bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital Cytomegalovirus Infection Manifesting as Neonatal Persistent Pulmonary Hypertension: Report of Two Cases
Authors: Walter-Nicolet Elizabeth , Leblanc Magali , Leruez-Ville Marianne , Hubert Philippe , Mitanchez Delphine
Published: June 2011

Various neonatal symptoms can lead to a diagnosis of congenital CMV infection. We report two cases of persistent pulmonary hypertension in relation with congenital CMV infection following maternal primary infection and reinfection, respectively. Both infants had severe refractory hypoxemia, requiring high-frequency ventilation, inhaled nitric oxide and inotropic support. One of them required extracorporeal membrane oxygenation for five days. Ganciclovir therapy was attempted in the two cases on day 12 postnatal. One of the infant died on day 15 postnatal. The other survived and is developing uneventfully at 15 months of age.Conclusion: Neonatal persistent pulmonary hypertension can be the consequence of congenital CMV infection. Intensive respiratory support and IV ganciclovir are indicated in case of life-threatening condition.
Genetic Variability in Susceptibility to Occupational Respiratory Sensitization
Authors: Yucesoy Berran , Johnson Victor J.
Published: June 2011

Respiratory sensitization can be caused by a variety of substances at workplaces, and the health and economic burden linked to allergic respiratory diseases continues to increase. Although the main factors that affect the onset of the symptoms are the types and intensity of allergen exposure, there is a wide range of interindividual variation in susceptibility to occupational/environmental sensitizers. A number of gene variants have been reported to be associated with various occupational allergic respiratory diseases. Examples of genes include, but are not limited to, genes involved in immune/inflammatory regulation, antioxidant defenses, and fibrotic processes. Most of these variants act in combination with other genes and environmental factors to modify disease progression, severity, or resolution after exposure to allergens. Therefore, understanding the role of genetic variability and the interaction between genetic and environmental/occupational factors provides new insights into disease etiology and may lead to the development of novel preventive and therapeutic strategies. This paper will focus on the current state of knowledge regarding genetic influences on allergic respiratory diseases, with specific emphasis on diisocyanate-induced asthma and chronic beryllium disease.
Leaf Extracts of Calocedrus formosana (Florin) Induce G2/M Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells
Authors: Yuan Sheau-Yun , Lin Chi-Chen , Hsu Shih-Lan , Cheng Ya-Wen , Wu Jyh-Horng , Cheng Chen-Li , Yang Chi-Rei
Published: June 2011

Calocedrus formosana (Florin) bark acetone/ethylacetate extracts are known to exert an antitumor effect on some human cancer cell lines, but the mechanism is yet to be defined. The aim of this study was to determine the effects of Florin leaf methanol extracts on the growth and apoptosis of human bladder cancer cell lines. MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay showed that the growth of these bladder cancer cells was potently inhibited by the Florin leaf extracts. The cell cycle of these extract‐treated cells (TCCSUP cells) was arrested at the G2/M phase as determined by flow cytometry. Western blot analysis revealed the increases of cyclin B1 and Cdc2 kinase levels, alone with the decrease of phosphorylated Cdc2 kinase, after treating these cells with the extracts. An immunofluorescence assessment of β‐tubulin showed decreased levels of polymerized tubulin in treated cells. However, the proteolytic cleavage of poly ADP‐ribose polymerase and the activation of caspase‐3/‐8/‐9 were all increased upon treatments of extracts. The concurrent increase of Bax and decrease of Bcl‐2 levels indicated that the extracts could induce apoptosis in these treated cells. Taken together, these results suggest that the Florin leaf extracts may be an effective antibladder cancer agent.
Novel NoC Topology Construction for High-Performance Communications
Authors: Ezhumalai P. , Chilambuchelvan A. , Arun C.
Published: June 2011

Different intellectual property (IP) cores, including processor and memory, are interconnected to build a typical system-on-chip (SoC) architecture. Larger SoC designs dictate the data communication to happen over the global interconnects. Network-on-Chip(NoC) architectures have been proposed as a scalable solution to the global communication challenges in nanoscale systems-on-chip (SoC) design. We proposed an idea on building customizing synthesis network—on-chip with the better flow partitioning and also considered power and area reduction as compared to the already presented regular topologies. Hence to improve the performance of SoC, first, we did a performance study of regular interconnect topologies MESH, TORUS, BFT and EBFT, we observed that the overall latency and throughput of the EBFT is better compared to other topologies, The next best in case of latency and throughput is BFT. Experimental results on a variety of NoC benchmarks showed that our synthesis results were achieved reduction in power consumption and average hop count over custom topology implementation.
Anaplastic Thyroid Cancer: A Review of Epidemiology, Pathogenesis, and Treatment
Authors: Nagaiah Govardhanan , Hossain Akm , Mooney Colin J. , Parmentier James , Remick Scot C.
Published: June 2011

