bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased fetal insulin concentrations for one week fail to improve insulin secretion or β-cell mass in fetal sheep with chronically reduced glucose supply
Authors: Lavezzi Jinny R. , Thorn Stephanie R. , O'Meara Meghan C. , LoTurco Dan , Brown Laura D. , Hay William W. , Rozance Paul J.
Published: November 2012

Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic β-cells. Prolonged reduced glucose supply to the fetus is a feature of both. It is unknown if reduced glucose supply, independent of other complications of maternal undernutrition and placental insufficiency, would cause similar β-cell defects. Therefore, we measured fetal insulin secretion and β-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any β-cell defects. Pregnant sheep received either a direct saline infusion (CON = control, n = 5) or an insulin infusion (HG = hypoglycemic, n = 5) for 8 wk in late gestation (75 to 134 days) to decrease maternal glucose concentrations and reduce fetal glucose supply. A separate group of HG fetuses also received a direct fetal insulin infusion for the final week of the study with a dextrose infusion to prevent a further fall in glucose concentration [hypoglycemic + insulin (HG+I), n = 4]. Maximum glucose-stimulated insulin concentrations were 45% lower in HG fetuses compared with CON fetuses. β-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively ( P < 0.05). Insulin secretion and β-cell mass did not improve in the HG+I fetuses. These results indicate that chronically reduced fetal glucose supply is sufficient to reduce pancreatic insulin secretion in response to glucose, primarily due to reduced pancreatic and β-cell mass, and is not correctable with insulin.
Increased renal sympathetic nerve activity leads to hypertension and renal dysfunction in offspring from diabetic mothers
Authors: de Almeida Chaves Rodrigues Aline Fernanda , de Lima Ingrid Lauren Brites , Bergamaschi Cássia Toledo , Campos Ruy Ribeiro , Hirata Aparecida Emiko , Schoorlemmer Guus Hermanus Maria , Gomes Guiomar Nascimento
Published: November 2012

The exposure of the fetus to a hyperglycemic environment promotes the development of hypertension and renal dysfunction in the offspring at adult age. We evaluated the role of renal nerves in the hypertension and renal changes seen in offspring of diabetic rats. Diabetes was induced in female Wistar rats (streptozotocin, 60 mg/kg ip) before mating. Male offspring from control and diabetic dams were studied at an age of 3 mo. Systolic blood pressure measured by tail cuff was increased in offspring of diabetic dams (146 ± 1.6 mmHg, n = 19, compared with 117 ± 1.4 mmHg, n = 18, in controls). Renal function, baseline renal sympathetic nerve activity (rSNA), and arterial baroreceptor control of rSNA were analyzed in anesthetized animals. Glomerular filtration rate, fractional sodium excretion, and urine flow were significantly reduced in offspring of diabetic dams. Two weeks after renal denervation, blood pressure and renal function in offspring from diabetic dams were similar to control, suggesting that renal nerves contribute to sodium retention in offspring from diabetic dams. Moreover, basal rSNA was increased in offspring from diabetic dams, and baroreceptor control of rSNA was impaired, with blunted responses to infusion of nitroprusside and phenylephrine. Thus, data from this study indicate that in offspring from diabetic mothers, renal nerves have a clear role in the etiology of hypertension; however, other factors may also contribute to this condition.
Response of the mitochondrial proteome of rat renal proximal convoluted tubules to chronic metabolic acidosis
Authors: Freund Dana M. , Prenni Jessica E. , Curthoys Norman P.
Published: November 2012

Metabolic acidosis is a common clinical condition that is caused by a decrease in blood pH and bicarbonate concentration. Increased extraction and mitochondrial catabolism of plasma glutamine within the renal proximal convoluted tubule generates ammonium and bicarbonate ions that facilitate the excretion of acid and partially restore acid-base balance. Previous studies identified only a few mitochondrial proteins, including two key enzymes of glutamine metabolism, which are increased during chronic acidosis. A workflow was developed to characterize the mitochondrial proteome of the proximal convoluted tubule. Based upon the increase in specific activity of cytochrome c oxidase, the isolated mitochondria were enriched eightfold. Two-dimensional liquid chromatography coupled with mass spectrometry was utilized to compare mitochondrial-enriched samples from control and chronic acidotic rats. Proteomic analysis identified 901 proteins in the control and acidotic samples. Further analysis identified 37 peptides that contain an N-ε-acetyl-lysine; of these, 22 are novel sites. Spectral counting analysis revealed 33 proteins that are significantly altered in abundance in response to chronic metabolic acidosis. Western blot analysis was performed to validate the calculated changes in abundance. Thus the current study represents the first comprehensive analysis of the mitochondrial proteome of the rat renal proximal convoluted tubule and its response to metabolic acidosis.
Gain-of-function variant of the human epithelial sodium channel
Authors: Chen Jingxin , Kleyman Thomas R. , Sheng Shaohu
Published: November 2012

