bluuebunny/crossref_metadata_2025 huggingface dataset:
Volcanic ash in the Lower Cretaceous Chaswood Formation of Nova Scotia: source and implicationsGeological Survey of Canada Contribution 20100082.
Authors: Pe-Piper Georgia , Piper David J.W.
Published: October 2010

Lignites and coals, because of their low sedimentation rates of terrigenous detritus, may preserve a record of volcanic ash fall. Lignite from the Lower Cretaceous Chaswood Formation in central Nova Scotia was studied to identify whether any volcanic ash is present and can be correlated to known Early Cretaceous volcanism in southeastern Canada and adjacent New England. The bulk mineralogy and geochemistry of lignite and lignitic mudstones was determined by X-ray diffraction and whole-rock geochemical analysis of ashed samples; selected samples were examined by electron microprobe and scanning electron microscope. Much of the terrigenous component of some lignites consists of detrital sediments. In some lignites, distinctive rare earth element patterns are due to leaching from monazite and concentration in organic matter. Some lignites, however, lack illite and (or) quartz indicative of detrital sources, but show unusual abundance of stable high-field-strength elements such as Nb, Ta, and Hf, suggesting a volcanic source. Wood or charcoal fragments appear mineralized and diagenetic talc is present. Most of any ash component has been altered to kaolinite. Bulk composition of original ash ranges from basaltic to rhyolitic and matches chemically with subalkaline volcanic rocks on the SW Grand Banks and Orpheus graben. Coeval volcanic rocks on the U.S. continental margin and the New England–Quebec igneous province are more alkaline. Altered ash in lignite in the lower member of the Chaswood Formation correlates with Neocomian volcanism on the SW Grand Banks; and in the middle and upper members with Aptian–Albian volcanism in Orpheus graben.
Coupled two-dimensional finite element modelling of mine backfilling with cemented tailings
Authors: Helinski Matthew , Fahey Martin , Fourie Andy
Published: October 2010

Mine backfilling is a process whereby mine tailings mixed with small amounts of cement are placed hydraulically into mined-out voids (“stopes”) to stabilize the rockmass and allow full extraction of adjacent ore. A containment barricade is constructed to block the access point at the base of the stope, the design of which requires calculation of the total stress on the barricade during and following filling. For fine-grained backfill containing cement, the rate of development of stresses is governed by the rates of filling, consolidation, and cement hydration, each with its own timescale. As “consolidation” in backfill undergoing hydration can be dominated by “self-desiccation”, this mechanism must also be incorporated. Interaction between the backfill and the stope walls (“arching”) also has an influence. The paper describes a finite element (FE) model (“Minefill-2D”) that can model these interactions, although only in a two-dimensional (plane–strain or axisymmetric) fashion. It is shown that arching significantly influences the total stress distribution in a typical stope during filling, but only if and when effective stress develops. For cemented backfill, arching sometimes does not fully mobilize the cement bond strength, so that assessment of arching using traditional limit equilibrium methods is often not appropriate.
Contact versus noncontact piled raft foundations
Authors: Fioravante Vincenzo , Giretti Daniela
Published: October 2010

In the last few decades there has been a rapid increase in the number of piled foundations where the piles have been employed as settlement reducers; in some recent projects, the piles have been separated from the raft by a granular layer, which creates a more uniform pressure distribution on the raft bottom and reduces constraint reactions in the soil, foundation, and superstructure. A series of centrifuge model tests has been performed to investigate the load transfer mechanisms between a square rigid raft and a group of instrumented piles jacked in dry dense sand, in direct contact with the raft or separated from the raft by an interposed granular layer. The test results have shown that contact piles act as settlement reducers by diffusing the load applied to their heads to greater and deeper volumes of soil. The insertion of a deformable layer between a raft and pile heads does not ensure displacement compatibility, and the pressure diffused by the granular fill acts partly on the pile heads and partly produces shallow soil settlements, which mobilize negative skin friction on the upper part of the pile shaft. Noncontact piles act mainly as soil reinforcement.
Soil–pile separation effect on the performance of a pile group under static and dynamic lateral loads
Authors: Hussien Mahmoud N. , Tobita Tetsuo , Iai Susumu , Rollins Kyle M.
Published: October 2010

The effect of soil–pile separation is studied with respect to the performance of a laterally loaded pile group. Full-scale tests, which consist of a combination of a single and a 3 × 5 group pile under static and dynamic lateral loads, present a unique opportunity and allow a rigorous study without arbitrary parameter back-fitting. The coupled soil–pile system is idealized through two-dimensional finite elements with soil models idealized by a hyperbolic-type multiple shear mechanism. Nonlinear spring elements are used to idealize the soil–pile interaction through a hysteretic nonlinear load–displacement relationship. Joint elements with a separation–contact mechanism are used to idealize the separation effect at the soil–pile interface. Ignoring soil–pile separation in static tests overestimates the ultimate lateral load–carrying capacity by 43% for a single pile and 73% for the trailing pile in a closely spaced pile group. Moreover, neglecting soil–pile separation in dynamic tests overestimates the total group load–deflection curve in both the loading and unloading phases.
On determining the elastic modulus of a cylindrical sample subjected to flexural excitation in a resonant column apparatus
Authors: Kumar Jyant , Madhusudhan B. N.
Published: October 2010

