bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of CHD5 Inactivation in Neuroblastomas
Authors: Koyama Hiroshi , Zhuang Tiangang , Light Jennifer E. , Kolla Venkatadri , Higashi Mayumi , McGrady Patrick W. , London Wendy B. , Brodeur Garrett M.
Published: February 2012

Purpose: Neuroblastomas (NBs) have genomic, biological, and clinical heterogeneity. High-risk NBs are characterized by several genomic changes, including MYCN amplification and 1p36 deletion. We identified the chromatin-remodeling gene CHD5 as a tumor suppressor gene that maps to 1p36.31. Low or absent CHD5 expression is associated with a 1p36 deletion and an unfavorable outcome, but the mechanisms of CHD5 inactivation in NBs are unknown.

Experimental Design: We examined (i) the CHD5 sequence in 188 high-risk NBs investigated through the TARGET initiative, (ii) the methylation status of the CHD5 promoter in 108 NBs with or without 1p36 deletion and/or MYCN amplification, and (iii) mRNA expression of CHD5 and MYCN in 814 representative NBs using TaqMan low-density array microfluidic cards.

Results: We found no examples of somatically acquired CHD5 mutations, even in cases with 1p36 deletion, indicating that homozygous genomic inactivation is rare. Methylation of the CHD5 promoter was common in the high-risk tumors, and it was generally associated with both 1p deletion and MYCN amplification. High CHD5 expression was a powerful predictor of favorable outcome, and it showed prognostic value even in multivariable analysis after adjusting for MYCN amplification, 1p36 deletion, and/or 11q deletion.

Conclusions: We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) high CHD5 expression is strongly correlated with favorable clinical/biological features and outcome. Clin Cancer Res; 18(6); 1588–97. ©2012 AACR.
A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients
Authors: Messing Edward , Gee Jason R. , Saltzstein Daniel R. , Kim KyungMann , diSant'Agnese Anthony , Kolesar Jill , Harris Linda , Faerber Adrienne , Havighurst Thomas , Young Jay M. , Efros Mitchell , Getzenberg Robert H. , Wheeler Marcia A. , Tangrea Joseph , Parnes Howard , House Margaret , Busby J. Erik , Hohl Raymond , Bailey Howard
Published: February 2012

The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents. Cancer Prev Res; 5(4); 621–30. ©2012 AACR.
Amelogenin Exons 8 and 9 Encoded Peptide Enhances Leucine Rich Amelogenin Peptide Mediated Dental Pulp Repair
Authors: Huang Yulei , Goldberg Michel , Le Thuan , Qiang Ran , Warner Douglas , Witkowska Halina Ewa , Liu Haichuan , Zhu Li , DenBesten Pamela , Li Wu
Published: February 2012

Amelogenins containing exons 8 and 9 are alternatively spliced variants of amelogenin. Some amelogenin spliced variants have been found to promote pulp regeneration following pulp exposure. The function of the amelogenin spliced variants with the exons 8 and 9 remains unknown. In this study, we synthesized recombinant leucine rich amelogenin peptide (LRAP, A–4), LRAP plus exons 8 and 9 peptide (LRAP 8, 9) or exons 8 and 9 peptide (P89), to determine their effects on odontoblasts. In vivo analyses were completed following the insertion of agarose beads containing LRAP or LRAP 8, 9 into exposed cavity preparations of rat molars. After 8, 15 or 30 days’ exposure, the pulp tissues were analyzed for changes in histomorphometry and cell proliferation by PCNA stainings. In vitro analyses included the effects of the addition of the recombinant proteins or peptide on cell proliferation, differentiation and adhesion of postnatal human dental pulp cells (DPCs). These studies showed that in vivo LRAP 8, 9 enhanced the reparative dentin formation as compared to LRAP. In vitro LRAP 8, 9 promoted DPC proliferation and differentiation to a greater extent than LRAP. These data suggest that amelogenin exons 8 and 9 may be useful in amelogenin-mediated pulp repair.
Delivery of a DNA Vaccine for Alzheimer’s Disease by Electroporation versus Gene Gun Generates Potent and Similar Immune Responses
Authors: Davtyan Hayk , Ghochikyan Anahit , Movsesyan Nina , Ellefsen Barry , Petrushina Irina , Cribbs David H. , Hannaman Drew , Evans Claire F. , Agadjanyan Michael G.
Published: February 2012