Anaplastic thyroid cancer (ATC) is an uncommon malignancy of the thyroid. Only 1-2% of thyroid cancers are anaplastic, but the disease contributes to 14–50% of the mortality with a median survival of 3 to 5 months. Most patients diagnosed with this disease are 65 years of age or older. The incidence of anaplastic thyroid cancer is decreasing worldwide. Most patients present with a rapidly growing neck mass, dysphagia, or voice change. We performed a comprehensive literature search using PubMed focusing on the treatment of anaplastic thyroid cancer including historical review of treatment and outcomes and investigations of new agents and approaches. A total of sixteen chart review and retrospective studies and eleven prospective studies and/or clinical trials were reviewed. The current standard therapeutic approach is to consider the disease as systemic at time of diagnosis and pursue combined modality therapy incorporating cytoreductive surgical resection where feasible and/or chemoradiation either concurrently or sequentially. Doxorubicin is the most commonly used agent, with a response rate of 22%. Several new agents are currently under investigation. Referral of patients for participation in clinical trials is needed.
NOD Dendritic Cells Stimulated withLactobacilliPreferentially Produce IL-10 versus IL-12 and Decrease Diabetes Incidence
Authors: Manirarora Jean N. , Parnell Sarah A. , Hu Yoon-Hyeon , Kosiewicz Michele M. , Alard Pascale
Published: June 2011

Dendritic cells (DCs) from NOD mice produced high levels of IL-12 that induce IFNγ-producing T cells involved in diabetes development. We propose to utilize the microorganism ability to induce tolerogenic DCs to abrogate the proinflammatory process and prevent diabetes development. NOD DCs were stimulated withLactobacilli(nonpathogenic bacteria targeting TLR2) or lipoteichoic acid (LTA) fromStaphylococcus aureus(TLR2 agonist). LTA-treated DCs produced much more IL-12 than IL-10 and accelerated diabetes development when transferred into NOD mice. In contrast, stimulation of NOD DCs withL. caseifavored the production of IL-10 over IL-12, and their transfer decreased disease incidence which anti-IL-10R antibodies restored. These data indicated thatL. caseican induce NOD DCs to develop a more tolerogenic phenotype via production of the anti-inflammatory cytokine, IL-10. Evaluation of the relative production of IL-10 and IL-12 by DCs may be a very useful means of identifying agents that have therapeutic potential.
Repeated Muscle Injury as a Presumptive Trigger for Chronic Masticatory Muscle Pain
Authors: Dessem Dean , Lovering Richard M.
Published: June 2011

skeletal muscles sustain a significant loss of maximal contractile force after injury, but terminally damaged fibers can eventually be replaced by the growth of new muscle (regeneration), with full restoration of contractile force over time. After a second injury, limb muscles exhibit a smaller reduction in maximal force and reduced inflammation compared with that after the initial injury (i.e., repeated bout effect). In contrast, masticatory muscles exhibit diminished regeneration and persistent fibrosis, after a single injury; following a second injury, plasma extravasation is greater than after a single injury and maximal force is decreased more than after the initial injury. Thus, masticatory muscles do not exhibit a repeated bout effect and are instead increasingly damaged by repeated injury. We propose that the impaired ability of masticatory muscles to regenerate contributes to chronic muscle pain by leading to an accumulation of tissue damage, fibrosis, and a persistent elevation and prolonged membrane translocation of nociceptive channels such as P2X3as well as enhanced expression of neuropeptides including CGRP within primary afferent neurons. These transformations prime primary afferent neurons for enhanced responsiveness upon subsequent injury thus triggering and/or exacerbating chronic muscle pain.
Ramsey Numbers for Theta Graphs
Authors: Jaradat M. M. M. , Bataineh M. S. A. , Radaideh S. M. E.
Published: June 2011

The graph Ramsey number is the smallest integer with the property
that any complete graph of at least vertices whose edges are colored with two colors
(say, red and blue) contains either a subgraph isomorphic to all of whose edges are
red or a subgraph isomorphic to all of whose edges are blue. In this paper, we
consider the Ramsey numbers for theta graphs. We determine , for
. More specifically, we establish that for .
Furthermore, we determine for . In fact, we establish that if is even, if is odd.
Domination Conditions for Families of Quasinearly Subharmonic Functions
Authors: Riihentaus Juhani
Published: June 2011

Domar has given a condition that ensures the existence of the largest subharmonic minorant of a
given function. Later Rippon pointed out that a modification of Domar′s argument gives in fact a better result.
Using our previous, rather general and flexible, modification of Domar′s original argument, we extend their
results both to the subharmonic and quasinearly subharmonic settings.
Early Responses to Intravitreal Ranibizumab in Typical Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Authors: Matsumiya Wataru , Honda Shigeru , Bessho Hiroaki , Kusuhara Sentaro , Tsukahara Yasutomo , Negi Akira
Published: June 2011