For resonant column tests conducted in the flexure mode of excitation, a new methodology has been proposed to find the elastic modulus and associated axial strain of a cylindrical sample. The proposed method is an improvement over the existing one, and it does not require the assumption of either the mode shape or zero bending moment condition at the top of the sample. A stepwise procedure is given to perform the necessary calculations. From a number of resonant column experiments on aluminum bars and dry sand samples, it has been observed that the present method as compared with the one available in literature provides approximately (i) 5.9%–7.3% higher values of the elastic modulus and (ii) 6.5%–7.3% higher values of the associated axial strains.
Steel-shot method for measuring the density of soils
Authors: Freeman Reed B. , Gartrell Chad A. , Wakeley Lillian D. , Berney Ernest S. , Kelley Julie R.
Published: October 2010

The density of soil is crucial in engineering, construction, and research. Standard methods to determine density use procedures, equipment or expendable materials that limit their effectiveness in challenging field conditions. Some methods require burdensome logistics or have time requirements that limit their use or the number of tests that can be executed. A test method, similar to the sand-cone method, was developed that uses steel shot as the material to which a volume of soil is compared to calculate soil density. Steel shot is easily recovered and reused, eliminating the need for specialty sand and calibrated cones or containers, and allows rapid determination of the volume of displaced soil. Excavated soil also provides measurements of total mass and moisture content. Volume, mass, and moisture content are applied in simple calculations to determine wet and dry densities and unit weight of the soil. Proficiency in performing the test can be achieved with minimal training, and the required kit can be assembled for a reasonable cost. Field uses of the method in dry environments in a variety of soil types demonstrated that the method can produce repeatable results within 2% of the values of soil density determined by traditional methods, with advantages in logistics.
MicroRNA-92b regulates expression of the oligopeptide transporter PepT1 in intestinal epithelial cells
Authors: Dalmasso Guillaume , Nguyen Hang Thi Thu , Yan Yutao , Laroui Hamed , Charania Moiz A. , Obertone Tracy S. , Sitaraman Shanthi V. , Merlin Didier
Published: October 2010

MicroRNAs (miRNAs), which are noncoding RNAs that posttranscriptionally inhibit expression of target genes, have recently emerged as important regulators of many cellular functions such as cell differentiation. The epithelial di/tripeptide membrane transporter PepT1 is expressed in highly differentiated cells (the villous tip) but not in undifferentiated cells (the crypt) of the small intestine. Here, we investigated the regulation of PepT1 expression by miRNAs and its functional consequences. We observed a reverse correlation between the expression levels of PepT1 and mature miRNA-92b (miR-92b) during the differentiation of intestinal epithelial Caco2-BBE cells, suggesting a miR-92b-mediated regulation of PepT1 expression. We demonstrate that miR-92b suppressed PepT1 expression at both mRNA and protein levels, with subsequent reduced PepT1 transport activity, in Caco2-BBE cells by directly targeting the PepT1 3′-untranslated region. In addition, miR-92b suppresses bacterial peptide-induced proinflammatory responses in intestinal epithelial cells by inhibiting PepT1 expression. Altogether, our study provides for the first time evidence for the regulation of PepT1 expression at a posttranscriptional level by miRNAs in intestinal epithelial cells during pathophysiological states.
The Rac1/JNK pathway is critical for EGFR-dependent barrier formation in human airway epithelial cells
Authors: Terakado Masahiro , Gon Yasuhiro , Sekiyama Akiko , Takeshita Ikuko , Kozu Yutaka , Matsumoto Ken , Takahashi Noriaki , Hashimoto Shu
Published: October 2010