Epithelial Na+ channel (ENaC) mutations are associated with several human disorders, underscoring the importance of these channels in human health. Recent human genome sequencing projects have revealed a large number of ENaC gene variations, several of which have been found in individuals with salt-sensitive hypertension, cystic fibrosis, and other disorders. However, the functional consequences of most variants are unknown. In this study, we used the Xenopus oocyte expression system to examine the functional properties of a human ENaC variant. Oocytes expressing αβγL511Q human ENaCs showed 4.6-fold greater amiloride-sensitive currents than cells expressing wild-type channels. The γL511Q variant did not significantly alter channel surface expression. Single channel recordings revealed that the variant had fourfold higher open probability than wild type. In addition, γL511Q largely eliminated the Na+ self-inhibition response, which reflects a downregulation of ENaC open probability by extracellular Na+. Moreover, γL511Q diminished chymotrypsin-induced activation of the mutant channel. We conclude that γL511Q is a gain-of-function human ENaC variant. Our results suggest that γL511Q enhances ENaC activity by increasing channel open probability and dampens channel regulation by extracellular Na+ and proteases.
A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction
Authors: Caplan Stacee Lee , Milton Sarah L. , Dawson-Scully Ken
Published: November 2012

Increasing evidence demonstrates that modulating the cGMP-dependent protein kinase G (PKG) pathway produces an array of behavioral phenotypes in the fruit fly, Drosophila melanogaster. Altering PKG activity, either genetically via the foraging ( for) gene or using pharmacology modifies tolerance to acute abiotic stresses such as hyperthermia and hypoxia. PKG signaling has been shown to modulate neuroprotection in many experimental paradigms of acute brain trauma and chronic neurodegenerative diseases. However, relatively little is known about how this stress-induced neuroprotective mechanism affects neural communication. In this study, we investigated the role PKG activity has on synaptic transmission at the Drosophila larval neuromuscular junction (NMJ) during acute oxidative stress and found that the application of 2.25 mM hydrogen peroxide (H2O2) disrupts synaptic function by rapidly increasing the rate of neuronal failure. Here, we report that reducing PKG activity through either natural genetic variation or an induced mutation of the for gene increases synaptic tolerance during acute oxidative conditions. Furthermore, pharmacological manipulations revealed that neurotransmission is significantly extended during acute H2O2 exposure upon inhibition of the PKG pathway. Conversely, activation of this signaling cascade using either genetics or pharmacology significantly reduced the time until synaptic failure. Therefore, these findings suggest a potential role for PKG activity to regulate the tolerance of synaptic transmission during acute oxidative stress, where inhibition promotes functional protection while activation increases susceptibility to neurotransmission breakdown.
The dominant functional nicotinic receptor in progenitor cells in the rostral migratory stream is the α3β4 subtype
Authors: Sharma Geeta
Published: November 2012

Addition of newly generated neurons into mature neural circuits in the adult CNS responds to changes in neurotransmitter levels and is tightly coupled to the activity of specific brain regions. This postnatal neurogenesis contributes to plasticity of the olfactory bulb and hippocampus and is thought to play a role in learning and memory, context and odor discrimination, as well as perceptual learning. While acetylcholine plays an important role in odor discrimination and perceptual learning, its role in adult neurogenesis in the olfactory bulb has not been elucidated. In this study, I have examined the functional expression of nAChRs in progenitor cells of the rostral migratory stream (RMS) in the adult olfactory bulb of mice. I show that most of these cells in the RMS exhibit large nAChR-mediated calcium transients upon application of acetylcholine (ACh). Unlike in the hippocampus, the predominant functional nAChRs on progenitor cells are of α3β4 subtype. Interestingly, functional receptor expression is lost once progenitor cells mature, and are incorporated into the granule cell layer. Instead, nAChRs are now expressed on some presynaptic terminals and modulate glutamate release onto granule cells. My results imply that ACh is a part of the permissive niche and likely plays a role in development of progenitor cells.
Consumption of High-Polyphenol Dark Chocolate Improves Endothelial Function in Individuals with Stage 1 Hypertension and Excess Body Weight
Authors: Nogueira Lívia de Paula , Knibel Marcela Paranhos , Torres Márcia Regina Simas Gonçalves , Nogueira Neto José Firmino , Sanjuliani Antonio Felipe
Published: November 2012