Background: Induction of a humoral response against amyloid-β peptide may be beneficial for Alzheimer’s disease (AD) patients and may alleviate the onset and progression of AD. DNA-based vaccination provides a unique alternative method of immunization for treatment and prevention of AD. Currently, the two major delivery methods used for enhancing DNA uptake and immune responses to DNA vaccines in humans are electroporation (EP) and gene gun (GG). Objective: The goal of this translational study was to evaluate the efficacy of an AD DNA epitope vaccine (DepVac) delivered intramuscularly by EP or intradermally by GG. Methods: Humoral and cellular immune responses to immunization with DepVac were evaluated by ELISA and ELISPOT, respectively. Functional activity of the antibodies was also assessed. Results: EP- and GG-mediated immunizations with DepVac induced similar anti-amyloid-β (Aβ) antibody and T cell responses. Anti-Aβ antibodies bound to amyloid plaques in AD brain tissue and to toxic forms of Aβ42 peptide. Conclusion: Both delivery methods are effective at promoting potent antibodies specific for Aβ.
Acquired Hemophilia A in a Patient with Essential Thrombocythemia
Authors: Mori Naoki , Totsuka Kyoichi , Ishimori Noriko , Yoshinaga Kentaro , Teramura Masanao , Noguchi Sanshiro , Oda Hideaki , Motoji Toshiko
Published: February 2012

A 69-year-old woman with essential thrombocythemia (ET) developed giant ecchymosis, and she was admitted to hospital. Marked anemia (Hb 8.1 g/dl) accompanied by a prolonged activated partial thromboplastin time (89.6 s) was observed, and she received red blood cells (RBC) and fresh frozen plasma (FFP). On day 2 after admission, consciousness disturbance suddenly occurred, whereas computed tomography of the brain showed no evidence of bleeding. As the ecchymosis progressed, she developed shock. Although RBC and FFP transfusions were administered, she developed multi-organ failure and died 48 h after admission. Low factor VIII activity (<1%) accompanied by factor VIII inhibitor (17 Bethesda units) was found after her death. An autopsy revealed cerebral infarction without cerebral herniation. To date, acquired hemophilia A accompanying ET has been described in only one other patient. Although acquired factor VIII inhibitor is a rare disease, it should be tested for in ET patients with marked hemorrhagic tendency.
Combination of Biomarkers: PET [18F]Flutemetamol Imaging and Structural MRI in Dementia and Mild Cognitive Impairment
Authors: Thurfjell Lennart , Lötjönen Jyrki , Lundqvist Roger , Koikkalainen Juha , Soininen Hilkka , Waldemar Gunhild , Brooks David J. , Vandenberghe Rik
Published: February 2012

Background:The New National Institute on Aging-Alzheimer’s Association diagnostic guidelines for Alzheimer’s disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury. Objective:It was the aim of this study to compute hippocampus volume from MRI and a neocortical standard uptake value ratio (SUVR) from [18F]flutemetamol PET and investigate the performance of these biomarkers when used individually and when combined. Methods: Fully automated methods for hippocampus segmentation and for computation of neocortical SUVR were applied to MR and scans with the investigational imaging agent [18F]flutemetamol in a cohort comprising 27 AD patients, 25 healthy volunteers (HVs) and 20 subjects with amnestic mild cognitive impairment (MCI). Clinical follow-up was performed 2 years after the initial assessment. Results:Hippocampus volumes showed extensive overlap between AD and HV cases while PET SUVRs showed clear group clustering. When both measures were combined, there was a relatively compact cluster of HV scans and a less compact AD cluster. MCI cases had a bimodal distribution of SUVRs. [18F]Flutemetamol-positive MCI subjects showed a large variability in hippocampus volumes, indicating that these subjects were in different stages of neurodegeneration. Some [18F]flutemetamol-negative MCI scans had hippocampus volumes that were well below the HV range. Clinical follow-up showed that 8 of 9 MCI to AD converters came from the [18F]flutemetamol-positive group. Conclusion:Combining [18F]flutemetamol PET with structural MRI provides additional information for categorizing disease and potentially predicting shorter time to progression from MCI to AD, but this has to be validated in larger longitudinal studies.
Left Atrial Wall Stress Distribution and Its Relationship to Electrophysiologic Remodeling in Persistent Atrial Fibrillation
Authors: Hunter Ross J. , Liu Yankai , Lu Yiling , Wang Wen , Schilling Richard J.
Published: February 2012

Background—

Atrial stretch causes remodeling that predisposes to atrial fibrillation. We tested the hypothesis that peaks in left atrial (LA) wall stress are associated with focal remodeling.

Methods and Results—

Nineteen patients underwent LA mapping before catheter ablation for persistent atrial fibrillation. Finite Element Analysis was used to predict wall stress distribution based on LA geometry from CT. The relationship was assessed between wall stress and (1) electrogram voltage and (2) complex fractionated atrial electrograms (CFAE), using CFAE mean (the mean interval between deflections). Wall stress varied widely within atria and between subjects (median, 36 kPa; interquartile range, 26–51 kP). Peaks in wall stress (≥90th percentile) were common at the pulmonary vein (PV) ostia (93%), the appendage ridge (100%), the high posterior wall (84%), and the anterior wall and septal regions (42–84%). Electrogram voltage showed an inverse relationship across quartiles for wall stress (19% difference across quartiles,
P
=0.016). There was no effect on CFAE mean across quartiles of wall stress. Receiver operating characteristic analysis showed high wall stress was associated with low voltage (ie, <0.5 mV) and electrical scar (ie, <0.05 mV; both
P
<0.0001) and with absence of CFAE (ie, CFAE mean <120 ms;
P
<0.0001). However, peaks in wall stress and CFAE were found at 88% of PV ostia.