The airway epithelial barrier provides defenses against inhaled antigens and pathogens, and alterations of epithelial barrier function have been proposed to play a significant role in the pathogenesis of chronic airway diseases. Although the epidermal growth factor receptor (EGFR) plays roles in various physiological and pathological processes on the airway epithelium, the role of EGFR on barrier function in the airway remains largely unknown. In the present study, we assessed the effects of EGFR activation on paracellular permeability in airway epithelial cells (AECs). EGFR activation induced by the addition of EGF increased transepithelial electrical resistance (TER) in AECs. An EGFR-blocking antibody eradicated the development of TER, paracellular influx of dextran, and spatial organization of tight junction. Moreover, the effects of EGFR activation on paracellular permeability were eradicated by knockdown of occludin. To identify the EGFR signaling pathway that regulates permeability barrier development, we investigated the effects of several MAP kinase inhibitors on permeability barrier function. Pretreatment with a JNK-specific inhibitor, but not an ERK- or p38-specific inhibitor, attenuated the development of TER induced by EGFR activation. Rac1 is one of the upstream activators for JNK in EGFR signaling. Rac1 knockdown attenuated the phosphorylation of JNK activation and EGFR-mediated TER development. These results suggest that EGFR positively regulates permeability barrier development through the Rac1/JNK-dependent pathway.
Intracoronary gastrin 17 increases cardiac perfusion and function through autonomic nervous system, CCK receptors, and nitric oxide in anesthetized pigs
Authors: Grossini Elena , Caimmi Philippe , Molinari Claudio , Uberti Francesca , Mary David , Vacca Giovanni
Published: October 2010

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCK1/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary co-administration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone ( P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 ( P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCK1/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-l-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release.
Variability in training-induced skeletal muscle adaptation
Authors: Timmons James A.
Published: October 2010

When human skeletal muscle is exposed to exercise training, the outcomes, in terms of physiological adaptation, are unpredictable. The significance of this fact has long been underappreciated, and only recently has progress been made in identifying some of the molecular bases for the heterogeneous response to exercise training. It is not only of great medical importance that some individuals do not substantially physiologically adapt to exercise training, but the study of the heterogeneity itself provides a powerful opportunity to dissect out the genetic and environmental factors that limit adaptation, directly in humans. In the following review I will discuss new developments linking genetic and transcript abundance variability to an individual's potential to improve their aerobic capacity or endurance performance or induce muscle hypertrophy. I will also comment on the idea that certain gene networks may be associated with muscle “adaptability” regardless the stimulus provided.
The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration
Authors: Chang Chung-Hsun , Tsai Wen-Chung , Lin Miao-Sui , Hsu Ya-Hui , Pang Jong-Hwei Su
Published: October 2010

Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon. The outgrowth of tendon fibroblasts from tendon explants cultured with or without BPC 157 was examined. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants. Cell proliferation of cultured tendon fibroblasts derived from rat Achilles tendon was not directly affected by BPC 157 as evaluated by MTT assay. However, the survival of BPC 157-treated cells was significantly increased under the H2O2stress. BPC 157 markedly increased the in vitro migration of tendon fibroblasts in a dose-dependent manner as revealed by transwell filter migration assay. BPC 157 also dose dependently accelerated the spreading of tendon fibroblasts on culture dishes. The F-actin formation as detected by FITC-phalloidin staining was induced in BPC 157-treated fibroblasts. The protein expression and activation of FAK and paxillin were determined by Western blot analysis, and the phosphorylation levels of both FAK and paxillin were dose dependently increased by BPC 157 while the total amounts of protein was unaltered. In conclusion, BPC 157 promotes the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts, which is likely mediated by the activation of the FAK-paxillin pathway.
Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans
Authors: Marimuthu Kanagaraj , Murton Andrew J. , Greenhaff Paul L.
Published: October 2010

Muscle mass loss accompanies periods of bedrest and limb immobilization in humans and requires rehabilitation exercise to effectively restore mass and function. Although recent evidence points to an early and transient rise in muscle protein breakdown contributing to this decline in muscle mass, the driving factor seems to be a reduction in muscle protein synthesis, not least in part due to the development of anabolic resistance to amino acid provision. Although the AKT signaling pathway has been identified in small animals as central to the regulation of muscle protein synthesis, several studies in humans have now demonstrated a disassociation between AKT signaling and muscle protein synthesis during feeding, exercise, and immobilization, suggesting that the mechanisms regulating protein synthesis in human skeletal muscle are more complex than initially thought (at least in non-inflammatory states). During rehabilitation, exercise-induced myogenesis may in part be responsible for the recovery of muscle mass. Rapid and sustained exercise-induced suppression of myostatin mRNA expression, that precedes any gain in muscle mass, points to this, along with other myogenic proteins, as being potential regulators of muscle regeneration during exercise rehabilitation in humans.
Histone modifications and exercise adaptations
Authors: McGee Sean L. , Hargreaves Mark
Published: October 2010

The spatial association between genomic DNA and histone proteins within chromatin plays a key role in the regulation of gene expression and is largely governed by post-translational modifications to histone proteins, particularly H3 and H4. These modifications include phosphorylation, acetylation, and mono-, di-, and tri-methylation, and while some are associated with transcriptional repression, acetylation of lysine residues within H3 generally correlates with transcriptional activation. Histone acetylation is regulated by the balance between the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). In skeletal muscle, the class II HDACs 4, 5, 7, and 9 play a key role in muscle development and adaptation and have been implicated in exercise adaptations. As just one example, exercise results in the nuclear export of HDACs 4 and 5, secondary to their phosphorylation by CaMKII and AMPK, two kinases that are activated during exercise in response to changes in sarcoplasmic Ca2+ levels and energy status, in association with increased GLUT4 expression in human skeletal muscle. Unraveling the complexities of the so-called “histone code” before and after exercise is likely to lead to a greater understanding of the regulation of exercise/activity-induced alterations in skeletal muscle gene expression and reinforce the importance of skeletal muscle plasticity in health and disease.
Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle
Authors: Yan Zhen , Okutsu Mitsuharu , Akhtar Yasir N. , Lira Vitor A.
Published: October 2010

Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations.
Local exposure of the rat cortex to radiofrequency electromagnetic fields increases local cerebral blood flow along with temperature
Authors: Masuda Hiroshi , Hirata Akimasa , Kawai Hiroki , Wake Kanako , Watanabe Soichi , Arima Takuji , Poulletier de Gannes Florence , Lagroye Isabelle , Veyret Bernard
Published: October 2010

Few studies have shown that local exposure to radiofrequency electromagnetic fields (RF) induces intensity-dependent physiological changes, especially in the brain. The aim of the present study was to detect reproducible responses to local RF exposure in the parietal cortex of anesthetized rats and to determine their dependence on RF intensity. The target cortex tissue was locally exposed to 2-GHz RF using a figure-eight loop antenna within a range of averaged specific absorption rates (10.5, 40.3, 130, and 263 W/kg averaged over 4.04 mg) in the target area. Local cerebral blood flow (CBF) and temperatures in three regions (target area, rectum, and calf hypodermis) were measured using optical fiber blood flow meters and thermometers during RF exposure. All parameters except for the calf hypodermis temperature increased significantly in exposed animals compared with sham-exposed ones during 18-min exposures. Dependence of parameter values on exposure intensity was analyzed using linear regression models. The elevation of local CBF was correlated with temperature rise in both target and rectum at the end of RF exposure. However, the local CBF elevation seemed to be elevated by the rise in target temperature, but not by that of the rectal temperature, in the early part of RF exposure or at low-intensity RF exposure. These findings suggest that local RF exposure of the rat cortex drives a regulation of CBF accompanied by a local temperature rise, and our findings may be helpful for discussing physiological changes in the local cortex region, which is locally exposed to RF.
The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers
Authors: Sasaki Takaaki , Okuda Katsuhiro , Zheng Wei , Butrynski James , Capelletti Marzia , Wang Liping , Gray Nathanael S. , Wilner Keith , Christensen James G. , Demetri George , Shapiro Geoffrey I. , Rodig Scott J. , Eck Michael J. , Jänne Pasi A.
Published: October 2010

The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers. Cancer Res; 70(24); 10038–43. ©2010 AACR.
Development of Central Nervous System Metastases in Patients with Advanced Non–Small Cell Lung Cancer and Somatic EGFR Mutations Treated with Gefitinib or Erlotinib
Authors: Heon Stephanie , Yeap Beow Y. , Britt Gregory J. , Costa Daniel B. , Rabin Michael S. , Jackman David M. , Johnson Bruce E.
Published: October 2010

Purpose: Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non–small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases.

Experimental Design: Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.

Results: Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months.

Conclusions: Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients. Clin Cancer Res; 16(23); 5873–82. ©2010 AACR.
Sequence Analysis and Mapping of the Sry Gene in Species of the Subfamily Arvicolinae (Rodentia)
Authors: Acosta M.J. , Marchal J.A. , Romero-Fernández I. , Megías-Nogales B. , Modi W.S. , Sánchez A.
Published: October 2010

The rodent subfamily Arvicolinae, which contains about 125 species, presents some interesting exceptions concerning Sry, the sex determining gene in mammals. In some species multiple Sry copies have been described on the Y chromosome and in the Iberian vole, Microtus cabrerae, several Sry sequences have been cloned and mapped not only on the Y but also on the X chromosome. Here we present a comparative analysis of Sry sequences from a total of 22 species. Our study demonstrates for the first time that for most North American species, as previously reported for the European species, multiple copies of the Sry gene exist on the Y chromosome. Furthermore, we have sequenced and analyzed the full sequence of Sry from several European species, showing that the sequence and structure of the gene in this group of species present the main features described for Sry in other mammals. Finally, FISH analyses on some of these species demonstrated that all Sry sequences, despite their functional status, mapped on the euchromatic short arm of the Y chromosome.
Oxygen-Sensitive Global Regulator, Anr, Is Involved in the Biosynthesis of Poly(3-Hydroxybutyrate) in Pseudomonas extremaustralis
Authors: Tribelli Paula M. , Méndez Beatriz S. , López Nancy I.
Published: October 2010