Background. Hypertension and excess body weight are important risk factors for endothelial dysfunction. Recent evidence suggests that high-polyphenol dark chocolate improves endothelial function and lowers blood pressure. This study aimed to evaluate the association of chocolate 70% cocoa intake with metabolic profile, oxidative stress, inflammation, blood pressure, and endothelial function in stage 1 hypertensives with excess body weight.Methods. Intervention clinical trial includes 22 stage 1 hypertensives without previous antihypertensive treatment, aged 18 to 60 years and presents a body mass index between 25.0 and 34.9 kg/m2. All participants were instructed to consume 50 g of chocolate 70% cocoa/day (2135 mg polyphenols) for 4 weeks. Endothelial function was evaluated by peripheral artery tonometry using Endo-PAT 2000 (Itamar Medical).Results. Twenty participants (10 men) completed the study. Comparison of pre-post intervention revealed that (1) there were no significant changes in anthropometric parameters, percentage body fat, glucose metabolism, lipid profile, biomarkers of inflammation, adhesion molecules, oxidized LDL, and blood pressure; (2) the assessment of endothelial function through the reactive hyperemia index showed a significant increase: 1.94 ± 0.18 to 2.22 ± 0.08,P=0.01.Conclusion.In individuals with stage 1 hypertension and excess body weight, high-polyphenol dark chocolate improves endothelial function.
Sphingosine 1-Phosphate Distribution in Human Plasma: Associations with Lipid Profiles
Authors: Hammad Samar M. , Al Gadban Mohammed M. , Semler Andrea J. , Klein Richard L.
Published: November 2012

The physiological significance of sphingosine 1-phosphate (S1P) transport in blood has been debated. We have recently reported a comprehensive sphingolipid profile in human plasma and lipoprotein particles (VLDL, LDL, and HDL) using HPLC-MS/MS (Hammad et al., 2010). We now determined the relative concentrations of sphingolipids including S1P in the plasma subfraction containing lipoproteins compared to those in the remaining plasma proteins. Sphingomyelin and ceramide were predominantly recovered in the lipoprotein-containing fraction. Total plasma S1P concentration was positively correlated with S1P concentration in the protein-containing fraction, but not with S1P concentration in the lipoprotein-containing fraction. The percentage of S1P transported in plasma lipoproteins was positively correlated with HDL cholesterol (HDL-C) concentration; however, S1P transport in lipoproteins was not limited by the concentration of HDL-C in the individual subject. Thus, different plasma pools of S1P may have different contributions to S1P signaling in health and disease.
Multigrid Discretization and Iterative Algorithm for Mixed Variational Formulation of the Eigenvalue Problem of Electric Field
Authors: Yang Yidu , Zhang Yu , Bi Hai
Published: November 2012

This paper discusses highly finite element algorithms for the eigenvalue problem of electric field. Combining the mixed finite element method with the Rayleigh quotient iteration method, a new multi‐grid discretization scheme and an adaptive algorithm are proposed and applied to the eigenvalue problem of electric field. Theoretical analysis and numerical results show that the computational schemes established in the paper have high efficiency.
Deafferentation-Induced Plasticity of Visual Callosal Connections: Predicting Critical Periods and Analyzing Cortical Abnormalities Using Diffusion Tensor Imaging
Authors: Olavarria Jaime F. , Bock Andrew S. , Leigland Lindsey A. , Kroenke Christopher D.
Published: November 2012

Callosal connections form elaborate patterns that bear close association with striate and extrastriate visual areas. Although it is known that retinal input is required for normal callosal development, there is little information regarding the period during which the retina is critically needed and whether this period correlates with the same developmental stage across species. Here we review the timing of this critical period, identified in rodents and ferrets by the effects that timed enucleations have on mature callosal connections, and compare it to other developmental milestones in these species. Subsequently, we compare these events to diffusion tensor imaging (DTI) measurements of water diffusion anisotropy within developing cerebral cortex. We observed that the relationship between the timing of the critical period and the DTI-characterized developmental trajectory is strikingly similar in rodents and ferrets, which opens the possibility of using cortical DTI trajectories for predicting the critical period in species, such as humans, in which this period likely occurs prenatally. Last, we discuss the potential of utilizing DTI to distinguish normal from abnormal cerebral cortical development, both within the context of aberrant connectivity induced by early retinal deafferentation, and more generally as a potential tool for detecting abnormalities associated with neurodevelopmental disorders.
Occurrence and Impact of Minor Histocompatibility Antigens' Disparities on Outcomes of Hematopoietic Stem Cell Transplantation from HLA-Matched Sibling Donors
Authors: Dzierzak-Mietla Monika , Markiewicz M. , Siekiera Urszula , Mizia Sylwia , Koclega Anna , Zielinska Patrycja , Sobczyk-Kruszelnicka Malgorzata , Kyrcz-Krzemien Slawomira
Published: November 2012

We have examined the alleles of eleven minor histocompatibility antigens (MiHAs) and investigated the occurrence of immunogenic MiHA disparities in 62 recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning performed between 2000 and 2008 and in their HLA-matched sibling donors. Immunogenic MiHA mismatches were detected in 42 donor-recipient pairs: in 29% MiHA was mismatched in HVG direction, in another 29% in GVH direction; bidirectional MiHA disparity was detected in 10% and no MiHA mismatches in 32%. Patients with GVH-directed HY mismatches had lower both overall survival and disease-free survival at 3 years than patients with compatible HY; also higher incidence of both severe acute GvHD and extensive chronic GVHD was observed in patients with GVH-directed HY mismatch. On contrary, GVH-directed mismatches of autosomally encoded MiHAs had no negative effect on overall survival. Results of our study help to understand why posttransplant courses of allo-HCT from siblings may vary despite the complete high-resolution HLA matching of a donor and a recipient.
Preparation of Bioactive Titanium Surfaces via Fluoride and Fibronectin Retention
Authors: Elias Carlos Nelson , Gravina Patricia Abdo , Silva Filho Costa e , Nascente Pedro Augusto de Paula
Published: November 2012