Purpose. To evaluate the early response to intravitreal ranibizumab (IVR) in two different phenotypes of age-related macular degenerations (AMD): typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV).Methods. Sixty eyes from 60 patients (tAMD 28, PCV 32 eyes) were recruited. Three consecutive IVR treatments (0.5 mg) were performed every month. Change in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT) was then compared between the tAMD and PCV groups.Results. The mean BCVA logMAR was significantly improved at month 1 and month 3 after the initial IVR in the tAMD group, but there was no change in the PCV group. Both phenotypes showed significant improvements in the CRT during the 3 months after the initial IVR. There were no significant differences in the improvements of the CRT in the tAMD versus the PCV group. In the stepwise analysis, a worse pretreatment BCVA and tAMD lesions were significantly beneficial for a greater improvement of BCVA at 3 months after the initial IVR.Conclusions. The phenotype of tAMD showed a significantly better early response to IVR than PCV in terms of BCVA improvement.
Terahertz Spectroscopy of Novel Superconductors
Authors: Lupi Stefano
Published: June 2011

Through the coupling of Synchrotron Radiation and Michelson interferometry, one may obtain in the terahertz (THz) range transmittance and reflectivity spectra with a signal-to-noise ratio (S/N) up to 103. In this paper we review the application of this spectroscopic technique to novel superconductors with an increasing degree of complexity: the single-gap boron-doped diamond; the isotropic multiband V3Si, where superconductivity opens two gaps at the Fermi energy; the CaAlSi superconductor, isostructural to MgB2, with a single gap in the hexagonal ab plane and two gaps along the orthogonalcaxis.
Partial Sums of Generalized Class of Analytic Functions Involving Hurwitz‐Lerch Zeta Function
Authors: Murugusundaramoorthy G. , Uma K. , Darus M.
Published: June 2011

Let be the sequence of partial sums of the analytic function . In this paper, we determine sharp lower bounds for and . The usefulness of the main result not
only provides the unification of the results discussed in the literature but also generates certain
new results.
Remote Synchronization Experiments for Quasi-Zenith Satellite System Using Multiple Navigation Signals as Feedback Control
Authors: Iwata Toshiaki , Matsuzawa Takashi , Machita Kumiko , Abei Akiyoshi
Published: June 2011

The remote synchronization system for the onboard crystal oscillator (RESSOX) is a remote control method that permits synchronization between a ground station atomic clock and Japanese quasi-zenith satellite system (QZSS) crystal oscillators. To realize the RESSOX of the QZSS, the utilization of navigation signals of QZSS for feedback control is an important issue. Since QZSS transmits seven navigation signals (L1C/A, L1CP, L1CD, L2CM, L2CL, L5Q, and L5I), all combinations of these signals should be evaluated. First, the RESSOX algorithm will be introduced. Next, experimental performance will be demonstrated. If only a single signal is available, ionospheric delay should be input from external measurements. If multiple frequency signals are available, any combination, except for L2 and L5, gives good performance with synchronization error being within two nanoseconds that of RESSOX. The combination of L1CD and L5Q gives the best synchronization performance (synchronization error within 1.14 ns). Finally, in the discussion, comparisons of long-duration performance, computer simulation, and sampling number used in feedback control are considered. Although experimental results do not correspond to the simulation results, the tendencies are similar. For the overlapping Allan deviation of long duration, the stability of 1.23×10−14 at 100,160 s is obtained.
Lack of Restorationin Vivoby K+-Channel Modulators of Jejunal Fluid Absorption after Heat StableEscherichia coliEnterotoxin (STa) Challenge
Authors: Lucas M. L. , Gilligan L. C. , Whitelaw C. C. , Wynne P. J. , Morrison J. D.
Published: June 2011

Enhanced potassium ion permeability at the enterocyte basolateral membrane is assumed to facilitate sustained chloride ion and fluid secretion into the intestinal lumen during episodes of secretory diarrhoeal disease. To examine this conceptin vivo, two potassium ion channel blockers and a channel opener were coperfused withE. coliheat stable STa enterotoxin to determine whether such compounds improved or worsened the inhibited fluid absorption. In the STa (80 ng/mL) challenged jejunal loop, the fluid absorption rate of28.6 ± 5.8(14) μL/cm/hr was significantly below (P<.001) the normal rate of98.8 ± 6.2(17) μL/cm/hr. Intraluminal (300 uM) glibenclamide added to STa perfused loops failed to improve the inhibited fluid absorption rate, which was7.4 ± 3.2(6) μL/cm/hr on coperfusion with STa. Similarly, on coperfusion with 30 uM clotrimazole, the fluid absorption rate with STa present remained inhibited at11.4 ± 7.0(4) μL/cm/hr. On coperfusion with intraluminal 1 uM cromakalim, STa reduced fluid absorption significantly (P<.02) to24.7 ± 8.0(10) μL/cm/hr, no different from STa challenge in the absence of cromakalim. Infusion i.v. with these agents also failed to restore fluid absorption after STa challenge. These observations do not support the proposed potassium ion permeability event as a necessary corollary of enterotoxin-mediated secretion. This makes it unlikely that modulators of such permeability prevent enterocyte secretion in diarrhoeal disease.
Real-Time Monitoring System and Advanced Characterization Technique for Civil Infrastructure Health Monitoring
Authors: Bennett V. , Abdoun T. , Zeghal M. , Koelewijn A. , Barendse M. , Dobry R.
Published: June 2011