We analyzed the influence of the redox global regulator Anr on the accumulation of poly(3-hydroxybutyrate) (PHB) in Pseudomonas extremaustralis. Anr regulates a set of genes in the aerobic-anaerobic transition including genes involved in nitrate reduction and arginine fermentation. An anr mutant was constructed using PCR-based strategies. The wild-type strain was able to grow in both microaerobic and anaerobic conditions using nitrate as the terminal electron acceptor while the mutant strain was unable to grow under anaerobic conditions. In bioreactor cultures, PHB content in the wild-type strain was higher in microaerobic and anaerobic cultures compared with highly aerated cultures. The mutant strain showed decreased PHB levels in both aerobic and microaerobic conditions compared with the wild-type strain. Inactivation of anr led to decreased expression of phaC and phaR genes as demonstrated in real-time RT-PCR experiments. Associated with the PHB gene region, two putative binding sites for Anr were found that, in line with the phenotype observed in bioreactor cultures, suggest a role of this regulator in PHB biosynthesis.
A Randomized Controlled Trial of Electrocoagulation-Enabled Biopsy versus Conventional Biopsy in the Diagnosis of Endobronchial Lesions
Authors: Khan Ajmal , Aggarwal Ashutosh N. , Agarwal Ritesh , Bal Amanjit , Gupta Dheeraj
Published: October 2010

Background: Although electrocoagulation at time of endobronchial biopsy can potentially reduce procedure-related bleeding during fiberoptic bronchoscopy (FOB), it can also impair quality of tissue specimen; credible data for either are lacking. Objective: To evaluate the impact of hot biopsy on the quality of tissue samples and to quantify the amount of procedure-related bleeding during endobronchial biopsy. Methods: In this single-center, prospective, single-blind, randomized controlled study we included adult patients referred for FOB and having endobronchial lesions. Patients were randomized to bronchial biopsy using an electrocoagulation-enabled biopsy forceps, with (EC+ group) or without (EC– group) application of electrocoagulation current (40 W for 10 s in a monopolar mode). Procedure-related bleeding was semi-quantified by observer description, as well as through a visual analogue scale. Overall quality of biopsy specimen and tissue damage were assessed and graded by a pulmonary pathologist blinded to FOB details. Result: 160 patients were randomized to endobronchial biopsy with (n = 81) or without (n = 79) the application of electrocoagulation. There were no severe bleeding episodes in either group, and severity of bleeding in the EC+ and EC– groups was similar (median visual analogue scale scores of 14 and 16, respectively). Histopathological diagnosis was similar in the EC+ and EC– groups (77.8% and 82.3%, respectively). There was no significant difference in tissue quality between the two groups. Conclusion: Use of electrocoagulation-enabled endobronchial biopsy does not alter specimen quality and does not result in any significant reduction in procedure-related bleeding.
Profile and Frequency of p53 Gene Alterations in Gastritis Lesions from Iran
Authors: Najjar Sadeghi Rouhallah , Azimzadeh Pedram , Vahedi Mohsen , Mirsattari Dariush , Molaei Mahsa , Mohebbi Seyed Reza , Zojaji Homayon , Fatemi Seyed Reza , Zali Mohamad Reza
Published: October 2010

Background: It has been frequently shown that p53 alterations have an important role in the development of gastric cancers but there is no data on p53 alteration in gastric cancer and its precancerous lesions from Iran although this country experiences one of the highest gastric cancer incidence and mortality rates in the world. The purpose of this study was to do a comprehensive assessment of p53 alterations in the Iranian population of gastritis patients and to evaluate the association between p53 alterations, microsatellite status and clinicopathological aspects. Methods: After DNA extraction, PCR sequencing was done for exons 2–7. Also microsatellite status was evaluated using five microsatellite markers: NR-27, NR-21, NR-24, BAT-25 and BAT-26. Results: The highest rate of alteration was seen in codons 72 (85.6%, SNP) and 248 (30.9%, mutation). Also, we found 2 new mutations in codons 9 and 146. In contrast with previous work, transition at the CpG codons was relatively rare. Nucleotide alterations were more prevalent in the Helicobacter pylori-positive group but not significantly. Neither nuclear staining for p53 protein nor microsatellite instability was seen in gastritis lesions. Conclusion: p53 alterations might contribute to the pathogenesis of gastritis and perhaps gastric cancer in Iran. However, the different spectrum seen here implies other mechanism(s) in gastritis and gastric cancer development in the Iranian population.
Morphogenetic Targets and Genetics of Undescended Testis
Authors: Massart F. , Saggese G.
Published: October 2010

Although important advances in testicular physiology have been achieved, the aetiology of human cryptorchidism remains mostly unknown. Next to sex steroidal signaling pathways, morphogenetic genes are specifically involved in the testicular descent via gubernacular development. Mutations in the human genes encoding insulin-like factor 3 (INSL3) and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), zinc finger 214 (ZNF214) and 215 (ZNF215) have occasionally been identified but do not seem to be a frequent cause of cryptorchidism. On the other hand, common polymorphisms in these genes have recently been investigated as contributing risk factors for idiopathic isolated (nonsyndromic) cryptorchidism.
Cysteine-Cysteinyl Chemokine Receptor 6 Mediates Invariant Natural Killer T Cell Airway Recruitment and Innate Stage Resistance during Mycobacterial Infection
Authors: Stolberg Valerie R. , Chiu Bo-chin , Martin Brian E. , Shah Samir A. , Sandor Matyas , Chensue Stephen W.
Published: October 2010

