explore the possibility of studying the effect of learning more generally and with better computational efficiency. Throughout, the implications of these simulations for more realistic scenarios are discussed.
Can Metric Feedback Training Hinder Actions Involving Distance?
Authors: Jones Keith S. , DeLucia Patricia R. , Hall Allyson R. , Johnson Brian R.
Published: July 2009

Objective: The present studies tested whether distance estimation training with metric feedback can degrade the performance of untrained primarily perceptual-motor tasks. Background: Training with metric feedback can improve distance estimations. However, previous research led to the conclusion that those improvements stemmed from changes in cognitive processing rather than in perception. If trainees applied their new cognitive strategies to primarily perceptual-motor tasks, then the performance of those tasks should degrade. The present studies tested that possibility. Method: Experiment 1 sought to replicate that training with metric feedback would improve metric distance estimations. Experiments 2 and 3 investigated whether such training would degrade the performance of a primarily perceptual-motor task. Experiment 4 investigated whether such training would affect a perceptual-motor task that required cognition. Results: Metric feedback improved metric distance estimation (Experiments 1—4) and throwing to a specified distance (Experiment 4). Metric feedback degraded throwing to a target (Experiments 2 and 3), although that effect was not evident when pretesting was omitted (Experiment 3). Conclusion: If distance estimation trainees apply what they learned from metric feedback to untrained primarily perceptual-motor tasks, then the performance of those tasks will suffer. However, if trainees apply what they learned to untrained tasks that require metric estimation, then the performance of those tasks will improve. Application: Distance estimation training with metric feedback may not generalize to other tasks and may even degrade performance on certain tasks. Future research must specify the conditions under which distance estimation training with metric feedback leads to performance improvements and decrements.
Metaphor Analysis as an Approach for Exploring Theoretical Concepts: The Case of Social Capital
Authors: Andriessen Daniel , Gubbins Claire
Published: July 2009

In many fields within management and organizational literature there is considerable debate and controversy about key theoretical concepts and their definitions and meanings. Systematic metaphor analysis can be a useful approach to study the underlying conceptualizations that give rise to these controversies and putting them in perspective. It can help identify the different ways a theoretical concept is structured and given meaning, provide insight into the way these different conceptualizations relate to each other, and show how these conceptualizations impact further theorization about the concept. This article describes the procedure for a systematic analysis of the metaphors used to conceptualize key theoretical concepts. To examine its usefulness, the authors apply the approach to the field of social capital, and in particular to the concept of ‘relationships’ in organizations. In the metaphor analysis of three seminal articles on social capital, the authors identify seven metaphoric concepts for relationships. The metaphors are illuminated as important for providing imagery that adds specific meaning in the process of authors theorizing about social capital like ‘tie’, ‘path’ and ‘bridge’. They add dynamics and controllability to the concepts by attributing an array of verbs like ‘to move between’ or ‘to use’ relationships. In addition, the metaphors allow for the attribution of specific characteristics to the concept of relationships that can be used as variables in theory construction, such as the strength of a relationship or the ‘distance’ between people. These insights are useful in exploring and reconciling differences in social capital definitions.
Immigrant Self-Employment
Authors: Kanas Agnieszka , van Tubergen Frank , van der Lippe Tanja
Published: July 2009

Using large-scale data on immigrants in the Netherlands, the authors tested competing arguments about the role of origin- and host-country human capital and bonding and bridging social capital in immigrants' self-employment. When taking job-skill level into account, immigrants with a higher level of origin- and destination-country education are less likely to be self-employed than salary employed. Likewise, the likelihood of self-employment decreases with origin-country work experience but not with host-country work experience. The presumed positive effect of bonding social capital is not found, but this study's results suggest that immigrants with an access to bridging social capital are more likely to be self-employed than those without such contacts.
Student Teaching and Teacher Attrition in Special Education
Authors: Connelly Vincent , Graham Suzanne
Published: July 2009