Real-time monitoring of civil infrastructure provides valuable information to assess the health and condition of the associated systems. This paper presents the recently developed shape acceleration array (SAA) and local system identification (SI) technique, which constitute a major step toward long-term effective health monitoring and analysis of soil and soil-structure systems. The SAA is based on triaxial micro-electro-mechanical system (MEMS) sensors to measure in situ deformation (angles relative to gravity) and dynamic accelerations up to a depth of one hundred meters. This paper provides an assessment of this array's performance for geotechnical instrumentation applications by reviewing the recorded field data from a bridge replacement site and a full-scale levee test facility. The SI technique capitalizes on the abundance of static and dynamic measurements from the SAA. The geotechnical properties and constitutive response of soil contained within a locally instrumented zone are analyzed and identified independently of adjacent soil strata.
Molecular Dynamics Simulation of the Clustering of Minor Lead Additives in Liquid Sodium
Authors: Shimkevich Alexander L. , Shimkevich Inessa Yu.
Published: June 2011

A strong influence of minor lead additives on the liquid sodium microstructure is revealed in the molecular dynamics (MD) simulation of the Na0.98Pb0.02 alloy. The obtained results can be explained by the existence of lead-sodium clusters in liquid sodium built up by ionic bonds, Na+–Pb−, due to essential distinction of the alloy components in the electronegativity. On this reason, MD simulation of the Na0.98Pb0.02 alloy is carried out within the framework of a three-component bipolar model, Na + Na+ + Pb−, with Na↔Na+ recharging the nearest-neighbor particles of solvent in every 3 ps (an optimal period) during the numerical run.
Building Automation Networks for Smart Grids
Authors: Yi Peizhong , Iwayemi Abiodun , Zhou Chi
Published: June 2011

Smart grid, as an intelligent power generation, distribution, and control system, needs various communication systems to meet its requirements. The ability to communicate seamlessly across multiple networks and domains is an open issue which is yet to be adequately addressed in smart grid architectures. In this paper, we present a framework for end-to-end interoperability in home and building area networks within smart grids. 6LoWPAN and the compact application protocol are utilized to facilitate the use of IPv6 and Zigbee application profiles such as Zigbee smart energy for network and application layer interoperability, respectively. A differential service medium access control scheme enables end-to-end connectivity between 802.15.4 and IP networks while providing quality of service guarantees for Zigbee traffic over Wi-Fi. We also address several issues including interference mitigation, load scheduling, and security and propose solutions to them.
Nanostructures for Enhanced Light Absorption in Solar Energy Devices
Authors: Edman Jonsson Gustav , Fredriksson Hans , Sellappan Raja , Chakarov Dinko
Published: June 2011

The fascinating optical properties of nanostructured materials find important applications in a number of solar energy utilization schemes and devices. Nanotechnology provides methods for fabrication and use of structures and systems with size corresponding to the wavelength of visible light. This opens a wealth of possibilities to explore the new, often of resonance character, phenomena observed when the object size and the electromagnetic field periodicity (light wavelengthλ) match. Here we briefly review the effects and concepts of enhanced light absorption in nanostructures and illustrate them with specific examples from recent literature and from our studies. These include enhanced optical absorption of composite photocatalytically active TiO2/graphitic carbon films, systems with enhanced surface plasmon resonance, field-enhanced absorption in nanofabricated carbon structures with geometrical optical resonances and excitation of waveguiding modes in supported nanoparticle assembles. The case of Ag particles plasmon-mediated chemistry of NO on graphite surface is highlighted to illustrate the principle of plasmon-electron coupling in adsorbate systems.
New Evaluation Technique for WTG Design Wind Speed Using a CFD‐Model‐Based Unsteady Flow Simulation with Wind Direction Changes
Authors: Uchida Takanori , Maruyama Takashi , Ohya Yuji
Published: June 2011

