bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of 99mTechnetium-labeled mebrofenin hepatic extraction method to quantify meal-induced splanchnic blood flow responses using a porcine model
Authors: Zacho Helle Damgaard , Kristensen Niels Bastian , Henriksen Jens Henrik , Abrahamsen Jan
Published: December 2011

The aim of this study was to evaluate the measurement of the total splanchnic blood flow (SBF) using a clinical diagnostic method based on Fick's principle and hepatic extraction of 99mTc-mebrofenin (99mTc-MBF) compared with a paraaminohippuric acid (pAH) dilution method in a porcine model. Another aim was to investigate whether enterohepatic cycling of 99mTc-MBF affected the SBF measurement. Five indwelling catheters were placed in each pig ( n = 15) in the portal, mesenteric, and hepatic veins, as well as in the aorta and the vena cava. The SBF was measured using both methods. The portal blood flow; the intestinal and hepatic oxygen uptake; the net fluxes of oxygen, lactate, and glucose; and the extraction fraction (EF) of 99mTc-MBF were measured before and for 70 min after feeding. The mean baseline SBF was 2,961 ml/min vs. 2,762 ml/min measured by pAH and 99mTc-MBF, respectively, and increased significantly to 3,977 ml/min and 3,981 ml/min postprandially. The hepatic EF of 99mTc-MBF decreased from 40% at the start of the investigation to 16% 70 min after feeding. The arterial-portal difference in 99mTc-MBF concentration was 0.21% ( P = 0.48), indicating no intestinal extraction or metabolism. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is robust compared with the indicator dilution method, despite the decrease seen in hepatic extraction of 99mTc-MBF. Because there was no difference in the content of 99mTc-MBF between the arterial and portal vein plasma, the SBF can be calculated from an arterial and a hepatic vein sample.
Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS-Mutant Colorectal Cancer Models
Authors: Morelli M. Pia , Tentler John J. , Kulikowski Gillian N. , Tan Aik-Choon , Bradshaw-Pierce Erica L. , Pitts Todd M. , Brown Amy M. , Nallapareddy Sujatha , Arcaroli John J. , Serkova Natalie J. , Hidalgo Manuel , Ciardiello Fortunato , Eckhardt S. Gail
Published: December 2011

Purpose: Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%, supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor.

Experimental Design: Transcriptional profiling and gene set enrichment analysis (baseline and posttreatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts.

Results: In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups.

Conclusion: These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects. Clin Cancer Res; 18(4); 1051–62. ©2011 AACR.
Risk Factors Associated with Progression in Exfoliative Glaucoma Patients
Authors: Holló Gábor , Quaranta Luciano , Cvenkel Barbara , Astakhov Yuri S. , Teus Miguel A. , Kóthy Péter , Miglior Stefano , Riva Ivano , Akopov Evgeny L. , Gros Juan , Stewart Jeanette A. , Kristoffersen Michael S. , Nelson Lindsay A. , Stewart William C.
Published: December 2011

Purpose: To evaluate exfoliative glaucoma (XFG) patients over 5 years, determining risk factors associated with progression or non-progression of glaucoma. Methods: A retrospective, observational study. Patients were chosen from consecutive charts and data collected from each available visit included in the follow-up period. Data were abstracted for non-progressed XFG patients for 5 years and for progressed patients until glaucoma worsened. Progression was determined from patient records and by disc photographs. Results: There were 71 (53%) progressed and 63 (47%) non-progressed XFG patients.Baseline parameters demonstrated worse visual field damage (p = 0.014) and more prescribed medicines (p = 0.03) in progressed patients. The mean intraocular pressure (IOP) for progressed patients was 18.7 ± 4.3 and 17.3 ± 3.4 mm Hg for non-progressed patients (p = 0.047). The mean IOP that best separated the groups was 17 mm Hg with 60% staying non-progressed at or below this level and 30% above this level. At the last visit, progressed patients had more medicines prescribed (1.7) than non-progressed patients (1.3, p = 0.005). A multivariate regression analysis showed higher mean, peak and variance of IOP, number of glaucoma medications at the final visit and presence of a disc hemorrhage (n = 5) as independent risk factors for progression (p ≤ 0.05). Conclusion: IOP reduction in XFG may be essential in reducing disease progression. The presence of disc hemorrhage in XFG may suggest an increased probability of progression despite treatment to within the normal IOP range.
Vascular Disease, Alzheimer’s Disease Biomarkers and Cognition in Mild Cognitive Impairment: Additive or Synergetic Effects?
Authors: Nordlund Arto , Göthlin Mattias , Wallin Anders
Published: December 2011