This study examined the contribution of cysteine-cysteinyl chemokine receptor 6 (CCR6) to the innate pulmonary antimycobacterial immune response. Using a mouse model of Mycobacterium bovis BCG airway infection, we detected maximal induction of the CCR6 agonist CCL20 in lungs at 1 week after infection. Infected CCR6 knockout (CCR6–/–) mice displayed an early impairment of bacterial clearance, but ultimately eliminated the attenuated organisms with the onset of adaptive immunity. Flow-cytometric analyses of bronchoalveolar lavages and dispersed lungs revealed a 60% reduction in TCR-α/β+ T cells in airways but no compromise of TCR-γ/δ+ T cells. The subset of CD1d-restricted, CD8-TCR-α/β+ natural killer cells, which mediate innate mycobacterial resistance, was profoundly reduced (90%). Analysis of the adaptive response using ovalbumin-specific transgenic TCR T cell (OT-II) transfer combined with infection with recombinant M. bovis BCG producing ovalbumin peptide indicated no impairment of adaptive T cell activation in CCR6–/– mice. There was also no impairment of the induction of cytokine-producing cells in draining lymphoid tissue of CCR6–/– mice. Taken together, our findings indicate that CCR6 is not required for induction of the adaptive antimycobacterial response, but is likely critical to airway compartment mobilization of TCR-α/β+CCR6+ innate and adaptive effector T cells.
Cloning and Targeted Disruption of Two Lipopolysaccharide Biosynthesis Genes, kdsA and waaG, of Pseudomonas aeruginosa PAO1 by Site-Directed Mutagenesis
Authors: Perumal Deepak , Sakharkar Kishore R. , Tang Thean Hock , Chow Vincent T.K. , Lim Chu Sing , Samal Areejit , Sugiura Norio , Sakharkar Meena K.
Published: October 2010

The emergence of antibiotic resistance in bacterial pathogens poses a great challenge to public health and emphasizes the need for new antimicrobial targets. The recent development of microbial genomics and the availability of genome sequences allows for the identification of essential genes which could be novel and potential targets for antibacterial drugs. However, these predicted targets need experimental validation to confirm essentiality. Here, we report on experimental validation of a two potential targets in the lipopolysaccharide (LPS) biosynthesis pathway of the pathogen Pseudomonas aeruginosa PAO1 using insertion duplication. Two genes, kdsA and waaG, from LPS encoding proteins 2-dehydro-3-deoxyphosphooctonate aldolase and UDP-glucose (heptosyl) LPS α-1,3-glucosyltransferase were selected as putative target candidates for the gene disruption experiments using plasmid insertion mutagenesis to determine essentiality. The introduction of a selectable ampicillin and kanamycin resistance marker into the chromosome resulted in lack of recovery of antibiotic-resistant colonies suggesting the essentiality of these genes for the survival of P. aeruginosa. Several molecular analyses were carried out in order to confirm the essentiality of these genes. We propose that the above two validated drug targets are essential and can be screened for functional inhibitors for the discovery of novel therapeutic compounds against antibiotic-resistant opportunistic pathogen P. aeruginosa.
Intrapericardial, But Not Extrapericardial, Fat Is an Independent Predictor of Impaired Hyperemic Coronary Perfusion in Coronary Artery Disease
Authors: Bucci Marco , Joutsiniemi Esa , Saraste Antti , Kajander Sami , Ukkonen Heikki , Saraste Markku , Pietilä Mikko , Sipilä Hannu T. , Teräs Mika , Mäki Maija , Airaksinen K.E. Juhani , Hartiala Jaakko , Knuuti Juhani , Iozzo Patricia
Published: October 2010

Objective—

To measure intrapericardial fat (IPF), extrapericardial fat (EPF), and myocardial perfusion (MBF) in patients with and without coronary artery disease (CAD), hypothesizing that perfusion is more strongly associated with IPF because it is in direct anatomic contiguity with the myocardium or coronary arteries.