Research suggests that substantial pre-service student teaching is essential for the preparation and retention of special educators. Using logistic regression analysis, survey responses of beginning special educators were analyzed to answer the following questions: Are beginning special educators more likely to leave the field if they have had minimal or no pre-service student teaching? Are other characteristics of preparation related to the probability of attrition? It was found that substantial pre-service student teaching experience has a strong effect on the probability that a beginning special educator will remain in the field 1 year later (estimated odds ratio = 2.18). In addition, none of the effects of aspects of teacher pre-service preparation or teacher or school demographics analyzed had an impact on attrition, when controlling for the number of weeks of student teaching.
First-Year Teacher Knowledge of Phonemic Awareness and Its Instruction
Authors: Cheesman Elaine A. , McGuire Joan M. , Shankweiler Donald , Coyne Michael
Published: July 2009

Converging evidence has identified phonemic awareness (PA) as one of five essential components of beginning reading instruction. Evidence suggests that many teachers do not have the recommended knowledge or skills sufficient to provide effective PA instruction within the context of scientifically validated reading education. This study examines the knowledge of PA instruction of 223 first-year teachers initially certified in special education, early childhood education, and elementary education. Results indicate that significant numbers of beginning special and general education teachers in this sample appear to be inadequately prepared with respect to PA instruction. They have limited knowledge of PA, confuse PA with phonics, are generally unable to select task-appropriate materials or activities, and lack skill in analyzing written words into phonemes. Special educators did not have significantly more knowledge or skills than their general education counterparts. These findings suggest that university teacher education programs may not be providing future teachers with sufficient content or practice with respect to PA instruction.
Embedding Evidence-Based Practice in Pre-Service Teacher Preparation
Authors: Bain Alan , Lancaster Julie , Zundans Lucie , Parkes Robert John
Published: July 2009

In this study, the authors sought to establish the differential effects on achievement of embedding evidence-based practice in the design of an inclusive education teacher preparation course. Embedded design involves creating self-repeating patterns in the instructional design of a course by expressing essential design features at multiple levels in the teaching and learning experience. The results indicate that pre-service educators attained a mastery level knowledge of the course content that covaried with the application of the embedded design principle. The authors also found a statistically significant difference in student achievement as a function of the teaching approach (cooperative learning, peer-assisted learning, or self-study) employed as part of the embedded design process. The findings are discussed within the context of building more rigorous teacher preparation programs and the role of embedded design in pre-service inclusive education.
The Validity and Reliability of the Teacher Knowledge and Skills Survey for Positive Behavior Support
Authors: Blum Craig , Cheney Douglas
Published: July 2009

In this study, the authors evaluated the empirical properties of the 33-item Teacher Knowledge and Skills Survey (TKSS) 2.0 for positive behavioral support (PBS) in schools. Through an examination of internal consistency and confirmatory factor analysis (CFA) of the theorized construct, the construct validity of the survey was evaluated. Results indicate that the instrument had strong internal consistency and that the CFA supported the hypothesized Comprehensive Model to have a good fit with robust estimators (Comparative Fit Index = .952). The five factors in the Comprehensive Model are (a) Specialized Behavior Supports and Practices, (b) Targeted Intervention Supports and Practices, (c) Schoolwide Discipline Process, (d) Individualized Curriculum and Support Practices, and (e) Positive Classroom Supports and Practices. The authors discuss these findings and provide recommendations on how the TKSS 2.0 can be used in professional development and preservice education programs.
Predicting Nursing Human Resources
Authors: Squires Allison , Beltrán-Sánchez Hiram
Published: July 2009

The nurse-to-population ratio (NPOP) is a standard indicator used to indicate a country’s health care human resources capacity for responding to its disease burden. This study sought to explore if socioeconomic development indicators could predict the NPOP in a country. Mexico served as the case example for this exploratory study, with the final five variables selected based on findings from a qualitative study analyzing the development of nursing human resources in the country. Multiple linear regression showed that two variables proved significant predictors of the NPOP and the model itself explained 70% of the variance ( r 2 = .7; p = .0000). The findings have multiple implications for nursing human resources policy in Mexico and at a global level as governments attempt to build human capital to respond to population health needs.
Intra-Arterial Transplantation of Adult Bone Marrow Cells Restores Blood Flow and Regenerates Skeletal Muscle in Ischemic Limbs
Authors: Liu Qi , Chen Zhiqiang , Terry Toya , McNatt Janice M. , Willerson James T. , Zoldhelyi Pierre
Published: July 2009