Background/Aims: To study how vascular disease and Alzheimer-typical biomarkers relate to cognitive performance in mild cognitive impairment (MCI). Methods: Three groups diagnosed with MCI, one with vascular disease (MCI-vas, n = 61), one with Alzheimer-typical biomarkers (MCI-bio, n = 99) and one with both vascular disease and Alzheimer-typical biomarkers (MCI-vasbio, n = 56), were examined with a comprehensive neuropsychological test battery. Results: The MCI-vas and MCI-bio groups performed quite similarly on the test battery, whereas the MCI-vasbio group tended to perform worse than the other groups. MCI-vasbio patients performed significantly worse on tests within all cognitive domains, with the most clear-cut differences on an executive test. Conclusions: Considering the small differences between MCI-vas and MCI-bio, vascular disease or biomarkers alone do not seem to be associated with a specific cognitive profile. The combination of vascular disease and Alzheimer-typical biomarkers, on the other hand, seems to be associated with more severe cognitive deficits. The difference in an aspect of executive functioning is interpreted as a synergetic effect.
Effects of Pinitol on Glycemic Control, Insulin Resistance and Adipocytokine Levels in Patients with Type 2 Diabetes Mellitus
Authors: Kim Hyun Jin , Park Kang Seo , Lee Seong Kyu , Min Kyung Wan , Han Kyung Ah , Kim Young Kun , Ku Bon Jeong
Published: December 2011

Background: Pinitol is thought to mediate insulin action and improve insulin resistance. We evaluated the effects of pinitol on glycemic control, insulin resistance and adipocytokine levels in type 2 diabetic patients. Material and Method: A total of 66 patients with type 2 diabetes who had been taking oral hypoglycemic agents for at least 3 months were enrolled and randomized to receive pinitol (n = 33) or matching placebo (n = 33). All subjects took 1,200 mg pinitol or placebo and maintained their current oral hypoglycemic agents throughout the study. Results: Mean HbA1c, fasting plasma glucose, and HOMA-IR were significantly lowered more in patients taking pinitol than in those given a placebo. Patients who had an HbA1c over 8.0% showed a greater reduction (p < 0.01) than those who had an HbA1c below 8.0% (p =0.16). In addition, in the group of patients with a HOMA-IR over 2.5, there was a significant decrease in HbA1c compared to that in the group of patients with a HOMA-IR below 2.5. There were no differences in the changes in adiponectin, FFA and CRP between the two groups. Conclusions: Pinitol can mediate insulin action to improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus, especially in patients with insulin resistance.
Low-Dose Treatment with Erythropoiesis-Stimulating Agents and Cardiovascular Geometry in Chronic Kidney Disease: Is Darbepoetin-α More Effective than Expected?
Authors: Di Lullo Luca , Floccari Fulvio , Granata Antonio , Malaguti Moreno
Published: December 2011

Introduction: Chronic kidney disease (CKD) is a widespread invalidating condition, leading to erythropoietin deficiency and decreased cardiovascular performance. Darbepoetin-α and epoetin-α are extensively used to correct renal anemia. The aim of this study was to evaluate cardiological outcomes in two groups of CKD patients treated with erythropoiesis-stimulating agents (ESA: 20 µg darbepoetin-α weekly vs. 2,000 IU epoetin-α thrice weekly) with an unconventional 1:300 conversion ratio. Methods: The study was designed as a single center, retrospective, observational study. One hundred stage IV CKD patients were selected. Hemoglobin (Hb), hematocrit, C-reactive protein, pro-brain natriuretic peptide (BNP) and basal echocardiograms were monitored every 3 months. Results: Darbepoetin-α was significantly more effective in increasing Hb levels after 3 (p < 0.0001), 6 (p < 0.0001), 9 (p < 0.01) and 12 months (p < 0.01) compared to epoetin-α. The optimal Hb target level (11 g/dl < Hb < 12 g/dl) was completely reached after 1 year of treatment with darbepoetin-α and in 70% of the patients treated with epoetin-α (p < 0.01). Cardiovascular performance (left ventricular end-diastolic volume, ejection fraction and pro-BNP) was significantly improved after darbepoetin-α treatment at the 6- and 12-month follow-ups compared to epoetin-α. Discussion: Despite the limitations of a retrospective observational study, these results encourage nephrologists to test the 1:300 darbepoetin/epoetin conversion ratio in ‘easy’ patients, and aggressive protocols for the treatment of anemia in CKD patients are avoided. Darbepoetin-α appeared effective in anemia correction, improving cardiovascular performance in a significantly higher proportion than epoetin. At low doses, on the other hand, it has to be borne in mind that a treatment regimen with only one submaximal administration per week may increase patient compliance and adherence to therapy, explaining in part the observed results.
The Role of Fibroblasts in Complex Fractionated Electrograms During Persistent/Permanent Atrial Fibrillation
Authors: Ashihara Takashi , Haraguchi Ryo , Nakazawa Kazuo , Namba Tsunetoyo , Ikeda Takanori , Nakazawa Yuko , Ozawa Tomoya , Ito Makoto , Horie Minoru , Trayanova Natalia A.
Published: December 2011