Statement of Problem. The chemical or topographic modification of the dental implant surface can affect bone healing, promote accelerated osteogenesis, and increase bone-implant contact and bonding strength.Objective. In this work, the effects of dental implant surface treatment and fibronectin adsorption on the adhesion of osteoblasts were analyzed.Materials and Methods. Two titanium dental implants (Porous-acid etching and PorousNano-acid etching followed by fluoride ion modification) were characterized by high-resolution scanning electron microscopy, atomic force microscopy, and X-ray diffraction before and after the incorporation of human plasma fibronectin (FN). The objective was to investigate the biofunctionalization of these surfaces and examine their effects on the interaction with osteoblastic cells.Results. The evaluation techniques used showed that the Porous and PorousNano implants have similar microstructural characteristics. Spectrophotometry demonstrated similar levels of fibronectin adsorption on both surfaces (80%). The association indexes of osteoblastic cells in FN-treated samples were significantly higher than those in samples without FN. The radioactivity values associated with the same samples, expressed as counts per minute (cpm), suggested that FN incorporation is an important determinant of thein vitrocytocompatibility of the surfaces.Conclusion. The preparation of bioactive titanium surfaces via fluoride and FN retention proved to be a useful treatment to optimize and to accelerate the osseointegration process for dental implants.
Modeling of Optical Nanoantennas
Authors: Yousif Bedir B. , Samra Ahmed S.
Published: November 2012

The optical properties of plasmonic nanoantennas are investigated in detail using the finite integration technique (FIT). The validity of this technique is verified by comparison to the exact solution generalized Mie method (GMM). The influence of the geometrical parameters (antenna length, gap dimension, and shapes) on the antenna field enhancement and spectral response is discussed. Localized surface plasmon resonances of Au (gold) dimers nanospheres, bowtie, and aperture bowtie nanoantennas are modeled. The enhanced field is equivalent to a strong light spot which can lead to the resolution improvement of the microscopy and optical lithography, thus increasing the optical data storage capacity. Furthermore, the sensitivity of the antennas to index changes of the environment and substrate is investigated in detail for biosensing applications. We confirm that our approach yields an exact correspondence with GMM theory for Au dimers nanospheres at gap dimensions 5 nm and 10 nm but gives an approximation error of less than 1.37% for gap dimensions 1 nm and 2 nm with diameters approaching 80 nm. In addition, the far-field characteristics of the aperture bowtie nanoantenna such as directivity and gain are studied. The promising results of this study may have useful potential applications in near-field sample detection, optical microscopy, and so forth.
Forecast Accuracy and Uncertainty of Australian Bureau of Statistics State and Territory Population Projections
Authors: Wilson Tom
Published: November 2012

Errors from past rounds of population projections can provide both diagnostic information to improve future projections as well as information for users on the likely uncertainty of current projections. This paper assesses the forecast accuracy of official Australian Bureau of Statistics (ABS) population projections for the states and territories of Australia and is the first major study to do so. For the states and territories, it is found that, after 10-year projection durations, absolute percentage errors lie between about 1% and 3% for the states and around 6% for the territories. Age-specific population projections are also assessed. It is shown that net interstate migration and net overseas migration are the demographic components of change which contributed most to forecast error. The paper also compares ABS projections of total population against simple linear extrapolation, finding that, overall, ABS projections just outperformed extrapolation. No identifiable trend in accuracy over time is detected. Under the assumption of temporal stability in the magnitude of error, empirical prediction intervals are created from past errors and applied to the current set of ABS projections. The paper concludes with a few ideas for future projection rounds.
Motor Cortex Stimulation in Parkinson's Disease
Authors: De Rose Marisa , Guzzi Giusy , Bosco Domenico , Romano Mary , Lavano Serena Marianna , Plastino Massimiliano , Volpentesta Giorgio , Marotta Rosa , Lavano Angelo
Published: November 2012