Conclusions—

Peaks in wall stress were associated with areas of low voltage, suggestive of focal remodeling. Although peaks in wall stress were not associated with LA CFAE, the PV ostia may respond differently.
Genetic Analysis of Atherosclerosis and Glucose Homeostasis in an Intercross Between C57BL/6 and BALB/cJ Apolipoprotein E–Deficient Mice
Authors: Zhang Zhimin , Rowlan Jessica S. , Wang Qian , Shi Weibin
Published: February 2012

Background—

Diabetic patients have an increased risk of developing atherosclerosis and related complications compared with nondiabetic individuals. The increased cardiovascular risk associated with diabetes is due in part to genetic variations that influence both glucose homeostasis and atherosclerotic lesion growth. Mouse strains C57BL/6J (B6) and BALB/cJ (BALB) exhibit distinct differences in fasting plasma glucose and atherosclerotic lesion size when deficient in apolipoprotein E (
Apoe
−/−
). Quantitative trait locus (QTL) analysis was performed to determine genetic factors influencing the 2 phenotypes.

Methods and Results—

Female F
2
mice (n=266) were generated from an intercross between B6.
Apoe
−/−
and BALB.
Apoe
−/−
mice and fed a Western diet for 12 weeks. Atherosclerotic lesions in the aortic root, fasting plasma glucose, and body weight were measured. 130 microsatellite markers across the entire genome were genotyped. Four significant QTLs,
Ath1
on chromosome (Chr) 1,
Ath41
on Chr2,
Ath42
on Chr5, and
Ath29
on Chr9, and 1 suggestive QTL on Chr4, were identified for atherosclerotic lesion size. Four significant QTLs,
Bglu3
and
Bglu12
on Chr1,
Bglu13
on Chr5,
Bglu15
on Chr12, and 2 suggestive QTLs on Chr9 and Chr15 were identified for fasting glucose levels on the chow diet. Two significant QTLs,
Bglu3
and
Bglu13
, and 1 suggestive locus on Chr8 were identified for fasting glucose on the Western diet. One significant locus on Chr1 and 2 suggestive loci on Chr9 and Chr19 were identified for body weight.
Ath1
and
Ath42
coincided with
Bglu3
and
Bglu13
, respectively, in the confidence interval.

Conclusions—

We have identified novel QTLs that have major influences on atherosclerotic lesion size and glucose homeostasis. The colocalization of QTLs for atherosclerosis and diabetes suggests possible genetic connections between the 2 diseases.
No Association of
ABCB1
C3435T Genotype With Clopidogrel Response or Risk of Stent Thrombosis in Patients Undergoing Coronary Stenting
Authors: Jaitner Juliane , Morath Tanja , Byrne Robert A. , Braun Siegmund , Gebhard Daniela , Bernlochner Isabell , Schulz Stefanie , Mehilli Julinda , Schömig Albert , Koch Werner , Kastrati Adnan , Sibbing Dirk
Published: February 2012

Background—

The prodrug clopidogrel requires intestinal absorption by the efflux pump P-glycoprotein MDR1 (multidrug resistant-1), encoded by the
ABCB1
gene. Prior studies suggested that a common and functional genetic variant (C3435T, rs1045642) within
ABCB1
influences clopidogrel treatment efficacy; however, existing data are highly inconsistent, because other studies failed to replicate this postulated association. Thus, the aim of this study was to assess the association of
ABCB1
C3435T genotypes with the antiplatelet efficacy of clopidogrel and the risk of stent thrombosis (ST) in large cohorts of clopidogrel-treated patients undergoing percutaneous coronary intervention.

Methods and Results—

DNA samples from 1524 clopidogrel-treated patients undergoing percutaneous coronary intervention were genotyped for
ABCB1
C3435T, and ADP-induced platelet aggregation was assessed in whole blood on a Multiplate analyzer. The clinical impact of the genetic variant was investigated by comparison of genotype frequencies in a registry of 66 cases with definite drug-eluting stent ST versus an ST-free control cohort (n=1408). Platelet aggregation values were similar across
ABCB1
C3435T genotypes (
P
=0.73). No significant influence of
ABCB1
C3435T genotypes on the occurrence of ST was found when ST case subjects were compared with control subjects (
P
=0.89).