Rationale:

Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear.

Objective:

Because atrial fibrosis is associated with persistent/permanent AF, we hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation.

Methods and Results:

We used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone.

Conclusions:

Fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/permanent AF. Our findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.
Effect of Suture Properties on Stability of Middle Cerebral Artery Occlusion Evaluated by Synchrotron Radiation Angiography
Authors: Guan Yongjing , Wang Yongting , Yuan Falei , Lu Haiyan , Ren Yuqi , Xiao Tiqiao , Chen Kemin , Greenberg David A. , Jin Kunlin , Yang Guo-Yuan
Published: December 2011

Background and Purpose—

The intraluminal suture technique for producing middle cerebral artery occlusion in rodents is the most commonly used method for modeling focal cerebral ischemia associated with clinical ischemic stroke. Synchrotron radiation angiography may provide a novel solution to directly monitor the success of middle cerebral artery occlusion.

Methods—

Twenty adult Sprague-Dawley rats for middle cerebral artery occlusion models were prepared randomly with different suture head silicone coating. In vivo imaging was performed at beam line BL13W1, Shanghai Synchrotron Radiation Facility, Shanghai, China.

Results—

Silicone-coated suture was superior to uncoated suture for producing consistent brain infarction. Additionally, silicone coating length was an important variable controlling the extent of the ischemic lesion: infarcts affected predominantly the caudate–putamen with large variability (<2 mm), both the cortex and caudate–putamen (2–3.3 mm), and most of the hemisphere, including the hypothalamus (>3.3 mm).

Conclusions—

Synchrotron radiation angiography provides a useful tool to observe hemodynamic changes after middle cerebral artery occlusion, and the physical properties of suture are critical to the success of the middle cerebral artery occlusion model.
Sequential State and Observation Noise Covariance Estimation Using Combined Ensemble Kalman and Particle Filters
Authors: Frei Marco , Künsch Hans R.
Published: December 2011

The authors consider the joint state and parameter estimation problem for dynamical models where the system evolution is known and where the observations are linear with additive Gaussian noise whose covariance matrix depends on unknown parameters. The form of this dependence is general, both diagonal and off-diagonal elements of the covariance matrix may depend on the unknown parameters. In this situation, the ensemble Kalman filter (EnKF) cannot be applied directly to update state and parameters simultaneously. Two novel approximate Monte Carlo methods are proposed for this purpose, which are both based on the assumption that parameters and state are approximately independent after the propagation step. The first method begins with a particle filter update of the parameters followed by an EnKF update of the state. The second method first makes an EnKF update of the state based on an approximate likelihood that does not depend on the parameters, followed by a particle filter update of the parameters with weights proportional to the ratio of the correct to the approximate likelihood. To counteract sample depletion, the authors introduce algorithmic refinements like balanced sampling, kernel resampling, and increasing the number of samples for the parameters while keeping the size of the state ensemble fixed. The performance and flexibility of these methods is demonstrated in simulations with a linear Gaussian model and with the Lorenz-96 model. Provided the EnKF with all parameters known is reasonably well calibrated, then this is also true for the state estimates in the new algorithms, and the estimated posterior distributions of the parameters are consistent with the truth.
Tornado Climatology of Finland
Authors: Rauhala Jenni , Brooks Harold E. , Schultz David M.
Published: December 2011