Methods and Results—

Fat surrounding the heart may increase the risk of CAD and calcification, but little is known about the role of MBF in this relationship. The study included 107 patients with an intermediate likelihood of CAD. Positron emission tomography/computed tomography was used to measure IPF and EPF volumes and coronary artery calcium level, together with MBF at rest and during adenosine-induced hyperemia. Subsequently, all subjects underwent coronary angiography and were grouped for presence/absence of CAD and severity of myocardial hypoperfusion. IPF and EPF levels were higher in men and in patients with CAD (n=85) than in those without CAD (n=22) (
P
<0.001). EPF was increased regardless of the degree of stenoses (n=45), whereas IPF was selectively increased in subjects with obstructive stenoses (n=40). IPF and EPF levels were both associated with coronary artery calcium scores (
R
=0.25 and
R
=0.26, respectively;
P
<0.02), coronary flow reserve (
R
=−0.37 and
R
=−0.38, respectively;
P
<0.001), and hyperemic MBF (
R
=−0.36 and
R
=−0.44, respectively;
P
<0.0005). Male sex was a strong negative predictor of MBF. After discounting for confounders, myocardial hyperemic perfusion was predicted independently by sex, coronary artery calcium score, and IPF, but not EPF.

Conclusion—

CAD is accompanied by augmented fat depots surrounding the heart, which are negatively related to coronary flow hyperemia. Among fat depots, IPF was the only independent predictor of hyperemic MBF, supporting the hypothesis of a direct paracrine/vasocrine effect.
CD11c/CD18 Expression Is Upregulated on Blood Monocytes During Hypertriglyceridemia and Enhances Adhesion to Vascular Cell Adhesion Molecule-1
Authors: Gower R. Michael , Wu Huaizhu , Foster Greg A. , Devaraj Sridevi , Jialal Ishwarlal , Ballantyne Christie M. , Knowlton Anne A. , Simon Scott I.
Published: October 2010

Objective—

Atherosclerosis is associated with monocyte adhesion to the arterial wall that involves integrin activation and emigration across inflamed endothelium. Involvement of β
2
-integrin CD11c/CD18 in atherogenesis was recently shown in dyslipidemic mice, which motivates our study of its inflammatory function during hypertriglyceridemia in humans.

Methods and Results—

Flow cytometry of blood from healthy subjects fed a standardized high-fat meal revealed that at 3.5 hours postprandial, monocyte CD11c surface expression was elevated, and the extent of upregulation correlated with blood triglycerides. Monocytes from postprandial blood exhibited an increased light scatter profile, which correlated with elevated CD11c expression and uptake of lipid particles. Purified monocytes internalized triglyceride-rich lipoproteins isolated from postprandial blood through low-density lipoprotein–receptor–related protein-1, and this also elicited CD11c upregulation. Laboratory-on-a-chip analysis of whole blood showed that monocyte arrest on a vascular cell adhesion molecule-1 (VCAM-1) substrate under shear flow was elevated at 3.5 hours and correlated with blood triglyceride and CD11c expression. At 7 hours postprandial, blood triglycerides decreased and monocyte CD11c expression and arrest on VCAM-1 returned to fasting levels.

Conclusion—

During hypertriglyceridemia, monocytes internalize lipids, upregulate CD11c, and increase adhesion to VCAM-1. These data suggest that analysis of monocyte inflammation may provide an additional framework for evaluating individual susceptibility to cardiovascular disease.
Human CD34
+
/KDR
+
Cells Are Generated From Circulating CD34
+
Cells After Immobilization on Activated Platelets
Authors: de Boer H.C. , Hovens M.M. , van Oeveren-Rietdijk A.M. , Snoep J.D. , de Koning E.J.P. , Tamsma J.T. , Huisman M.V. , Rabelink A.J. , van Zonneveld A.J.
Published: October 2010

Objective—

The presence of kinase-insert domain-containing receptor (KDR) on circulating CD34
+
cells is assumed to be indicative for the potential of these cells to support vascular maintenance and repair. However, in bone marrow and in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood, less than 0.5% of CD34
+
cells co-express KDR. Therefore, we studied whether CD34
+
/KDR
+
cells are generated in the peripheral circulation.

Methods and Results—

Using an ex vivo flow model, we show that activated platelets enable CD34
+
cells to home to sites of vascular injury and that upon immobilization, KDR is translocated from an endosomal compartment to the cell-surface within 15 minutes. In patients with diabetes mellitus type 2, the percentage of circulating CD34
+
co-expressing KDR was significantly elevated compared to age-matched controls. When treated with aspirin, the patients showed a 49% reduction in the generation of CD34
+
/KDR
+
cells, indicating that the level of circulating CD34
+
/KDR
+
cells also relates to in vivo platelet activation.

Conclusion—

Circulating CD34
+
/KDR
+
are not mobilized from bone marrow as a predestined endothelial progenitor cell population but are mostly generated from circulating multipotent CD34
+
cells at sites of vascular injury. Therefore, the number of circulating CD34
+
/KDR
+
cells may serve as a marker for vascular injury.
Interplay Between Heme Oxygenase-1 and the Multifunctional Transcription Factor Yin Yang 1 in the Inhibition of Intimal Hyperplasia
Authors: Beck Konstanze , Wu Ben J. , Ni Jun , Santiago Fernando S. , Malabanan Kristine P. , Li Cheng , Wang Yutang , Khachigian Levon M. , Stocker Roland
Published: October 2010

Rationale:

Induction of heme oxygenase (HO)-1 protects against experimental atherosclerotic diseases, and certain pharmacological HO-1 inducers, like probucol, inhibit the proliferation of vascular smooth muscle cells and, at the same time, promote the growth of endothelial cells in vivo and in vitro.