Motor Cortex Stimulation (MCS) is less efficacious than Deep Brain Stimulation (DBS) in Parkinson's disease. However, it might be proposed to patients excluded from DBS or unresponsive to DBS. Ten patients with advanced PD underwent unilateral MCS contralaterally to the worst clinical side. A plate electrode was positioned over the motor cortex in the epidural space through single burr hole after identification of the area with neuronavigation and neurophysiological tests. Clinical assessment was performed by total UPDRS, UPDRS III total, UPDRS III-items 27–31, UPDRS IV, and UPDRS II before implantation in off-medication and on-medication states and after surgery at 1, 3, 6, 12, 18, 24, and 36 months in on-medication/on-stimulation and off-medication/on-stimulation states. We assessed changes of quality of life, throughout the Parkinson's disease quality of life scale (PDQoL-39), and the dose of anti-Parkinson's disease medications, throughout the Ldopa equivalent daily dose (LEDD). During off-medication state, we observed moderate and transitory reduction of total UPDRS and UPDRS total scores and significant and long-lasting improvement in UPDRS III items 27–31 score for axial symptoms. There was marked reduction of UPDRS IV score and LEDD. PDQL-39 improvement was also significant. No important complications and adverse events occurred.
Terminalia catappaExerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-κB and AP-1 Activity
Authors: Yeh Chao-Bin , Hsieh Ming-Ju , Hsieh Yih-Shou , Chien Ming-Hsien , Lin Pen-Yuan , Chiou Hui-Ling , Yang Shun-Fa
Published: November 2012

High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. Previous studies have identified thatTerminalia catappaleaf extracts (TCE) exert hepatoprotective, antioxidative, antiinflammatory, anticancer, and antimetastatic activities. However, the effects of TCE on HCC and the underlying molecular mechanisms of its activities have yet to be fully elucidated. The present study's findings demonstrate that TCE concentration dependently inhibits human HCC migration/invasion. Zymographic and western blot analyses revealed that TCE inhibited the activities and expression of matrix metalloproteinase-9 (MMP-9). Assessment of mRNA levels, using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR, and promoter assays confirmed the inhibitory effects of TCE on MMP-9 expression in HCC cells. The inhibitory effects of TCE on MMP-9 proceeded by upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as suppressing nuclear translocation and DNA binding activity of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) on the MMP-9 promoter in Huh7 cells. In conclusion, TCE inhibits MMP-9 expression and HCC cell metastasis and, thus, has potential use as a chemopreventive agent. Its inhibitory effects are associated with downregulation of the binding activities of the transcription factors NF-κB and AP-1.
Cost-Effectiveness of Antiretroviral Therapy for Multidrug-Resistant HIV: Past, Present, and Future
Authors: Harris Marianne , Nosyk Bohdan , Harrigan Richard , Lima Viviane Dias , Cohen Calvin , Montaner Julio
Published: November 2012

In the early years of the highly active antiretroviral therapy (HAART) era, HIV with resistance to two or more agents in different antiretroviral classes posed a significant clinical challenge. Multidrug-resistant (MDR) HIV was an important cause of treatment failure, morbidity, and mortality. Treatment options at the time were limited; multiple drug regimens with or without enfuvirtide were used with some success but proved to be difficult to sustain for reasons of tolerability, toxicity, and cost. Starting in 2006, data began to emerge supporting the use of new drugs from the original antiretroviral classes (tipranavir, darunavir, and etravirine) and drugs from new classes (raltegravir and maraviroc) for the treatment of MDR HIV. Their availability has enabled patients with MDR HIV to achieve full and durable viral suppression with more compact and cost-effective regimens including at least two and often three fully active agents. The emergence of drug-resistant HIV is expected to continue to become less frequent in the future, driven by improvements in the convenience, tolerability, efficacy, and durability of first-line HAART regimens. To continue this trend, the optimal rollout of HAART in both rich and resource-limited settings will require careful planning and strategic use of antiretroviral drugs and monitoring technologies.
Robust ℋ∞ Dynamic Output Feedback Control Synthesis with Pole Placement Constraints for Offshore Wind Turbine Systems
Authors: Bakka Tore , Karimi Hamid Reza
Published: November 2012

The problem of robust ℋ∞ dynamic output feedback control design with pole placement constraints is studied for a linear parameter‐varying model of a floating wind turbine. A nonlinear model is obtained and linearized using the FAST software developed for wind turbines. The main contributions of this paper are threefold. Firstly, a family of linear models are represented based on an affine parameter‐varying model structure for a wind turbine system. Secondly, the bounded parameter‐varying parameters are removed using upper bounded inequalities in the control design process. Thirdly, the control problem is formulated in terms of linear matrix inequalities (LMIs). The simulation results show a comparison between controller design based on a constant linear model and a controller design for the linear parameter‐varying model. The results show the effectiveness of our proposed design technique.
DNMT3AMutations in Patients with Acute Myeloid Leukemia in South Brazil
Authors: Pezzi Annelise , Moraes Lauro , Valim Vanessa , Amorin Bruna , Melchiades Gabriela , Oliveira Fernanda , da Silva Maria Aparecida , Matte Ursula , Pombo-de-Oliveira Maria S. , Bittencourt Rosane , Daudt Liane , Silla Lúcia
Published: November 2012