Objective: Bone marrow cell therapy promotes angiogenesis, but the cellular fate of bone marrow cells (BMCs) in the absence of immunosuppressant interventions is unclear. We created a model of severe hind limb ischemia to address whether BMCs form new blood vessels or differentiate into other tissues. Methods and Results: After ligating the common femoral artery in ApoE knockout mice, we injected either phosphate buffered saline (PBS) or 5 × 107 adult unfractionated BMCs obtained from green fluorescent protein-positive mice. Laser Doppler imaging of the ischemic limbs revealed that intra-arterial BMCs significantly increased blood flow recovery in ischemic limbs beginning 21 days after surgery and peaking at 27 days (61.8% ± 15% vs. 41.9% ± 13.9%, respectively, for BMCs and PBS, P < .05). The BMCs differentiated into small blood vessels, skeletal myofibers, and supporting membranes, and these changes were associated with increased serum levels of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), transforming growth factor β (TGFβ), interleukin 4 (IL-4), and tumor necrosis factor α (TNF-α). Conclusions: Adult BMCs injected into ischemic limbs without immunosuppressant therapy differentiated into blood vessels and skeletal myofibers, and this was associated with accelerated blood flow restoration and increased serum levels of VEGF, FGF-2, TGF-β, IL-4, and TNF-α. Skeletal muscle formation may provide benefits beyond angiogenesis to patients with chronic peripheral arterial disease or to patients with low cardiac output states who also suffer from skeletal muscle atrophy.
The GALA Trial: Will It Influence Clinical Practice?
Authors: Paraskevas Kosmas I. , Mikhailidis Dimitri P. , Bell Peter R.F.
Published: July 2009

The General Anesthesia vs. Local Anesthesia for Carotid Surgery (GALA) trial did not show a difference in 30-day postoperative stroke, myocardial infarction and death rates between patients undergoing carotid endarterectomy (CEA) under local vs. general anesthesia. The present article discusses some limitations of the GALA trial. Firstly, the expected stroke and death rates following CEA is so low, that it was unlikely that the GALA trial would show any significant difference between local and general anesthesia. Secondly, preoperative statin use was not recorded. Thirdly, intraoperative shunt usa ge rates (a possible parameter for the development of stroke) varied considerably between the 2 groups (43% vs. 14%, for general vs. local anesthesia, respectively; P < .0001), as well as between UK and non-UK surgeons who always (73.6% vs. 20.8%, respectively; P < .0001), never (4.2% vs. 26%, respectively; P < .0002), or selectively (22.2% vs. 53.2%, respectively; P < .0001) used a shunt. Furthermore, no information was provided regarding the type of shunts used; for example, atraumatic shunts may be associated with lower perioperative stroke rates. These limitations could influence the interpretation of the results of the GALA trial. Due to lack of differences between the 2 groups and the presence of the above limitations, it seems likely that this trial will have little effect on clinical practice.
Endothelial colony-forming cells from patients with chronic myeloproliferative disorders lack the disease-specific molecular clonality marker
Authors: Piaggio Giovanna , Rosti Vittorio , Corselli Mirko , Bertolotti Francesca , Bergamaschi Gaetano , Pozzi Sarah , Imperiale Davide , Chiavarina Barbara , Bonetti Elisa , Novara Francesca , Sessarego Mario , Villani Laura , Garuti Anna , Massa Margherita , Ghio Riccardo , Campanelli Rita , Bacigalupo Andrea , Pecci Alessandro , Viarengo Gianluca , Zuffardi Orsetta , Frassoni Francesco , Barosi Giovanni
Published: July 2009