Objective:

Because such cell-specific effects are reminiscent of the action of the transcription factor Yin Yang (YY)1, we tested the hypothesis that there is a functional relationship between HO-1 and YY1.

Methods and Results:

We report that probucol increases the number of YY1
+
cells in rat carotid artery following balloon injury at a time coinciding with increased HO-1 expression. The drug also induces the expression of YY1 mRNA and protein in rat aortic smooth muscle cells (RASMCs) in vitro, as do other known HO-1 inducers (
tert
-butylhydroquinone and hemin) and overexpression of HO-1 using a human
HMOX1
cDNA plasmid. Conversely, overexpression of YY1 induces expression of HO-1 in RASMCs. Induction of YY1 expression is dependent on HO-1 enzyme activity and its reaction product CO, because pharmacological inhibition of heme oxygenase activity or CO scavenging block, whereas exposure of RASMCs to a CO-releasing molecule increases, YY1 expression. Furthermore, RNA interference knockdown of YY1 prevents probucol or adeno–HO-1 from inhibiting RASMC proliferation in vitro and neointimal formation in vivo.

Conclusions:

Our findings show, for the first time, that HO-1 functionally interplays with the multifunctional transcription factor YY1 and that this interplay explains some of the protective activities of HO-1.
The Safety of Driving a Commercial Motor Vehicle After a Stroke
Authors: Rabadi Meheroz H. , Akinwuntan Abiodun , Gorelick Philip
Published: October 2010

Background and Purpose—

Current guidelines for commercial motor vehicle (CMV) drivers to return to driving after a TIA or stroke was last reviewed in 1988. Updated recommendations are presented based on recent evidence.

Methods—

A 3-member medical expert panel chosen by the U.S. Department of Transportation’s Federal Motor Carrier Safety Administration used findings of systematic literature review up to January 2008 to provide updated recommendations for return to driving for CMV drivers after TIA or stroke.

Results—

Evidence from the systematic review showed that TIA patients are at increased risk for stroke, and stroke patients are at increased risk for motor vehicle crash. Although no studies provide direct evidence of predictability of crash risk of CMV drivers using outcomes of neuropsychological assessments, there is evidence that certain neuropsychological tests can identify on-road driving performance after stroke.

Conclusions—

The medical expert panel recommended driving cessation for 1 year after a TIA or stroke, and return to driving a CMV should be allowed only after successful completion of a comprehensive neurological evaluation, neuropsychological assessments, and on-road testing.
Endovascular Treatment of Very Small Unruptured Aneurysms
Authors: Pierot Laurent , Barbe Coralie , Spelle Laurent ,   ATENA investigators
Published: October 2010

Background and Purpose—

The strategy of treatment of small unruptured intracranial aneurysms is complex because of their presumably low risk of rupture. A precise knowledge of the perioperative complications in this specific subgroup is mandatory. The purpose of this study was to compare the results of the endovascular treatment of aneurysms ≤3 mm and aneurysms >3 mm included in the Analysis of Treatment by Endovascular Approach of Nonruptured Aneurysms study.

Methods—

The study included 626 patients harboring 682 unruptured aneurysms. Perioperative adverse events and clinical outcome were analyzed in patients treated for aneurysms ≤3 mm (51 patients, 51 aneurysms) and in patients treated for aneurysms >3 mm (575 patients, 631 aneurysms).

Results—

Endovascular treatment failed more often in aneurysms ≤3 mm (13.7%) compared to aneurysms >3 mm (3.3%;
P
=0.003). The rate of intraoperative rupture for aneurysms ≤3 mm (3.9%; 95% CI, 0.5–13.5) did not significantly differ compared to aneurysms >3 mm (2.4%; 95% CI, 1.2–3.6;
P
=0.37). Thromboembolic events were not significantly different in both groups (3.9%; 95% CI, 0.5–13.5 in very small aneurysms and 7.1%; 95% CI, 5.1–9.1 in larger aneurysms;
P
=0.57). One month morbidity/mortality was not significantly different for patients with very small aneurysms (2.0%; 95% CI, 0.05–10.45) and for patients with larger aneurysms (3.3%; 95% CI, 1.8–4.8;
P
=0.60).

Conclusions—

The risks of endovascular treatment are similar in patients with very small or with larger aneurysms. Because the risk of spontaneous rupture is lower in very small aneurysms, their management will include follow-up MRI and active treatment in case of morphological modification.