Acute myeloid leukemia (AML) is a complex and heterogeneous hematopoietic tissue neoplasm. Several molecular markers have been described that help to classify AML patients into risk groups. DNA methyltransferase 3A (DNMT3A) gene mutations have been recently identified in about 22% of AML patients and associated with poor prognosis as an independent risk factor. Our aims were to determine the frequency of somatic mutations in the geneDNMT3Aand major chromosomal translocations in a sample of patients with AML. We investigated in 82 samples of bone marrow from patients with AML for somatic mutations inDNMT3Agene by sequencing and sought major fusion transcripts by RT-PCR. We found mutations in theDNMT3Agene in 6 patients (8%); 3 were type R882H. We found fusion transcripts in 19 patients, namely, AML1/ETO (n=5; 6.1%), PML/RARα(n=12; 14.6%), MLL/AF9 (0; 0%), and CBFβ/MYH11 (n=2; 2.4%). The identification of recurrent mutations in theDNMT3Agene and their possible prognostic implications can be a valuable tool for making treatment decisions. This is the first study on the presence of somatic mutations of theDNMT3Agene in patients with AML in Brazil. The frequency of these mutations suggests a possible ethnogeographic variation.

Erratum to “DNMT3AMutations in Patients with Acute Myeloid Leukemia in South Brazil”
Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2
Authors: Romei C. , Pardi E. , Cetani F. , Elisei R.
Published: November 2012

Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. HeterozygousMEN 1germline mutations have been detected in about 70–80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of theRETprotooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specificRETmutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target theRETpathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.
From Fabrication to Characterization of 3D Organic Microresonators: A Complementary Alliance of Microfluidics and Optics
Authors: Pluchon David , Huby Nolwenn , Moréac Alain , Panizza Pascal , Bêche Bruno
Published: November 2012

This paper introduces a preview of targeted current research on organic optofluidic materials and devices devoted to 3D photonics microresonators (MRs). First, such an approach takes advantage from a significant know-how on optical simulations of 3D spherical MRs by complementary and coupled ways based on electromagnetism and quantum mechanics principle. Such simulations have allowed to preset the quantization of whispering gallery modes (WGMs) and to define a new formulation of optical caustics in global 3D MRs cavities. Leaning from these simulations, an interdisciplinary approach has been achieved by combining microfluidics techniques and thin layer processes that allowed with flow rates control the realization of 3D droplets MRs of several tens of micrometers in radii. Finally, free-space optical characterizations have been performed on such 3D polymeric MRs by judicious protocols based, respectively, on a modified Raman spectroscopy laser excitation and an adequate direct beam waist optical coupling. Spectral analysis on such 3D MRs of various sizes confirms the excitation of the expected WGMs revealing free spectral range (FSR) and caustics values close to the analytical ones.
Not Significant: What Now?
Authors: Marinell Gerhard , Steckel-Berger Gabriele , Ulmer Hanno
Published: November 2012

In a classic significance test, based on a random sample with size , a value will be calculated at size aiming to reject the null hypothesis. The sample size , however, can retrospectively be divided into partial samples and a test of significance can be calculated for each partial sample. As a result, several partial samples will provide significant values whereas others will not show significant values. In this paper, we propose a significance test that takes into account the additional information from the values of the partial samples of a random sample. We show that the    values can greatly modify the results of a classic significance test.
Effectiveness of Yoga for Menopausal Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Cramer Holger , Lauche Romy , Langhorst Jost , Dobos Gustav
Published: November 2012

Objectives. To systematically review and meta-analyze the effectiveness of yoga for menopausal symptoms.Methods. Medline, Scopus, the Cochrane Library, and PsycINFO were screened through April 2012. Randomized controlled trials (RCTs) were included if they assessed the effect of yoga on major menopausal symptoms, namely, (1) psychological symptoms, (2) somatic symptoms, (3) vasomotor symptoms, and/or (4) urogenital symptoms. For each outcome, standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated. Two authors independently assessed risk of bias using the risk of bias tool recommended by the Cochrane Back Review Group.Results. Five RCTs with 582 participants were included in the qualitative review, and 4 RCTs with 545 participants were included in the meta-analysis. There was moderate evidence for short-term effects on psychological symptoms (SMD=−0.37; 95% CI −0.67 to −0.07;P=0.02). No evidence was found for total menopausal symptoms, somatic symptoms, vasomotor symptoms, or urogenital symptoms. Yoga was not associated with serious adverse events.Conclusion. This systematic review found moderate evidence for short-term effectiveness of yoga for psychological symptoms in menopausal women. While more rigorous research is needed to underpin these results, yoga can be preliminarily recommended as an additional intervention for women who suffer from psychological complaints associated with menopause.
Is There a Role of Targeted Agents in the Management of Adrenocortical Cancers?
Authors: Saif M. W. , Fallon B. , Syrigos K. N.
Published: November 2012