Conclusions—

ABCB1
C3435T genotypes did not influence the antiplatelet response to clopidogrel or the risk of ST in clopidogrel-treated patients undergoing percutaneous coronary intervention. Routine genotyping of
ABCB1
C3435T polymorphisms should not be recommended for risk stratification in clopidogrel-treated patients undergoing percutaneous coronary intervention who are similar to those evaluated in the present study.
Stochastic Perturbation Methods for Spike-Timing-Dependent Plasticity
Authors: Leen Todd K. , Friel Robert
Published: February 2012

Online machine learning rules and many biological spike-timing-dependent plasticity (STDP) learning rules generate jump process Markov chains for the synaptic weights. We give a perturbation expansion for the dynamics that, unlike the usual approximation by a Fokker-Planck equation (FPE), is well justified. Our approach extends the related system size expansion by giving an expansion for the probability density as well as its moments. We apply the approach to two observed STDP learning rules and show that in regimes where the FPE breaks down, the new perturbation expansion agrees well with Monte Carlo simulations. The methods are also applicable to the dynamics of stochastic neural activity. Like previous ensemble analyses of STDP, we focus on equilibrium solutions, although the methods can in principle be applied to transients as well.
Learning Invariance from Natural Images Inspired by Observations in the Primary Visual Cortex
Authors: Teichmann Michael , Wiltschut Jan , Hamker Fred
Published: February 2012

The human visual system has the remarkable ability to largely recognize objects invariant of their position, rotation, and scale. A good interpretation of neurobiological findings involves a computational model that simulates signal processing of the visual cortex. In part, this is likely achieved step by step from early to late areas of visual perception. While several algorithms have been proposed for learning feature detectors, only few studies at hand cover the issue of biologically plausible learning of such invariance. In this study, a set of Hebbian learning rules based on calcium dynamics and homeostatic regulations of single neurons is proposed. Their performance is verified within a simple model of the primary visual cortex to learn so-called complex cells, based on a sequence of static images. As a result, the learned complex-cell responses are largely invariant to phase and position.
Pediatric Dog Bite Victims
Authors: Boat Barbara W. , Dixon Cinnamon A. , Pearl Erica , Thieken Lacey , Bucher Sarah E.
Published: February 2012

The authors assessed the ongoing needs of 34 pediatric dog bite victims and their families 1 month after receiving care in a pediatric emergency department. More than 70% of the parents noted at least 1 new concerning behavior in their children, and more than 85% of the parents also endorsed concerns about their own reactions. Half of the parents believed that children, in general, might benefit from interventions to help with postbite fears and nearly three quarters felt that families would benefit from education regarding dog bite prevention. The majority (85%) of the parents believed that additional supportive services could be offered effectively at emergency department or pediatric office/clinic visits. A template for a dog bite information card is presented.
Design of a sliding mode controller for synchronizing chaotic systems with parameter and model uncertainties and external disturbances
Authors: Aghababa Mohammad Pourmahmood , Feizi Hassan
Published: January 2012

Finite-time synchronization of two different uncertain chaotic systems using a new non-singular terminal sliding mode approach is studied in this paper. Both master and slave systems are perturbed by parameter and model uncertainties, as well as external disturbances. A novel non-singular terminal sliding manifold is introduced. Based on the Lyapunov stability theory and finite-time control idea, a robust sliding mode controller is designed. It is shown that both reaching and sliding phases have the finite-time convergence property. In other words, it is proved that the state trajectories of the slave system can reach the state trajectories of the master system in a given finite time. The robustness and applicability of the proposed technique are demonstrated by two illustrative examples.
“Not Out to Start a Revolution”
Authors: Wilkins Amy
Published: February 2012

In this article, I use in-depth interviews with black university men to investigate race, gender, and emotions. Participation in dominant institutions requires African American men to exhibit extraordinary emotional restraint. Because anger is culturally associated with men, however, black men’s suppression of anger violates masculine expectations. Thus, racial subordination not only creates difficult emotional expectations but may also create emotional dilemmas in which expected emotional displays undermine other identity expectations. In this article, I examine both how a group of black university men achieve emotional restraint and how they use their emotions to craft and manage their identities as black middle-class men. I argue that black men distance themselves from the controlling image of the angry black man by developing a shared identity I call moderate blackness. Moderate blackness entails emotional restraint, a moderate approach to campus racial politics, and the ability to get along with white people. These strategies work together to produce positive, restrained emotions and to manage anger and agitation, but they require black university men to “not see” racism. Black men use defensive othering to push the stereotype of the angry black onto black women. In doing so, they shore up their masculinity but leave women responsible for combating racial inequality.
Refusal of treatment and decision-making capacity
Authors: Bingham Sarah-Louise
Published: February 2012

This article explores refusal of medical treatment by adult patients from ethical and legal perspectives. Initially, consequentialist and deontological ethical theory are outlined. The concepts of autonomy, paternalism and competence are described and an overview of Beauchamp and Childress’s principle-based approach to moral reasoning is given. Relevant common law is discussed and the provisions of the Mental Capacity Act 2005 in assessing competence is evaluated. In order to demonstrate the consideration of moral issues in clinical practice, ethical theory is applied to two well-known incidents: the case of Re MB, where doubt over decision-making capacity led to a paternalistic act to override a patient’s choice; and the death of Emma Gough, a situation where respect for autonomy prevailed when healthcare staff acted lawfully in following a patient’s refusal of life-saving treatment. Finally, guidance from regulatory bodies on the roles and responsibilities of health professionals in relation to this topic are considered.
Evaluating Metrics for Quality
Authors: Chang David C. , Rhee Daniel S. , Zhang Yiyi , Salazar Jose H. , Chrouser Kristin , Choo Shelly , Colombani Paul M. , Abdullah Fizan
Published: February 2012