Two putative types of circulating endothelial progenitor cells have been recently identified in vitro: (1) endothelial colony-forming cell (ECFC) and (2) colony-forming unit–endothelial cell (CFU-EC). Only the former is now recognized to belong to endothelial lineage. We have used the ECFC and CFU-EC assays to readdress the issue of the clonal relation between endothelial progenitor cells and hematopoietic stem cells in patients with Philadelphia-positive and Philadelphia-negative chronic myeloproliferative disorders. Both ECFCs and CFU-ECs were cultured from peripheral blood mononuclear cells, and either BCR-ABL rearrangement or JAK2-V617F mutation were assessed in both types of endothelial colonies. We found that ECFCs lack the disease-specific markers, which are otherwise present in CFU-ECs, thus reinforcing the concept that the latter belongs to the hematopoietic lineage, and showing that in chronic myeloproliferative disorders the cell that gives rise to circulating ECFC has a distinct origin from the cell of the hematopoietic malignant clone.
CalDAG-GEFI is at the nexus of calcium-dependent platelet activation
Authors: Stefanini Lucia , Roden R. Claire , Bergmeier Wolfgang
Published: July 2009

The importance of the second messengers calcium (Ca2+) and diacylglycerol (DAG) in platelet signal transduction was established more than 30 years ago. Whereas protein kinase C (PKC) family members were discovered as the targets of DAG, little is known about the molecular identity of the main Ca2+ sensor(s). We here identify Ca2+ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) as a critical molecule in Ca2+-dependent platelet activation. CalDAG-GEFI, through activation of the small GTPase Rap1, directly triggers integrin activation and extracellular signal-regulated kinase-dependent thromboxane A2 (TxA2) release. CalDAG-GEFI–dependent TxA2 generation provides crucial feedback for PKC activation and granule release, particularly at threshold agonist concentrations. PKC/P2Y12 signaling in turn mediates a second wave of Rap1 activation, necessary for sustained platelet activation and thrombus stabilization. Our results lead to a revised model for platelet activation that establishes one molecule, CalDAG-GEFI, at the nexus of Ca2+-induced integrin activation, TxA2 generation, and granule release. The preferential activation of CalDAG-GEFI over PKC downstream of phospholipase C activation, and the different kinetics of CalDAG-GEFI– and PKC/P2Y12-mediated Rap1 activation demonstrate an unexpected complexity to the platelet activation process, and they challenge the current model that DAG/PKC-dependent signaling events are crucial for the initiation of platelet adhesion.
An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels
Authors: Nassir Rami , Kosoy Roman , Tian Chao , White Phoebe A , Butler Lesley M , Silva Gabriel , Kittles Rick , Alarcon-Riquelme Marta E , Gregersen Peter K , Belmont John W , De La Vega Francisco M , Seldin Michael F
Published: July 2009

Background

Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia.

Results

In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups.

Conclusion

These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.
Distinct retroelement classes define evolutionary breakpoints demarcating sites of evolutionary novelty
Authors: Longo Mark S , Carone Dawn M ,   NISC Comparative Sequencing Program, Green Eric D , O'Neill Michael J , O'Neill Rachel J
Published: July 2009

Background

Large-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are also associated with karyotype diversification during species evolution. Recent research has shown that these breakpoints are nonrandomly distributed throughout the mammalian genome and many, termed "evolutionary breakpoints" (EB), are specific genomic locations that are "reused" during karyotypic evolution. When the phylogenetic trajectory of orthologous chromosome segments is considered, many of these EB are coincident with ancient centromere activity as well as new centromere formation. While EB have been characterized as repeat-rich regions, it has not been determined whether specific sequences have been retained during evolution that would indicate previous centromere activity or a propensity for new centromere formation. Likewise, the conservation of specific sequence motifs or classes at EBs among divergent mammalian taxa has not been determined.

Results

To define conserved sequence features of EBs associated with centromere evolution, we performed comparative sequence analysis of more than 4.8 Mb within the tammar wallaby, Macropus eugenii, derived from centromeric regions (CEN), euchromatic regions (EU), and an evolutionary breakpoint (EB) that has undergone convergent breakpoint reuse and past centromere activity in marsupials. We found a dramatic enrichment for long interspersed nucleotide elements (LINE1s) and endogenous retroviruses (ERVs) and a depletion of short interspersed nucleotide elements (SINEs) shared between CEN and EBs. We analyzed the orthologous human EB (14q32.33), known to be associated with translocations in many cancers including multiple myelomas and plasma cell leukemias, and found a conserved distribution of similar repetitive elements.