A tornado climatology for Finland is constructed from 1796 to 2007. The climatology consists of two datasets. A historical dataset (1796–1996) is largely constructed from newspaper archives and other historical archives and datasets, and a recent dataset (1997–2007) is largely constructed from eyewitness accounts sent to the Finnish Meteorological Institute and news reports. This article describes the process of collecting and evaluating possible tornado reports. Altogether, 298 Finnish tornado cases compose the climatology: 129 from the historical dataset and 169 from the recent dataset. An annual average of 14 tornado cases occur in Finland (1997–2007). A case with a significant tornado (F2 or stronger) occurs in our database on average every other year, composing 14% of all tornado cases. All documented tornadoes in Finland have occurred between April and November. As in the neighboring countries in northern Europe, July and August are the months with the maximum frequency of tornado cases, coincident with the highest lightning occurrence both over land and sea. Waterspouts tend to be favored later in the summer, peaking in August. The peak month for significant tornadoes is August. The diurnal peak for tornado cases is 1700–1859 local time.
Money, Benefits, and Power
Authors: Smith Ryan A.
Published: December 2011

This article explores the manner in which race, ethnicity, and gender intersect to produce inequality in wages and employer benefits among “workers” (employees with no job authority), “supervisors” (employees with broad supervisory responsibilities), and “managers” (employees who can hire/fire and set the pay of others). Using data uniquely suited to examine these relationships, the author finds that, contrary to the glass ceiling hypothesis, the white male advantage over women and minorities in wages and retirement benefits generally does not increase with movement up the authority hierarchy net of controls. Instead, relative inequality remains constant at higher and lower levels of authority. However, in nontraditional work settings where white men report to minority and female supervisors, there is evidence that a glass ceiling stifles women and minorities while a glass escalator helps white men. Instead of representing mutually exclusive processes and outcomes, glass ceilings and glass escalators may actually overlap in certain employment contexts. The implications of these results for future analyses of workplace inequality are discussed.
Interactive Diffusion
Authors: della Porta Donatella , Tarrow Sidney
Published: December 2011

In this article, the authors focus attention on a poorly understood aspect of contentious politics: the interaction between the transnational diffusion of new forms of protest behavior and police practices in response to them. Studies of diffusion are usually limited to the diffusion of one kind of innovation by one set of actors to another, as in the diffusion of technical innovations from innovators to adopters. But collective action diffusion also produces a parallel and interactive sequence of “public order” reactions. Using the transnational countersummits that emerged around the turn of the century as their source of evidence, the authors focus on the coevolution of protester and police innovations across national boundaries. The authors’ major finding is that the mechanisms that cause protester and police innovations to diffuse are remarkably similar, even though they can combine in different ways at different moments: promotion, the proactive intervention by a sender actor aimed at deliberate diffusion of an innovation; assessment, the analysis of information on past events and their definition as successes or failures, which leads to adaption of the innovation to new sites and situations; and theorization, the location of technical innovations within broader normative and cognitive frameworks. The authors close with a speculative application of their findings to the recent diffusion of protester tactics and regime responses in the Middle East and North Africa.
Pregnancy Outcome Following Exposure to Topical Retinoids: A Multicenter Prospective Study
Authors: Panchaud Alice , Csajka Chantal , Merlob Paul , Schaefer Christof , Berlin Maya , De Santis Marco , Vial Thierry , Ieri Alessandra , Malm Heli , Eleftheriou Georgios , Stahl Bracha , Rousso Philippe , Winterfeld Ursula , Rothuizen Laura E. , Buclin Thierry
Published: December 2011

Concerns have been raised about the use of topical retinoids since the publication of isolated cases of characteristic retinoid embryopathy, originally described after oral use. A collaborative study of the European Network of Teratology Information Services was carried out to evaluate the rate of congenital malformations following first‐trimester topical retinoid exposure. A population of 235 exposed pregnant women was compared with 444 controls. No significant differences were observed between groups with regard to the rates of spontaneous abortion (odds ratio [95% confidence interval], 1.5 [0.8–2.7]), minor birth defects (1.3 [0.4–3.7]), and major birth defects (1.8 [0.6–5.4]). No child showed features of retinoid embryopathy. The rate of elective termination in the exposed group was increased 3‐fold (3.4 [1.5–7.8]). In conclusion, these results do not suggest an increased risk of retinoid embryopathy. However, according to current knowledge, topical retinoids cannot be advised for use during pregnancy because their risk/benefit ratio remains questionable.
Analytical solution for thermal stresses in a hollow cylinder under periodic thermal loading
Authors: Mahmoudi Hamid , Atefi Gholamali
Published: December 2011