Surgical mortality is considered a benchmark for measuring quality of care. This study quantifies the incidence of death on the day of elective pediatric surgery, which generally is considered preventable and might be considered a “never” event. The authors conducted a retrospective analysis of national state inpatient databases from 1988 to 2007 that included elective pediatric surgical patients. A descriptive analysis of same-day mortality by demographics, surgical specialties, and age was performed. Of 835 880 elective pediatric surgical cases identified, 174 patients died on the day of surgery—that is, 2.1 deaths/10 000 cases. Surgical specialty mortality rates ranged from 0.06 (otolaryngology) to 17.4 (cardiothoracic surgery) deaths per 10 000 cases. Death on the day of elective pediatric surgery is rare, limiting its utility to compare performance in pediatric surgery. However, this metric may be useful at individual institutions as a case-finding tool for root-cause analysis in quality improvement efforts.
Balancing of flexible rotors without trial weights based on finite element modal analysis
Authors: Li Xiaofeng , Zheng Longxi , Liu Zhenxia
Published: January 2012

With the continuous improvement of aviation engine performance, the engine rotor’s working speed is above the first critical speed, and some small engine rotor’s operating speed exceeds the second critical speed, thus most of the aircraft engine rotor is now flexible rotor. The primary goal of this research is to provide a new method without trial weights for flexible rotor balancing, which is based on the traditional modal balancing method and combines the dynamic characteristics of the rotor, such as the model shape, obtained by using finite element analysis software, the critical speed, the modal damping ratio, and so on. To demonstrate the validity and accuracy of the new method, two experiments are carried out. One is on a four-disk simply supported structure rotor experiment, which is balanced by using three balancing planes. After balancing the amplitude of the rotor through the first critical speed is reduced 80%. The other is on a turboshaft engine power turbine rotor which had been balanced quite well. The initial amplitude of the turboshaft engine power turbine rotor is 0.05 mm when it rotates at low speed, and the maximum amplitude is just 0.12 mm when it rotates at the first critical speed. After balancing the amplitude of the rotor through the first critical speed is reduced to 0.06 mm. The results of the experiments indicate that the new without trial weights method is a significant effective method for the flexible rotor dynamic balancing, and it will be widely used to balance the engine rotor.
Enhancing the Translation of Physical Activity Interventions in Afterschool Programs
Authors: Beets Michael W.
Published: February 2012

Afterschool programs (3-6 pm, ASPs) represent a promising approach to promote physical activity (PA) and are positioned to make a substantial contribution to children’s overall daily PA. This article synthesizes both descriptive and intervention focused efforts aimed at describing/increasing PA within the ASP setting and outlines future directions for research. ASPs provide anywhere from 8 to 24 minutes of moderate-to-vigorous PA daily, with children accumulating between 2600 and 3200 steps per day. State and national organizations have developed policies related to PA in ASPs, but the limited available evidence indicates that ASPs are far from meeting PA policy goals. A total of 17 ASP PA intervention studies have been conducted, more than half (9/17) within ASPs that were initiated and developed by researchers. Based on the review of evidence, key strategies to increase PA include high-quality professional development training, allocating time in the ASP schedule for children to engage in sufficient amounts of PA, and tailoring the intervention to local conditions. Future directions should focus on evaluating these key strategies, conducting descriptive studies of common ASP characteristics nationally and their influence on children’s PA, evaluation/refinement of existing ASP PA curricula, cost-effectiveness of interventions, and identification of feasible PA policy goals.
Lengthening z-Osteotomy of the Fibula to Correct Persistent Talar Shift Following Open Reduction Internal Fixation of Ankle Fractures
Authors: Thangarajah Tanujan , Lakdawala Ayaz , Battaloglu Emir , Malik Atul , Tillu Abhay
Published: February 2012

Background: In cases where ankle fracture union has been compromised by persistent syndesmotic diastasis following open reduction internal fixation, both external rotation and shortening of the fibula have been identified as prominent features. Objective: This study reports a technique that uses a z-osteotomy to achieve both lengthening and internal rotation of the fibula to correct persistent talar shift following ankle fracture fixation. Methods: Four patients with persistent talar shift following open reduction internal fixation for an ankle fracture received z-osteotomy of the fibula to achieve both lengthening and internal rotation. Results: At the latest clinic review, all 4 ankles exhibited satisfactory clinical and radiological union. All patients have returned to full mobility and are satisfied with the outcome. Conclusions: This study demonstrates the effectiveness of lengthening z-osteotomy of the fibula in correcting persistent talar shift following internal fixation of ankle fractures.