Conclusion

Our data indicate that EBs tracked within the class Mammalia harbor sequence features retained since the divergence of marsupials and eutherians that may have predisposed these genomic regions to large-scale chromosomal instability.
A comparative genomics approach to understanding the biosynthesis of the sunscreen scytonemin in cyanobacteria
Authors: Soule Tanya , Palmer Kendra , Gao Qunjie , Potrafka Ruth M , Stout Valerie , Garcia-Pichel Ferran
Published: July 2009

Background

The extracellular sunscreen scytonemin is the most common and widespread indole-alkaloid among cyanobacteria. Previous research using the cyanobacterium Nostoc punctiforme ATCC 29133 revealed a unique 18-gene cluster (NpR1276 to NpR1259 in the N. punctiforme genome) involved in the biosynthesis of scytonemin. We provide further genomic characterization of these genes in N. punctiforme and extend it to homologous regions in other cyanobacteria.

Results

Six putative genes in the scytonemin gene cluster (NpR1276 to NpR1271 in the N. punctiforme genome), with no previously known protein function and annotated in this study as scyA to scyF, are likely involved in the assembly of scytonemin from central metabolites, based on genetic, biochemical, and sequence similarity evidence. Also in this cluster are redundant copies of genes encoding for aromatic amino acid biosynthetic enzymes. These can theoretically lead to tryptophan and the tyrosine precursor, p-hydroxyphenylpyruvate, (expected biosynthetic precursors of scytonemin) from end products of the shikimic acid pathway. Redundant copies of the genes coding for the key regulatory and rate-limiting enzymes of the shikimic acid pathway are found there as well. We identified four other cyanobacterial strains containing orthologues of all of these genes, three of them by database searches (Lyngbya PCC 8106, Anabaena PCC 7120, and Nodularia CCY 9414) and one by targeted sequencing (Chlorogloeopsis sp. strain Cgs-089; CCMEE 5094). Genomic comparisons revealed that most scytonemin-related genes were highly conserved among strains and that two additional conserved clusters, NpF5232 to NpF5236 and a putative two-component regulatory system (NpF1278 and NpF1277), are likely involved in scytonemin biosynthesis and regulation, respectively, on the basis of conservation and location. Since many of the protein product sequences for the newly described genes, including ScyD, ScyE, and ScyF, have export signal domains, while others have putative transmembrane domains, it can be inferred that scytonemin biosynthesis is compartmentalized within the cell. Basic structural monomer synthesis and initial condensation are most likely cytoplasmic, while later reactions are predicted to be periplasmic.

Conclusion

We show that scytonemin biosynthetic genes are highly conserved among evolutionarily diverse strains, likely include more genes than previously determined, and are predicted to involve compartmentalization of the biosynthetic pathway in the cell, an unusual trait for prokaryotes.
Antinociception Induced by Chronic Glucocorticoid Treatment is Correlated to Local Modulation of Spinal Neurotransmitter Content
Authors: Pinto-Ribeiro Filipa , Moreira Vitor , Pěgo José M , Leão Pedro , Almeida Armando , Sousa Nuno
Published: July 2009

Background

While acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT) and dexamethasone (DEX) in order to discriminate the role of each type of corticosteroid receptors in antinociception.

Results

Both experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT); however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SS) andB2-γ-aminobutiric acid receptors (GABAB2) expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period.

Conclusion

These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the exclusive GR activation resulted in more profound and sustained behavioural and neurochemical changes, than the one observed with a mixed ligand of corticosteroid receptors. These results might be of relevance for the pharmacological management of certain types of chronic pain, in which corticosteroids are used as adjuvant analgesics.
Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy
Authors: Nicolini Giorgia , Clivio Alessandro , Fogliata Antonella , Vanetti Eugenio , Cozzi Luca
Published: July 2009

Purpose

A study was performed comparing dosimetric characteristics of volumetric modulated arcs (RapidArc, RA) and fixed field intensity modulated therapy (IMRT) on patients with bilateral breast carcinoma.