The aim of this article is to obtain a comprehensive analytical solution for thermal stresses in a hollow cylinder, subjected to periodic time-varying thermal loading on the inner circular and insulated outer circular surfaces, where both lateral surfaces are kept at constant temperature. Temperature distribution as a function of time, and radial, and longitudinal directions is analytically solved using Fourier series and the resulting thermal stresses are obtained. The proposed method is very comprehensive and covers many theoretical and practical problems. The results for both temperature field and thermal stresses have been compared with those obtained in the former works and show excellent agreement for the same conditions.
Lake-level changes and fire history at Lagunillo del Tejo (Spain) during the last millennium: Climate or humans?
Authors: López-Blanco Charo , Gaillard Marie-José , Miracle María Rosa , Vicente Eduardo
Published: December 2011

Hydroclimatic variability is expected to be affected by global warming in the Mediterranean region where climate, fire and human activities are known to be interdependent. The latter is examined here for the past millennium by studying paleoenvironmental indicators from a sedimentary sequence at Lagunillo del Tejo (Cuenca, central Spain). Inferred changes in fire activity and lake levels are based on records of macrocharcoals and plant/algal macrofossils, respectively, and are compared with independent information on climate change and socio-economical transformations from historical and meteorological records. The results show that there is an obvious climatic forcing behind the lake-level changes recorded at Lagunillo del Tejo, and a good correlation between the periods of high fire activity/frequent fires and low lake level/drought conditions. The reconstructed fire regime may therefore be natural (climate-induced), but can also be explained by important socio-economical events/changes, including wars and the introduction of the Transhumance practices (ad 1273). There is a good chronological agreement between lowest fire activity and high lake levels ( c. ad 1600–1800), concurrent with the late ‘Little Ice Age’ (LIA) and the collapse of the Transhumance system. We propose that periods of drought favored both natural and human-induced fires during the ‘Medieval Climatic Anomaly’ (around ad 1200), at the start of the LIA (around ad 1400), in the middle of the LIA (sixteenth century) and during the entire nineteenth century. This record is an example of long-term interplay between climate changes and human activities and its impact on environmental changes such as fire regimes.
Computational and experimental characterization of a low-cost piezoelectric valveless diaphragm pump
Authors: Choi Andres , Vatanabe Sandro L. , de Lima Cícero R. , Silva Emílio C. N.
Published: December 2011

Flow pumps act as important devices in areas such as Bioengineering, Medicine, and Pharmacy, among other areas of Engineering, mainly for delivering liquids or gases at small-scale and precision flow rate quantities. Principles for pumping fluids based on piezoelectric actuators have been widely studied, since they allow the construction of pump systems for displacement of small fluid volumes with low power consumption. This work studies valveless piezoelectric diaphragm pumps for flow generation, which uses a piezoelectric ceramic (PZT) as actuator to move a membrane (diaphragm) up and down as a piston. The direction of the flow is guaranteed by valveless configuration based on a nozzle–diffuser system that privileges the flow in just one pumping direction. Most research efforts on development of valveless flow pump deal either with computational simulations based on simplified models or with simplified physical approaches based on analytical models. The main objective of this work is the study of a methodology to develop a low-cost valveless piezoelectric diaphragm flow pump using computational simulations, parametric study, prototype manufacturing, and experimental characterization. The parametric study has shown that the eccentricity of PZT layer and metal layer plays a key role in the performance of the pump.
The Identification and Assessment of Late-Life ADHD in Memory Clinics
Authors: Fischer Barbara L. , Gunter-Hunt Gail , Steinhafel Courtney Holm , Howell Timothy
Published: December 2011

Objective: Little data exist about ADHD in late life. While evaluating patients’ memory problems, the memory clinic staff has periodically identified ADHD in previously undiagnosed older adults. The authors conducted a survey to assess the extent to which other memory clinics view ADHD as a relevant clinical issue. Method: The authors developed and sent a questionnaire to memory clinics in the United States to determine the extent to which they identified patients with ADHD and the extent to which they took it into consideration. Results: Approximately one half of the memory clinics that responded reported seeing ADHD patients, either identifying previously diagnosed cases and/or newly diagnosing ADHD themselves. One fifth of clinics reported screening regularly for ADHD, and few clinics described accessing collateral informants to establish the diagnosis. Conclusion: This article suggests that U.S. memory clinics may not adequately identify and address ADHD in the context of late-life cognitive disorders.
GPIbα regulates platelet size by controlling the subcellular localization of filamin
Authors: Kanaji Taisuke , Ware Jerry , Okamura Takashi , Newman Peter J.
Published: December 2011