Level of evidence: Therapeutic Level V
Pre-ICU Management of Patients With Head Trauma
Authors: Tang Julin F. , Stiver Shirley I.
Published: February 2012

Patients presenting with traumatic brain injury (TBI) pose special challenges for critical care personnel throughout the hospital, especially for emergency department and operating room personnel who care for TBI patients during their initial evaluation. Many of these patients proceed from the emergency department to an operating room for emergent cranial decompression en route to the ICU. At the authors’ hospital, a level I trauma center, steps have been taken to improve treatment in this pre-ICU care setting. In this report, the authors describe changes that have been made over time in the care of patients with TBI and the improved patient mortality that occurred after the introduction of these practice changes. The measures consisted of early goal-directed fluid resuscitation to correct intravascular volume depletion and vigilant hemodynamic monitoring by arterial line, central venous pressure, and transesophageal echocardiography. Despite these improved results, additional studies are needed to better define the best early treatment practices for the TBI patient.
Aortic Dissection
Authors: Dagher Gilbert Abou , Favot Mark , Njeim Mario , Chebel Ralph Bou , Younes Mohamad
Published: February 2012

Aortic dissection is a potentially catastrophic disease with significant mortality and morbidity. Presentations are often atypical and the physician needs to have a high index of suspicion and low threshold to work up these cases. Ultrasound use in the emergency department is becoming an important tool for physicians and can expedite care in many ways. The authors describe the case of a 55-year-old man with uncontrolled hypertension, who presented to the emergency department with acute chest pain radiating to the back and abdomen. A bedside cardiac ultrasound done by the emergency medicine resident showed a flap in the descending thoracic aorta with a preserved ejection fraction and no evidence of a pericardial effusion. Appropriate management was started with intravenous esmolol and nitroprusside and based on the seriousness of the ultrasound findings, a computed tomography scan was done immediately, which revealed a Stanford type B dissection extending from the aortic arch down to the left common and external iliac arteries with a likely area of infarction in the left kidney. The patient was admitted to the cardiovascular intensive care unit and a stent was placed in his left renal artery. He was subsequently discharged home in a stable condition with adequate blood pressure control. The case presentation is followed by a discussion on the diagnosis and management of acute aortic dissection, and the importance of point-of-care ultrasonography in the emergency department is also highlighted.
Early Mobilization in Critically Ill Patients
Authors: Lunardi Nadia , Bryant Martha , Smith Kellen , Lowson Stuart
Published: February 2012

Mortality in the ICU has dramatically decreased over the past decades because of a clearer understanding of disease pathophysiology, improved technology, and novel therapies. This success has led to the new challenge of treating patients with chronic disabilities resulting from prolonged ICU stays. In this review, the authors ( a) describe the emerging understanding of the basis for ICU-acquired weakness, including contributing factors such as prolonged bed rest; ( b) provide the background for the safety and efficacy of early mobilization; and ( c) give practical guidance for the implementation of ICU early mobilization based on their experience over the past 8 years.
A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes
Authors: Bryceson Yenan T. , Pende Daniela , Maul-Pavicic Andrea , Gilmour Kimberly C. , Ufheil Heike , Vraetz Thomas , Chiang Samuel C. , Marcenaro Stefania , Meazza Raffaella , Bondzio Ilka , Walshe Denise , Janka Gritta , Lehmberg Kai , Beutel Karin , zur Stadt Udo , Binder Nadine , Arico Maurizio , Moretta Lorenzo , Henter Jan-Inge , Ehl Stephan
Published: February 2012

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2–activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.
Genome-wide analysis of hepatic LRH-1 reveals a promoter binding preference and suggests a role in regulating genes of lipid metabolism in concert with FXR
Authors: Chong Hansook Kim , Biesinger Jacob , Seo Young-Kyo , Xie Xiaohui , Osborne Timothy F
Published: February 2012

Background

In a previous genome-wide analysis of FXR binding to hepatic chromatin, we noticed that an extra nuclear receptor (NR) half-site was co-enriched close to the FXR binding IR-1 elements and we provided limited support that the monomeric LRH-1 receptor that binds to NR half-sites might function together with FXR to activate gene expression.

Results

To analyze the global pattern for LRH-1 binding and to determine whether it might associate with FXR on a whole genome-wide scale, we analyzed LRH-1 binding to the entire hepatic genome using a non-biased genome-wide ChIP-seq approach. We identified over 10,600 LRH-1 binding sites in hepatic chromatin and over 20% were located within 2 kb of the 5' end of a known mouse gene. Additionally, the results demonstrate that a significant fraction of the genome sites occupied by LRH-1 are located close to FXR binding sites revealed in our earlier study. A Gene ontology analysis revealed that genes preferentially enriched in the LRH-1/FXR overlapping gene set are related to lipid metabolism. These results demonstrate that LRH-1 recruits FXR to lipid metabolic genes. A significant fraction of FXR binding peaks also contain a nuclear receptor half-site that does not bind LRH-1 suggesting that additional monomeric nuclear receptors such as RORs and NR4As family members may also target FXR to other pathway selective genes related to other areas of metabolism such as glucose metabolism where FXR has also been shown to play an important role.