Because a significant portion of the topography in Japan is characterized by steep, complex terrain, which results in a complex spatial distribution of wind speed, great care is necessary for selecting a site for the construction of wind turbine generators (WTG). We have developed a CFD model for unsteady flow called RIAM‐COMPACT (Research Institute for Applied Mechanics, Kyushu University, computational prediction of airflow over complex terrain). The RIAM‐COMPACT CFD model is based on large eddy simulation (LES). The computational domain of RIAM‐COMPACT can extend from several meters to several kilometers, and RIAM‐COMPACT can predict airflow and gas diffusion over complex terrain with high accuracy. The present paper proposes a technique for evaluating the deployment location of a WTG. The proposed technique employs the RIAM‐COMPACT CFD model and simulates a continuous wind direction change over 360 degrees.
Biliary Complications Post Laparoscopic Cholecystectomy: Mechanism, Preventive Measures, and Approach to Management: A Review
Authors: Machado Norman Oneil
Published: June 2011

Laparoscopic cholecystectomy has emerged as a gold standard therapeutic option for the management of symptomatic cholelithiasis. However, adaptation of LC is associated with increased risk of complications, particularly bile duct injury ranging from 0.3 to 0.6%. Occurrence of BDI results in difficult reconstruction, prolonged hospitalization, and high risk of long-term complications. Therefore, more emphasis is placed on preventing these complications. In addition to adequate training, several techniques have been proposed to prevent bile duct injury including use of 30∘ scope, adequate delineation of structures in Calot's triangle (critical view), avoidance of diathermy close to common hepatic duct, and intraoperative cholangiogram, and to maintain a low threshold to conversion to open approach when uncertain. Management of Bile duct injury depends on the nature of injury, time of detection, and the expertise available, and would range from simple subhepatic drainage to Roux-en-Y hepaticojejunostomy particularly performed at specialised centers. This article based on the literature review aims to review the biliary complications following laparoscopic cholecystectomy with reference to its mechanism , preventive measures to be taken, and the management approach.
Spatial Variation in General Medical Services Income in Dublin General Practitioners
Authors: Teljeur Conor , Kelly Alan , O'Dowd Tom
Published: June 2011

The general medical services (GMS) scheme provides care free at the point of use for the 30% most economically deprived section of the population and the elderly. Almost all people of over-70-year olds are eligible for the GMS scheme potentially directing resources away from those most in need. The aim of this study is to analyse the relationship between practice GMS income and deprivation amongst Dublin-based general practitioners (GPs).
The practice GMS income in Dublin was analysed in relation to practice characteristics including the number of GPs, catchment area population, proportion of over-70-year olds in the catchment area, catchment deprivation, number of GMS GPs within 2 km, and average GMS practice income within 2 km.
Practice GMS income was highest in deprived areas but is also a valuable source of income in the least deprived areas. The capitation rate for over-70-year olds provides an incentive for GPs to locate in affluent areas and potentially directs resources away from those in greater need.
Review of Vortices in Wildland Fire
Authors: Forthofer Jason M. , Goodrick Scott L.
Published: June 2011

Vortices are almost always present in the wildland fire environment and can sometimes interact with the fire in unpredictable ways, causing extreme fire behavior and safety concerns. In this paper, the current state of knowledge of the interaction of wildland fire and vortices is examined and reviewed. A basic introduction to vorticity is given, and the two common vortex forms in wildland fire are analyzed: fire whirls and horizontal roll vortices. Attention is given to mechanisms of formation and growth and how this information can be used by firefighters.
Existence of Positive Solutions for m‐Point Boundary Value Problem for Nonlinear Fractional Differential Equation
Authors: El-Shahed Moustafa , Shammakh Wafa M.
Published: June 2011

We investigate an m‐point boundary value problem for nonlinear fractional differential equations. The associated Green function for the boundary value problem is given at first, and some useful properties of the Green function are obtained. By using the fixed point theorems of cone expansion and compression of norm type and Leggett‐Williams fixed point theorem, the existence of multiple positive solutions is obtained.
Changes in Herbaceous Species Composition in the Absence of Disturbance in aCenchrus biflorusRoxb. Invaded Area in Central Kalahari Game Reserve, Botswana
Authors: Makhabu Shimane W. , Marotsi Balisana
Published: June 2011

A-nine year study was carried out to investigate changes in herbaceous species composition in an area invaded byCenchrus biflorusRoxb, an exotic invader grass species. The study ensued termination of livestock and human activities in the area when residents of the area were relocated to another area. Vegetation characteristics from the disturbed sites (previous occupied areas) and undisturbed sites (previously unoccupied areas) were determined. The results show thatC. biflorushas high tolerance to disturbance. It comprised the larger proportion of grasses in disturbed sites at the inception of the study. However, it decreased in abundance with time in disturbed areas and was absent in the undisturbed areas, suggesting that its ability to invade undisturbed sites is limited. Perennial species successfully reestablished on the third year after termination of disturbance. The study reveals thatC. biflorusinvasion in the Kalahari ecosystem can be controlled by termination of disturbances.
DTI and MR Volumetry of Hippocampus-PC/PCC Circuit: In Search of Early Micro- and Macrostructural Signs of Alzheimers's Disease
Authors: Palesi F. , Vitali P. , Chiarati P. , Castellazzi G. , Caverzasi E. , Pichiecchio A. , Colli-Tibaldi E. , D'Amore F. , D'Errico I. , Sinforiani E. , Bastianello S.
Published: June 2011