Materials and methods

Plans for IMRT and RA, were optimised for 10 patients prescribing 50 Gy to the breast (PTVII, 2.0 Gy/fraction) and 60 Gy to the tumour bed (PTVI, 2.4 Gy/fraction). Objectives were: for PTVs V90%>95%, Dmax<107%; Mean lung dose MLD<15 Gy, V20 Gy<22%; heart involvement was to be minimised. The MU and delivery time measured treatment efficiency. Pre-treatment dosimetry was performed using EPID and a 2D-array based methods.

Results

For PTVII minus PTVI, V90% was 97.8 ± 3.4% for RA and 94.0 ± 3.5% for IMRT (findings are reported as mean ± 1 standard deviation); D5%-D95% (homogeneity) was 7.3 ± 1.4 Gy (RA) and 11.0 ± 1.1 Gy (IMRT). Conformity index (V95%/VPTVII) was 1.10 ± 0.06 (RA) and 1.14 ± 0.09 (IMRT). MLD was <9.5 Gy for all cases on each lung, V20 Gy was 9.7 ± 1.3% (RA) and 12.8 ± 2.5% (IMRT) on left lung, similar for right lung. Mean dose to heart was 6.0 ± 2.7 Gy (RA) and 7.4 ± 2.5 Gy (IMRT). MU resulted in 796 ± 121 (RA) and 1398 ± 301 (IMRT); the average measured treatment time was 3.0 ± 0.1 minutes (RA) and 11.5 ± 2.0 (IMRT). From pre-treatment dosimetry, % of field area with γ <1 resulted 98.8 ± 1.3% and 99.1 ± 1.5% for RA and IMRT respectively with EPID and 99.1 ± 1.8% and 99.5 ± 1.3% with 2D-array (ΔD = 3% and DTA = 3 mm).

Conclusion

RapidArc showed dosimetric improvements with respect to IMRT, delivery parameters confirmed its logistical advantages, pre-treatment dosimetry proved its reliability.
Solving a Hamiltonian Path Problem with a bacterial computer
Authors: Baumgardner Jordan , Acker Karen , Adefuye Oyinade , Crowley Samuel Thomas , DeLoache Will , Dickson James O , Heard Lane , Martens Andrew T , Morton Nickolaus , Ritter Michelle , Shoecraft Amber , Treece Jessica , Unzicker Matthew , Valencia Amanda , Waters Mike , Campbell AMalcolm , Heyer Laurie J , Poet Jeffrey L , Eckdahl Todd T
Published: July 2009

Background

The Hamiltonian Path Problem asks whether there is a route in a directed graph from a beginning node to an ending node, visiting each node exactly once. The Hamiltonian Path Problem is NP complete, achieving surprising computational complexity with modest increases in size. This challenge has inspired researchers to broaden the definition of a computer. DNA computers have been developed that solve NP complete problems. Bacterial computers can be programmed by constructing genetic circuits to execute an algorithm that is responsive to the environment and whose result can be observed. Each bacterium can examine a solution to a mathematical problem and billions of them can explore billions of possible solutions. Bacterial computers can be automated, made responsive to selection, and reproduce themselves so that more processing capacity is applied to problems over time.

Results

We programmed bacteria with a genetic circuit that enables them to evaluate all possible paths in a directed graph in order to find a Hamiltonian path. We encoded a three node directed graph as DNA segments that were autonomously shuffled randomly inside bacteria by a Hin/hixC recombination system we previously adapted from Salmonella typhimurium for use in Escherichia coli. We represented nodes in the graph as linked halves of two different genes encoding red or green fluorescent proteins. Bacterial populations displayed phenotypes that reflected random ordering of edges in the graph. Individual bacterial clones that found a Hamiltonian path reported their success by fluorescing both red and green, resulting in yellow colonies. We used DNA sequencing to verify that the yellow phenotype resulted from genotypes that represented Hamiltonian path solutions, demonstrating that our bacterial computer functioned as expected.

Conclusion

We successfully designed, constructed, and tested a bacterial computer capable of finding a Hamiltonian path in a three node directed graph. This proof-of-concept experiment demonstrates that bacterial computing is a new way to address NP-complete problems using the inherent advantages of genetic systems. The results of our experiments also validate synthetic biology as a valuable approach to biological engineering. We designed and constructed basic parts, devices, and systems using synthetic biology principles of standardization and abstraction.