Conclusion

These results document an important role for LRH-1 in hepatic metabolism through acting predominantly at proximal promoter sites and working in concert with additional nuclear receptors that bind to neighboring sites
Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions
Authors: Cheng Shu , Prot Jean-Matthieu , Leclerc Eric , Bois Frédéric Y
Published: February 2012

Background

Understanding hepatic zonation is important both for liver physiology and pathology. There is currently no effective systemic chemotherapy for human hepatocellular carcinoma (HCC) and its pathogenesis is of special interest. Genomic and proteomic data of HCC cells in different culture models, coupled to pathway-based analysis, can help identify HCC-related gene and pathway dysfunctions.

Results

We identified zonation-related expression profiles contributing to selective phenotypes of HCC, by integrating relevant experimental observations through gene set enrichment analysis (GSEA). Analysis was based on gene and protein expression data measured on a human HCC cell line (HepG2/C3A) in two culture conditions: dynamic microfluidic biochips and static Petri dishes. Metabolic activity (HCC-related cytochromes P450) and genetic information processing were dominant in the dynamic cultures, in contrast to kinase signaling and cancer-specific profiles in static cultures. That, together with analysis of the published literature, leads us to propose that biochips culture conditions induce a periportal-like hepatocyte phenotype while standard plates cultures are more representative of a perivenous-like phenotype. Both proteomic data and GSEA results further reveal distinct ubiquitin-mediated protein regulation in the two culture conditions.

Conclusions

Pathways analysis, using gene and protein expression data from two cell culture models, confirmed specific human HCC phenotypes with regard to CYPs and kinases, and revealed a zonation-related pattern of expression. Ubiquitin-mediated regulation mechanism gives plausible explanations of our findings. Altogether, our results suggest that strategies aimed at inhibiting activated kinases and signaling pathways may lead to enhanced metabolism-mediated drug resistance of treated tumors. If that were the case, mitigating inhibition or targeting inactive forms of kinases would be an alternative.
Evaluation of cellular uptake and intracellular trafficking as determining factors of gene expression for amino acid-substituted gemini surfactant-based DNA nanoparticles
Authors: Singh Jagbir , Michel Deborah , Chitanda Jackson M , Verrall Ronald E , Badea Ildiko
Published: February 2012

Background

Gene transfer using non-viral vectors offers a non-immunogenic and safe method of gene delivery. Cellular uptake and intracellular trafficking of the nanoparticles can impact on the transfection efficiency of these vectors. Therefore, understanding the physicochemical properties that may influence the cellular uptake and the intracellular trafficking can aid the design of more efficient non-viral gene delivery systems. Recently, we developed novel amino acid-substituted gemini surfactants that showed higher transfection efficiency than their parent compound. In this study, we evaluated the mechanism of cellular uptake of the plasmid/gemini surfactant/helper lipid nanoparticles and their effect on the transfection efficiency.

Results

Nanoparticles were incubated with Sf 1 Ep cells in the presence of different endocytic inhibitors and gene expression (interferon-γ) was measured using ELISA. Clathrin-mediated and caveolae-mediated uptake were found to be equally contributing to cellular internalization of both P/12-7NH-12/L (parent gemini surfactant) and P/12-7NGK-12/L (amino acid-substituted gemini surfactant) nanoparticles. The plasmid and the helper lipid were fluorescently tagged to track the nanoparticles inside the cells, using confocal laser scanning microscopy. Transmission electron microscopy images showed that the P/12-7NGK-12/L particles were cylindrical while the P/12-7NH-12/L particles were spherical which may influence the cellular uptake behaviour of these particles. Dye exclusion assay and pH-titration of the nanoparticles suggested that high buffering capacity, pH-dependent increase in particle size and balanced DNA binding properties may be contributing to a more efficient endosomal escape of P/12-7NGK-12/L compared to the P/12-7NH-12/L nanoparticles, leading to higher gene expression.

Conclusion

Amino-acid substitution in the spacer of gemini surfactant did not alter the cellular uptake pathway, showing similar pattern to the unsubstituted parent gemini surfactant. Glycyl-lysine substitution in the gemini spacer improved buffering capacity and imparted a pH-dependent increase of particle size. This property conferred to the P/12-7NGK-12/L nanoparticles the ability to escape efficiently from clathrin-mediated endosomes. Balanced binding properties (protection and release) of the 12-7NGK-12 in the presence of polyanions could contribute to the facile release of the nanoparticles internalized via caveolae-mediated uptake. A more efficient endosomal escape of the P/12-7NGK-12/L nanoparticles lead to higher gene expression compared to the parent gemini surfactant.
L Type Ca2+ Channel Blockers Prevent Oxaliplatin-Induced Cold Hyperalgesia and TRPM8 Overexpression in Rats
Authors: Kawashiri Takehiro , Egashira Nobuaki , Kurobe Kentaro , Tsutsumi Kuniaki , Yamashita Yuji , Ushio Soichiro , Yano Takahisa , Oishi Ryozo
Published: February 2012

Background:

Oxaliplatin is an important drug used in the treatment of colorectal cancer. However, it frequently causes severe acute and chronic peripheral neuropathies. We recently reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats, and that oxalate derived from oxaliplatin is involved in the cold hyperalgesia. In the present study, we examined the effects of Ca2+ channel blockers on oxaliplatin-induced cold hyperalgesia in rats.