Interaction between the cytoplasmic domain of GPIbα with its cytoskeletal binding partner, filamin, is a major determinant of platelet size, and deficiency of either protein results in macrothrombocytopenia. To clarify the mechanism by which GPIbα-filamin interactions regulate platelet production, we manipulated the expression levels of filamin and GPIb in cultured embryonic stem cells (ESCs) that were subsequently differentiated into platelets. Knocking down filamins A and B resulted in the production of ESC-derived proplatelets with abnormally large swellings and proplatelet shafts that generated giant platelets in culture. Large platelets could also be generated by overexpressing GPIbα in ESCs, or by overexpressing in vivo a transgene encoding a chimeric protein containing the cytoplasmic domain of GPIbα. To identify the mechanism by which the GPIb:filamin ratio regulates platelet size, we manipulated filamin and GPIbα levels in HEK293T cells and examined the effects of overexpressing either protein on their ability to traffic to the cell periphery. Accumulation of either protein within the endoplasmic reticulum resulted in trapping of the other. Taken together, these data demonstrate that coordinated expression of GPIbα and filamin is required for efficient trafficking of either protein to the cell surface, and for production of normal-sized platelets.
HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis
Authors: Schuldenfrei Andrew , Belton Amy , Kowalski Jeanne , Talbot C Conover , Di Cello Francescopaolo , Poh Weijie , Tsai Hua-Ling , Shah Sandeep N , Huso Tait H , Huso David L , Resar Linda MS
Published: December 2011

Background

Although thehigh mobility group A1(HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive.HMGA1functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription,HMGA1is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells fromHMGA1atransgenic mice at different stages in tumorigenesis.

Results

RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.

Conclusions

We found thatHMGA1induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors.HMGA1also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight intoHMGA1function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrantHMGA1expression.
Genetic architecture of gene expression in ovine skeletal muscle
Authors: Kogelman Lisette JA , Byrne Keren , Vuocolo Tony , Watson-Haigh Nathan S , Kadarmideen Haja N , Kijas James W , Oddy Hutton V , Gardner Graham E , Gondro Cedric , Tellam Ross L
Published: December 2011

Background

In livestock populations the genetic contribution to muscling is intensively monitored in the progeny of industry sires and used as a tool in selective breeding programs. The genes and pathways conferring this genetic merit are largely undefined. Genetic variation within a population has potential, amongst other mechanisms, to alter gene expression via cis- or trans-acting mechanisms in a manner that impacts the functional activities of specific pathways that contribute to muscling traits. By integrating sire-based genetic merit information for a muscling trait with progeny-based gene expression data we directly tested the hypothesis that there is genetic structure in the gene expression program in ovine skeletal muscle.

Results

The genetic performance of six sires for a well defined muscling trait, longissimus lumborum muscle depth, was measured using extensive progeny testing and expressed as an Estimated Breeding Value by comparison with contemporary sires. Microarray gene expression data were obtained for longissimus lumborum samples taken from forty progeny of the six sires (4-8 progeny/sire). Initial unsupervised hierarchical clustering analysis revealed strong genetic architecture to the gene expression data, which also discriminated the sire-based Estimated Breeding Value for the trait. An integrated systems biology approach was then used to identify the major functional pathways contributing to the genetics of enhanced muscling by using both Estimated Breeding Value weighted gene co-expression network analysis and a differential gene co-expression network analysis. The modules of genes revealed by these analyses were enriched for a number of functional terms summarised as muscle sarcomere organisation and development, protein catabolism (proteosome), RNA processing, mitochondrial function and transcriptional regulation.

Conclusions

This study has revealed strong genetic structure in the gene expression program within ovine longissimus lumborum muscle. The balance between muscle protein synthesis, at the levels of both transcription and translation control, and protein catabolism mediated by regulated proteolysis is likely to be the primary determinant of the genetic merit for the muscling trait in this sheep population. There is also evidence that high genetic merit for muscling is associated with a fibre type shift toward fast glycolytic fibres. This study provides insight into mechanisms, presumably subject to strong artificial selection, that underpin enhanced muscling in sheep populations.
Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays?
Authors: Aziz Muhammad Hammad , Schneider Frank , Clausen Sven , Blank Elena , Herskind Carsten , Afzal Muhammad , Wenz Frederik
Published: December 2011

Background

Radiation induced secondary cancers are a rare but severe late effect after breast conserving therapy. Intraoperative radiotherapy (IORT) is increasingly used during breast conserving surgery. The purpose of this analysis was to estimate secondary cancer risks after IORT compared to other modalities of breast radiotherapy (APBI - accelerated partial breast irradiation, EBRT - external beam radiotherapy).