Hippocampal damage, by DTI or MR volumetry, and PET hypoperfusion of precuneus/posterior cingulate cortex (PC/PCC) were proposed as biomarkers of conversion from preclinical (MCI) to clinical stage of Alzheimer's disease (AD). This study evaluated structural damage, by DTI and MR volumetry, of hippocampi and tracts connecting hippocampus to PC/PCC (hipp-PC/PCC) in 10 AD, 10 MCI, and 18 healthy controls (CTRL). Normalized volumes, mean diffusivity (MD), and fractional anisotropy (FA) were obtained for grey matter (GM), white matter (WM), hippocampi, PC/PCC, and hipp-PC/PCC tracts. In hippocampi and hipp-PC/PCC tracts, decreased volumes and increased MD were found in AD versus CTRL (P<.001). The same results with lower significance (P<.05) were found in MCI versus CTRL. Verbal memory correlated (P<.05) in AD with left hippocampal and hipp-PC/PCC tract MD, and in MCI with FA of total WM. Both DTI and MR volumetry of hippocampi and hipp-PC/PCC tracts detect early signs of AD in MCI patients.
Copaiba Oil: An Alternative to Development of New Drugs against Leishmaniasis
Authors: dos Santos Adriana Oliveira , Ueda-Nakamura Tânia , Dias Filho Benedito Prado , da Veiga Junior Valdir Florêncio , Nakamura Celso Vataru
Published: June 2011

Leishmaniasis is a neglected disease that is increasing globally at an alarming rate. Glucantime has been the therapy of choice for more than 50 years. A recent study reported the antileishmanial activity of copaiba oil againstLeishmania amazonensis. These results led us to investigate morphological and ultrastructural changes inL. amazonensistreated with copaiba oil, using electron microscopy and flow cytometry to assess specific organelles as targets for copaiba oil. In the promastigote and axenic amastigote forms, this copaiba oil caused notable morphological and ultrastructural changes, including extensive mitochondrial damage and denaturation of the plasma membrane. Copaiba oil treatment also induced a decrease in Rh123 fluorescence, suggesting interference with the mitochondrial membrane potential and loss of cell viability with an increase in plasma membrane permeability, as observed by flow cytometry after staining with propidium iodide. In conclusion, copaiba oil could be exploited for the development of new antileishmanial drugs.
Combining Betulinic Acid and Mithramycin A Effectively Suppresses Pancreatic Cancer by Inhibiting Proliferation, Invasion, and Angiogenesis
Authors: Gao Yong , Jia Zhiliang , Kong Xiangyu , Li Qiang , Chang David Z. , Wei Daoyan , Le Xiangdong , Suyun Huang , Huang Shengdong , Wang Liwei , Xie Keping
Published: June 2011

Both betulinic acid (BA) and mithramycin A (MIT) exhibit potent antitumor activity through distinct mechanisms of Sp1 inhibition. However, it is unknown whether a combination of these two compounds results in a synergistic inhibitory effect on pancreatic cancer growth and/or has a therapeutic advantage over gemcitabine. In xenograft mouse models of human pancreatic cancer, treatment with either BA or MIT alone showed dose-dependent antitumor activity but led to systemic side effects as measured by overall weight loss. Treatment with a nontoxic dose of either compound alone had only marginal antitumor effects. Importantly, combination treatment with nontoxic doses of BA and MIT produced synergistic antitumor activity, including inhibitory effects on cell proliferation, invasion, and angiogenesis. The treatment combination also produced less discernible side effects than therapeutic doses of gemcitabine. Moreover, combined treatment of BA and MIT resulted in drastic inhibition of Sp1 recruitment onto Sp1 and VEGF promoters, leading to transcriptional inhibition of both Sp1 and VEGF and downregulation of Sp1 and VEGF protein expression. Ectopic overexpression of Sp1 rendered tumor cells resistant to BA, MIT, and the combination of the two. Overall, our findings argue that Sp1 is an important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer. Cancer Res; 71(15); 5182–93. ©2011 AACR.
FDG-PET as a Potential Tool for Selecting Patients with Advanced Non–Small Cell Lung Cancer Who May Be Spared Maintenance Therapy after First-Line Chemotherapy
Authors: Yoon Dok Hyun , Baek Sora , Choi Chang-Min , Lee Dae Ho , Suh Cheolwon , Ryu Jin-Sook , Moon Dae Hyuk , Lee Jung Shin , Kim Sang-We
Published: June 2011

Purpose: To investigate whether 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) may be a potential tool to select a subgroup of patients who might be spared maintenance treatment, if the metabolic response after first-line chemotherapy could predict time-to-progression (TTP).