Background. Adrenocortical carcinoma (ACC) is a rare and aggressive tumor arising from the adrenal cortex with an incidence of one to two cases per million within the general US population. Recent developments in the understanding of the pathogenesis of ACC have led to multiple clinical trials involving targeted agents in the management of ACC.Patients and Methods. We report two cases of refractory adrenocortical cancer (cisplatin, adriamycin, etoposide, and mitotane) who were treated with targeted agents such as erlotinib and sutent, respectively. A total of 2 women with adrenocortical cancer were reviewed and followed for a median time of 6 months. Radiological response, duration of response and toxicities were evaluated.Results. In both cases, the targeted agents were able to control the disease for a short duration, but due to the deterioration in performance status and fatigue the agents were discontinued.Conclusion. The current observations emphasize the need for better targeted treatment modalities and strategies for the management of this fatal disease.
Corrosion Behavior of Three Nanoclay Dispersion Methods of Epoxy/Organoclay Nanocomposites
Authors: Keyoonwong Wiwat , Guo Yi , Kubouchi Masatoshi , Aoki Saiko , Sakai Tetsuya
Published: November 2012

The aims of this study, firstly, to obtain high degree of clay exfoliation in the epoxy matrix by three dispersion methods such as normal mixing, shear mixing, and high-speed mixing and, secondly, to investigate corrosion behavior of epoxy/organoclay nanocomposite, immersion test, weight change, and penetration behavior were conducted. From the three mixing methods, the high-speed mixing method showed larger clay interlayer distance, smaller clay aggregate, and more homogeneity and expectedly resulted in high anticorrosive properties. Penetration depths of these nanocomposites showed a small difference; however, the most noticeable improvements in anticorrosion performance for epoxy/organoclay nanocomposites under high-speed mixing method were found to reduce penetration and weight uptake which are described via the model of nanoparticulate-filled structure and discussed in corrosion protection mechanism against environmental liquid penetration.
The Impact of Simultaneous Liver Resection for Occult Liver Metastases of Pancreatic Adenocarcinoma
Authors: Klein F. , Puhl G. , Guckelberger O. , Pelzer U. , Pullankavumkal J. R. , Guel S. , Neuhaus P. , Bahra M.
Published: November 2012

Backround. Pancreas resection is the only curative treatment for pancreatic adenocarcinoma. In the event of unexpected incidental liver metastases during operative exploration patients were traditionally referred to palliative treatment arms. With continuous progress in the surgical expertise simultaneous pancreas and liver resections seem technically feasible nowadays. The aim of this study therefore was to analyze the impact of synchronous liver-directed therapy on operative outcome and overall survival in patients with hepatic metastasized pancreatic adenocarcinoma (HMPA).Methods. 22 patients who underwent simultaneous pancreas resection and liver-directed therapy for HMPA between January 1, 2004 and January 1, 2009 were compared to 22 patients who underwent classic pancreas resection for nonmetastasized pancreatic adenocarcinoma (NMPA) in a matched pair study design. Postoperative morbidity, preoperative, and operative data and overall survival were analyzed.Results. Overall survival was significantly decreased in the HMPA group. Postoperative morbidity and mortality and median operation time did not significantly differ between the groups.Conclusion. The results of our study showed that simultaneous pancreas resection and liver-directed therapy may safely be performed and may therefore be applied in individual patients with HMPA. However, a potential benefit of this radical surgical approach with regard to overall survival and/or quality of life remains to be proven.
Impact of Trichloroethylene Exposure on the Microbial Diversity and Protein Expression in Anaerobic Granular Biomass at 37°C and 15°C
Authors: Siggins Alma , Enright Anne-Marie , Abram Florence , Botting Catherine , O'Flaherty Vincent
Published: November 2012

Granular biomass from a laboratory-scale anaerobic bioreactor trial was analysed to identify changes in microbial community structure and function in response to temperature and trichloroethylene (TCE). Two bioreactors were operated at 37°C, while two were operated at 15°C. At the time of sampling, one of each temperature pair of bioreactors was exposed to process failure-inducing concentrations of TCE (60 mg L−1) while the other served as a TCE-free control. Bacterial community structure was investigated using denaturing gradient gel electrophoresis (DGGE) and 16S rRNA gene clone library analysis. Temperature was identified as an important factor for bacterial community composition, while minor differences were associated with trichloroethylene supplementation. Proteobacteria was the dominant phylum in all bioreactors, while clone library analysis revealed a higher proportion of Bacteroidetes-, Chloroflexi-, and Firmicutes-like clones at 15°C than at 37°C. Comparative metaproteomics in the presence and absence of TCE was carried out by two-dimensional gel electrophoresis (2-DGE), and 28 protein spots were identified, with putative functions related to cellular processes, including methanogenesis, glycolysis, the glyoxylate cycle, and the methyl malonyl pathway. A good agreement between metaproteomic species assignment and phylogenetic information was observed, with 10 of the identified proteins associated with members of the phylum Proteobacteria.
Ex VivoFluorescence Molecular Tomography of the Spine
Authors: Pimpalkhare Monish , Chen Jin , Venugopal Vivek , Intes Xavier
Published: November 2012