Methods:

Cold hyperalgesia was assessed by the acetone test. Oxaliplatin (4 mg/kg), sodium oxalate (1.3 mg/kg) or vehicle was injected i.p. on days 1 and 2. Ca2+ (diltiazem, nifedipine and ethosuximide) and Na+ (mexiletine) channel blockers were administered p.o. simultaneously with oxaliplatin or oxalate on days 1 and 2.

Results:

Oxaliplatin (4 mg/kg) induced cold hyperalgesia and increased in the transient receptor potential melastatin 8 (TRPM8) mRNA levels in the dorsal root ganglia (DRG). Furthermore, oxalate (1.3 mg/kg) significantly induced the increase in TRPM8 protein in the DRG. Treatment with oxaliplatin and oxalate (500 μM for each) also increased the TRPM8 mRNA levels and induced Ca2+ influx and nuclear factor of activated T-cell (NFAT) nuclear translocation in cultured DRG cells. These changes induced by oxalate were inhibited by nifedipine, diltiazem and mexiletine. Interestingly, co-administration with nifedipine, diltiazem or mexiletine prevented the oxaliplatin-induced cold hyperalgesia and increase in the TRPM8 mRNA levels in the DRG.

Conclusions:

These data suggest that the L type Ca2+ channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca2+ channel blockers have prophylactic potential for acute neuropathy.
The yeast mitogen-activated protein kinase Slt2 is involved in the cellular response to genotoxic stress
Authors: Soriano-Carot María , Bañó M Carmen , Igual J Carlos
Published: February 2012

Background

The maintenance of genomic integrity is essential for cell viability. Complex signalling pathways (DNA integrity checkpoints) mediate the response to genotoxic stresses. Identifying new functions involved in the cellular response to DNA-damage is crucial. TheSaccharomyces cerevisiae SLT2gene encodes a member of the mitogen-activated protein kinase (MAPK) cascade whose main function is the maintenance of the cell wall integrity. However, different observations suggest thatSLT2may also have a role related to DNA metabolism.

Results

This work consisted in a comprehensive study to connect the Slt2 protein to genome integrity maintenance in response to genotoxic stresses. Theslt2mutant strain was hypersensitive to a variety of genotoxic treatments, including incubation with hydroxyurea (HU), methylmetanosulfonate (MMS), phleomycin or UV irradiation. Furthermore, Slt2 was activated by all these treatments, which suggests that Slt2 plays a central role in the cellular response to genotoxic stresses. Activation of Slt2 was not dependent on the DNA integrity checkpoint. For MMS and UV, Slt2 activation required progression through the cell cycle. In contrast, HU also activated Slt2 in nocodazol-arrested cells, which suggests that Slt2 may respond to dNTP pools alterations. However, neither the protein level of the distinct ribonucleotide reductase subunits nor the dNTP pools were affected in aslt2mutant strain. An analysis of the checkpoint function revealed that Slt2 was not required for either cell cycle arrest or the activation of the Rad53 checkpoint kinase in response to DNA damage. However,slt2mutant cells showed an elongated bud and partially impaired Swe1 degradation after replicative stress, indicating that Slt2 could contribute, in parallel with Rad53, to bud morphogenesis control after genotoxic stresses.

Conclusions

Slt2 is activated by several genotoxic treatments and is required to properly cope with DNA damage. Slt2 function is important for bud morphogenesis and optimal Swe1 degradation under replicative stress. The MAPK Slt2 appears as a new player in the cellular response to genotoxic stresses.
Caipirini: using gene sets to rank literature
Authors: Soldatos Theodoros G , O'Donoghue Seán I , Satagopam Venkata P , Barbosa-Silva Adriano , Pavlopoulos Georgios A , Wanderley-Nogueira Ana Carolina , Soares-Cavalcanti Nina Mota , Schneider Reinhard
Published: February 2012

Background

Keeping up-to-date with bioscience literature is becoming increasingly challenging. Several recent methods help meet this challenge by allowing literature search to be launched based on lists of abstracts that the user judges to be 'interesting'. Some methods go further by allowing the user to provide a second input set of 'uninteresting' abstracts; these two input sets are then used to search and rank literature by relevance. In this work we present the service 'Caipirini' (http://caipirini.org) that also allows two input sets, but takes the novel approach of allowing ranking of literature based on one or more sets of genes.

Results

To evaluate the usefulness of Caipirini, we used two test cases, one related to the human cell cycle, and a second related to disease defense mechanisms in Arabidopsis thaliana. In both cases, the new method achieved high precision in finding literature related to the biological mechanisms underlying the input data sets.

Conclusions

To our knowledge Caipirini is the first service enabling literature search directly based on biological relevance to gene sets; thus, Caipirini gives the research community a new way to unlock hidden knowledge from gene sets derived via high-throughput experiments.