Experimental Design: A total of 43 patients who underwent baseline FDG-PET scan and did not show disease progression (DP) after 4 cycles of first-line chemotherapy were enrolled and underwent second FDG-PET 3 weeks after completion of the first-line chemotherapy. The primary endpoint was to compare percent decrease in maximum standard uptake value (SUVmax) between early (TTP after second PET examination <8 weeks) and late (TTP ≥8 weeks) DP subgroups. Secondary endpoints were to determine whether fractional decrease in SUVmax could predict TTP and overall survival (OS), both calculated from the date of the second FDG-PET.

Results: Percent decreases in SUVmax in late DP subgroup were greater than those in early DP subgroup (mean reduction, 54.7% ± 27.2% vs. 27.8% ± 46.8%, P = 0.021). Receiver operating characteristic curves identified a 50.0% decrease in SUVmax as the optimal threshold to distinguish these subgroups. Using this value as the cutoff resulted in a positive predictive value of 82.6% and negative predictive value of 60.0% in predicting TTP ≥8 weeks. Patients with SUVmax decrease <50% had significantly longer median TTP (3.0 vs. 1.5 months, P = 0.001) and OS (not reached vs. 14.2 months, P = 0.003).

Conclusions: Fractional decrease in SUVmax of the main lesion after completion of 4 cycles of chemotherapy may discriminate patients with TTP ≥8 weeks and predict TTP and OS in patients with advanced NSCLC. Clin Cancer Res; 17(15); 5093–100. ©2011 AACR.
Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma
Authors: Kubo Takafumi , Toyooka Shinichi , Tsukuda Kazunori , Sakaguchi Masakiyo , Fukazawa Takuya , Soh Junichi , Asano Hiroaki , Ueno Tsuyoshi , Muraoka Takayuki , Yamamoto Hiromasa , Nasu Yasutomo , Kishimoto Takumi , Pass Harvey I. , Matsui Hideki , Huh Nam-ho , Miyoshi Shinichiro
Published: June 2011

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.

Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.

Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2′-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c–transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G1 cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.

Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965–74. ©2011 AACR.
Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors
Authors: Kummar Shivaani , Raffeld Mark , Juwara Lamin , Horneffer Yvonne , Strassberger Agnes , Allen Deborah , Steinberg Seth M. , Rapisarda Annamaria , Spencer Shawn D. , Figg William D. , Chen Xiaohong , Turkbey Ismail Baris , Choyke Peter , Murgo Anthony J. , Doroshow James H. , Melillo Giovanni
Published: June 2011

Purpose: Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan.

Experimental Design: Topotecan was administered orally at 1.6 mg/m2 once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment.

Results: Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m2/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1α nuclear staining became undetectable after treatment (7.5%–50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1α in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI.

Conclusions: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α showed that topotecan could decrease HIF-1α expression in advanced solid tumors. Clin Cancer Res; 17(15); 5123–31. ©2011 AACR.
Phenotypic Characterisation of the Inner and Outer Myometrium in Normal and Adenomyotic Uteri
Authors: Mehasseb Mohamed Khairy , Bell Stephen Charles , Brown Laurence , Pringle James Howard , Habiba Marwan
Published: June 2011

Background and Aim: To study the characteristics of the inner (IM) and outer (OM) myometrium in the presence and absence of uterine adenomyosis. Methods: Case control blinded comparison carried out in a university department. Morphometric features of the myometrium were studied in uteri from pre- and postmenopausal women with and without uterine adenomyosis as the sole pathology. Uteri were also divided according to the phase of the cycle and examined using immunohistochemistry and image analysis. Results: Cell density and total nuclear area were statistically significantly greater in the IM compared to OM, in pre- and postmenopausal women, in both the adenomyosis and control uteri. The difference in nuclear size was statistically significant only in the premenopausal group. The change from the IM to the OM in cell density and total nuclear area was gradual with no distinct zonation. Examined features did not vary with cycle phase. Both the IM and OM in adenomyosis exhibited lower cell density and larger nuclei compared to controls. In adenomyosis, immunostaining for α-smooth muscle actin, desmin and Ki-67 was consistent with myometrial hyperplasia and hypertrophy. Conclusions: There are clear differences between the IM and the OM but the transition is gradual, with no distinct zonation. Adenomyosis is characterised by reduced cell density, and increased nuclear size and features of hyperplasia and hypertrophy that are not confined to the IM.
Decline in Human Fertility Rates with Male Age: A Consequence of a Decrease in Male Fecundity with Aging?
Authors: Matorras Roberto , Matorras Francisco , Expósito Antonia , Martinez Lorea , Crisol Lorena
Published: June 2011