Methods

Computer-tomography scans of an anthropomorphic phantom were acquired with an INTRABEAM IORT applicator (diameter 4 cm) in the outer quadrant of the breast and transferred via DICOM to the treatment planning system. Ipsilateral breast, contralateral breast, ipsilateral lung, contralateral lung, spine and heart were contoured. An INTRABEAM source (50 kV) was defined with the tip of the drift tube at the center of the spherical applicator. A dose of 20 Gy at 0 mm depth from the applicator surface was prescribed for IORT and 34 Gy (5 days × 2 × 3.4 Gy) at 10 mm depth for APBI. For EBRT a total dose of 50 Gy in 2 Gy fractions was planned using two tangential fields with wedges. The mean and maximal doses, DVHs and volumes receiving more than 0.1 Gy and 4 Gy of organs at risk (OAR) were calculated and compared. The life time risk for secondary cancers was estimated according to NCRP report 116.

Results

IORT delivered the lowest maximal doses to contralateral breast (< 0.3 Gy), ipsilateral (1.8 Gy) and contralateral lung (< 0.3 Gy), heart (1 Gy) and spine (< 0.3 Gy). In comparison, maximal doses for APBI were 2-5 times higher. EBRT delivered a maximal dose of 10.4 Gy to the contralateral breast and 53 Gy to the ipsilateral lung. OAR volumes receiving more than 4 Gy were 0% for IORT, < 2% for APBI and up to 10% for EBRT (ipsilateral lung). The estimated risk for secondary cancer in the respective OAR is considerably lower after IORT and/or APBI as compared to EBRT.

Conclusions

The calculations for maximal doses and volumes of OAR suggest that the risk of secondary cancer induction after IORT is lower than compared to APBI and EBRT.
Regulatory coordination of clustered microRNAs based on microRNA-transcription factor regulatory network
Authors: Wang Jin , Haubrock Martin , Cao Kun-Ming , Hua Xu , Zhang Chen-Yu , Wingender Edgar , Li Jie
Published: December 2011

Background

MicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.

Results

We constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.

Conclusion

The genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.
Some Inequalities of Linear Combinations of Independent Random Variables. I.
Authors: Xu Maochao , Hu Taizhong
Published: December 2011

In this paper we provide some sufficient conditions to stochastically compare linear combinations of independent random variables. The main results extend those given in Proschan (1965), Ma (1998), Zhao et al. (2011), and Yu (2011). In particular, we propose a new sufficient condition to compare the peakedness of linear combinations of independent random variables which may have heavy-tailed properties.
Epidemiology and outcome of cardiac arrests reported in the lay-press: an observational study
Authors: Field Richard A , Soar Jasmeet , Nolan Jerry P , Perkins Gavin D
Published: December 2011

Objective

The aims of this study were to evaluate the frequency with which cardiac arrests are reported in newspapers, assess the level of detail reported and ascertain whether this coverage gives a realistic portrayal of cardiac arrest outcomes to the lay-reader.

Design

Observational study.

Setting

All UK newspaper articles published between 1 January 2010 and 30 June 2010.

Participants

Articles containing the words ‘cardiac arrest’, ‘CPR’ or ‘resuscitation’ were screen for eligibility. Any articles not involving reference to a real cardiac arrest were excluded.

Main outcome measures

Data relating to patient demographics, arrest characteristics, treatment (CPR and defibrillation) and survival using the Utstein template were extracted. The results were then compared with cardiac arrest statistics from epidemiological studies.

Results

Six hundred and forty-eight articles were reviewed, 203 of which referred to individual cardiac arrest events; 22 events occurred in-hospital and 181 occurred out-of-hospital. In the out-of-hospital cardiac arrest (OHCA) group 32 (17.7%) were reported to survive to hospital discharge, almost all with good neurological outcome. The median age group was 31–45-year-olds, 52 (28.7%) were women and 40 were children. Seventy-five percent of victims received bystander CPR with 13 being attended to by lay-responders using AEDs, eight of which presented with a shockable rhythm of which six made a full recovery.

Conclusion

Survival to hospital discharge rate among newspaper reports was double that of complete epidemiological studies of OHCAs in urban environments. Newspapers may give readers an over-optimistic portrayal of cardiac arrest survival and neurological outcome following successful resuscitation.
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue With Amyloid Deposition
Authors: Ryan Russell J.H. , Sloan J. Mark , Collins A. Bernard , Mansouri Jaleh , Raje Noopur S. , Zukerberg Lawrence R. , Ferry Judith A.
Published: December 2011

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a mature B-cell neoplasm that typically follows an indolent clinical course. Amyloid deposition associated with MALT lymphoma is uncommon. We describe the clinical and pathologic features of 20 cases of MALT lymphoma and associated amyloid deposition across diverse primary sites. Frozen section immunofluorescence performed on 4 cases suggests that these deposits are a localized form of AL amyloid.