We investigated the potential of fluorescence molecular tomography to imageex vivosamples collected from a large animal model, in this case, a dog spine. Wide-field time-gated fluorescence tomography was employed to assess the impact of multiview acquisition, data type, and intrinsic optical properties on the localization and quantification accuracy in imaging a fluorescent inclusion in the intervertebral disk. As expected, the TG data sets, when combining early and late gates, provide significantly better performances than the CW data sets in terms of localization and quantification. Moreover, the use of multiview imaging protocols led to more accurate localization. Additionally, the incorporation of the heterogeneous nature of the tissue in the model to compute the Jacobians led to improved imaging performances. This preliminary imaging study provides a proof of concept of the feasibility of quantitatively imaging complexex vivosamples nondestructively and with short acquisition times. This work is the first step towards employing optical molecular imaging of the spine to detect and characterize disc degeneration based on targeted fluorescent probes.
Computing Simple Roots by an Optimal Sixteenth‐Order Class
Authors: Soleymani F. , Shateyi S. , Salmani H.
Published: November 2012

The problem considered in this paper is to approximate the simple zeros of the function f(x) by iterative processes. An optimal 16th order class is constructed. The class is built by considering any of the optimal three‐step derivative‐involved methods in the first three steps of a four‐step cycle in which the first derivative of the function at the fourth step is estimated by a combination of already known values. Per iteration, each method of the class reaches the efficiency index , by carrying out four evaluations of the function and one evaluation of the first derivative. The error equation for one technique of the class is furnished analytically. Some methods of the class are tested by challenging the existing high‐order methods. The interval Newton′s method is given as a tool for extracting enough accurate initial approximations to start such high‐order methods. The obtained numerical results show that the derived methods are accurate and efficient.
1H,13C, and15N NMR Studies of Au(III) and Pd(II) Chloride Complexes and Organometallics with 2-Acetylpyridine and 2-Benzoylpyridine
Authors: Niedzielska Daria , Pawlak Tomasz , Czubachowski Tomasz , Pazderski Leszek
Published: November 2012

Au(III) and Pd(II) chloride complexes with N(1),O-chelating 2-acetylpyridine (2apy) and N(1)- monodentately binding 2-benzoylpyridine (2bz′py)-[Pd(2apy)Cl2], [Au(2bz′py)Cl3],trans-[Pd(2bz′py)2Cl2], as well as Au(III) chloride organometallics with monoanionic forms of 2apy or 2bz′py, deprotonated at the acetyl or benzyl side groups (2apy*, 2bz′py*)-[Au(2apy*)Cl2], [Au(2bz′py*)Cl2], were studied by1H,13C, and15N NMR.1H,13C, and15N coordination shifts (i.e., differences between the respective , , and chemical shifts of the same atom in the complex and ligand molecules: , , ) were discussed in relation to the molecular structures and coordination modes, as well as to the factors potentially influencing nuclear shielding. Analogous NMR measurements were performed for the new (2bz′pyH)[AuCl4] salt.
RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis
Authors: Kazerounian Shiva , Gerald Damien , Huang Minzhou , Chin Y. Rebecca , Udayakumar Durga , Zheng Ningning , O'Donnell Rebekah K. , Perruzzi Carole , Mangiante Lee , Pourat Jacob , Phung Thuy L. , Bravo-Nuevo Arturo , Shechter Sharon , McNamara Stephanie , DuHadaway James B. , Kocher Olivier N. , Brown Lawrence F. , Toker Alex , Prendergast George C. , Benjamin Laura E.
Published: November 2012

Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. Cancer Res; 73(1); 50–61. ©2012 AACR.
S100A9 Is a Novel Ligand of EMMPRIN That Promotes Melanoma Metastasis
Authors: Hibino Toshihiko , Sakaguchi Masakiyo , Miyamoto Shoko , Yamamoto Mami , Motoyama Akira , Hosoi Junichi , Shimokata Tadashi , Ito Tomonobu , Tsuboi Ryoji , Huh Nam-ho
Published: November 2012

The calcium-binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiologic and pathophysiologic effects of this damage-associated “danger signal” are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN specifically bound to S100A9 but not S100A8. Induction of cytokines and matrix metalloproteases (MMP) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaling used the TNF receptor–associated factor TRAF2 distinct from the known S100-binding signaling pathway mediated by RAGE (AGER). S100A9 strongly promoted migration when EMMPRIN was highly expressed, independent of RAGE, whereas EMMPRIN blockade suppressed migration by S100A9. Immunohistologic analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions and the adjacent epidermis, where S100A9 was also strongly expressed. In epidermal-specific transgenic mice, tail vein–injected melanoma accumulated in skin expressing S100A9 but not S100A8. Together, our results establish EMMPRIN as a receptor for S100A9 and suggest the therapeutic use in targeting S100A9–EMMPRIN interactions. Cancer Res; 73(1); 172–83. ©2012 AACR.