Clinical follow-up was available for 15 patients. Amyloid deposits distant from the initial site occurred in 5 cases, always at sites also involved by the underlying lymphoma. No definitive evidence of systemic amyloidosis affecting the heart, kidneys, or liver was present in any patient. Given the generally indolent clinical behavior of MALT lymphomas with associated amyloid, we do not recommend extensive follow-up testing for systemic amyloidosis or more aggressive therapy than would be indicated for other MALT lymphomas of similar clinical stage.
Responsiveness to Global and Local Consumer Culture Positioning: A Personality and Collective Identity Perspective
Authors: Westjohn Stanford A. , Singh Nitish , Magnusson Peter
Published: December 2011

Marketers have increasingly employed positioning strategies to appeal to either global or local consumer cultures. However, little is known about the characteristics of consumers most likely to respond to such positioning. The authors find that the collective identities of global and national identification are strongly related to responsiveness to global and local consumer culture positioning (GCCP and LCCP, respectively). The results also show that personality predisposes people to adopt collective identities. The personality traits of openness to experience and agreeableness are significantly related to global and national identity, respectively. On the basis of these findings, the authors present implications with regard to developing GCCP and LCCP strategies that are congruent with consumers’ personality and associated collective identity.
Efficient Mapping and Cloning of Mutations in Zebrafish by Low-Coverage Whole-Genome Sequencing
Authors: Bowen Margot E , Henke Katrin , Siegfried Kellee R , Warman Matthew L , Harris Matthew P
Published: December 2011

The generation and analysis of mutants in zebrafish has been instrumental in defining the genetic regulation of vertebrate development, physiology, and disease. However, identifying the genetic changes that underlie mutant phenotypes remains a significant bottleneck in the analysis of mutants. Whole-genome sequencing has recently emerged as a fast and efficient approach for identifying mutations in nonvertebrate model organisms. However, this approach has not been applied to zebrafish due to the complicating factors of having a large genome and lack of fully inbred lines. Here we provide a method for efficiently mapping and detecting mutations in zebrafish using these new parallel sequencing technologies. This method utilizes an extensive reference SNP database to define regions of homozygosity-by-descent by low coverage, whole-genome sequencing of pooled DNA from only a limited number of mutant F2 fish. With this approach we mapped each of the five different zebrafish mutants we sequenced and identified likely causative nonsense mutations in two and candidate mutations in the remainder. Furthermore, we provide evidence that one of the identified mutations, a nonsense mutation in bmp1a, underlies the welded mutant phenotype.
‘Chickens, Crops, and Tractors’
Authors: Shearer Tobin Miller
Published: December 2011

This essay argues that machines filled a sacred purpose in the middle of the twentieth century that has gone unrecognized by scholars of religion. The Mennonites who hosted African-American children from urban environments for one- to two-week stays in the country used tractors to promote their religious Fresh Air programs. From 1950 through 1979, tractors also figured prominently in the children’s testimonies about their rural sojourns. Fresh Air hosts, promoters, and participants thus used a diesel-powered machine for religious ends and, in so doing, featured an industrialized product as a symbol of a natural retreat. Mennonite Fresh Air programs also reveal similarities between the city and country that religious and secular narratives of the period have obscured. Scholarship in the tradition of Leo Marx will be enriched by shifting attention from the chronology of machine-based industrialization to the uses of machines in natural settings for religious purposes.
Grizzly Man and the Spiritual Life
Authors: Curry Patrick
Published: December 2011

The story of Timothy Treadwell, as portrayed in Werner Herzog’s film (2005), provides a basis for a critique of two opposing attitudes and programmes which can be identified, in broad metaphysical terms, as spiritual idealism and scientific materialism. I criticize the former, inferring from Treadwell’s fate the danger – for spiritual seekers, directly, and for scholars, indirectly – of trying to be at-one or achieve absolute unity with the beloved. I then recommend a radical but viable middle way, grounded in our embodied, imperfect, unstable, liminal nature – a view clearly evident in aboriginal and folk wisdom traditions but also articulated by philosophers including Merleau-Ponty, Plumwood, Abram, Snyder and Bateson.
Avatar as Rorschach
Authors: Taylor Bron
Published: December 2011

NA