Background: The objective of this study is to investigate the influence of male age on human fertility, defined as the birth rate for a given population. Methods: Data from the Spanish National Statistics Institute (INE) for the year 2004 from a total of 454,753 newborn infants and sorted by male and female age groups were evaluated. In order to correct the influence of female age-related fertility, a different analysis was performed considering only women under 30 years of age. Results: From a demographic point of view, male fertility started to decline at 35–39 years of age. This decline is constant and follows an exponential pattern (slope –0.11 to –0.12). The trend persisted when the data were adjusted for every 1,000 men in the age group, as well as when only women under the age of 30 were considered. Male fertility showed a 21–23% annual decrease starting at the age of 39. Conclusion: An exponential decrease in human fertility which is independent of the woman’s age was observed with male aging. This decay is probably due to a downfall in male fecundity, closely related to a decline in sperm quality. However, social or behavioral causes for this trend cannot be excluded.
Cadmium Chloride Induces the Expression of Metallothionein mRNA by Endometrial Stromal Cells and Amnion-Derived (WISH) Cells
Authors: Kawano Yasushi , Furukawa Yuichi , Kawano Yukie , Abe Wakana , Hirakawa Tomoko , Narahara Hisashi
Published: June 2011

Background: Metallothionein (MT) is known to bind to metals with high affinity. The potential for MT-1 mRNA expression in endometrial stromal cells (ESC) and amniotic cells in response to cytokines and cadmium chloride (CdCl2) was evaluated. Methods: Human ESC were cultured and treated with interleukin-1α, 12-O-tetradecanoylphobol 13-acetate (TPA), forskolin, transforming growth factor-β, and CdCl2. Amnion-derived (WISH) cells were also cultured and treated with the same reagents. The levels of MT mRNA were evaluated by Northern blot analysis in ESC and WISH cells. Results: In response to treatment with CdCl2 (0.01–10 µM), the expression of MT mRNA markedly increased in ESC and WISH cells in a dose-dependent manner. On the other hand, the expression of MT mRNA did not increase after treatment with interleukin-1α (1 nM), TPA (10 nM), forskolin (1 µM) or transforming growth factor-β (1 nM) in these cells. Conclusion: These findings indicate that MT expression in ESC and WISH cells is sensitive to the CdCl2 concentration, which is known to be evaluated in cigarette smokers. The present results suggest that increased levels of MT may affect metal metabolism at the feto-maternal interface.
Are Minimally Invasive Procedures Harder to Acquire than Conventional Surgical Procedures?
Authors: Hiemstra Ellen , Kolkman Wendela , le Cessie Saskia , Jansen Frank Willem
Published: June 2011

Background: It is frequently suggested that minimally invasive surgery (MIS) is harder to acquire than conventional surgery. To test this hypothesis, residents’ learning curves of both surgical skills are compared. Methods: Residents had to be assessed using a general global rating scale of the OSATS (Objective Structured Assessment of Technical Skills) for every procedure they performed as primary surgeon during a 3-month clinical rotation in gynecological surgery. Results: Nine postgraduate-year-4 residents collected a total of 319 OSATS during the 2 years and 3 months investigation period. These assessments concerned 129 MIS (laparoscopic and hysteroscopic) and 190 conventional (open abdominal and vaginal) procedures. Learning curves (in this study defined as OSATS score plotted against procedure-specific caseload) for MIS and conventional surgery were compared using a linear mixed model. The MIS curve revealed to be steeper than the conventional curve (1.77 vs. 0.75 OSATS points per assessed procedure; 95% CI 1.19–2.35 vs. 0.15–1.35, p < 0.01). Conclusions: Basic MIS procedures do not seem harder to acquire during residency than conventional surgical procedures. This may have resulted from the incorporation of structured MIS training programs in residency. Hopefully, this will lead to a more successful implementation of the advanced MIS procedures.
The Syndrome of Inappropriate Antidiuresis: Pathophysiology, Clinical Management and New Therapeutic Options
Authors: Esposito Pasquale , Piotti Giovanni , Bianzina Stefania , Malul Yehuda , Dal Canton Antonio
Published: June 2011

Hyponatremia is a marker of different underlying diseases and it can be a cause of morbidity itself; this implies the importance of a correct approach to the problem. The syndrome of inappropriate antidiuresis (SIAD) is one of the most common causes of hyponatremia: it is a disorder of sodium and water balance characterized by urinary dilution impairment and hypotonic hyponatremia, in the absence of renal disease or any identifiable non-osmotic stimulus able to induce antidiuretic hormone (ADH) release; according to its definition, it is diagnosed through an exclusion algorithm. SIAD is usually observed in hospitalized patients and its prevalence may be as high as 35%. The understanding of the syndrome has notably evolved over the last years, as reflected by the significant change in the name, once the syndrome of inappropriate secretion of ADH (SIADH), today SIAD. This review is up to date and it analyses the newest notions about pathophysiological mechanisms, classification, management and therapy of SIAD, including vaptans.
Expression of Transgelin in Human Glomerulonephritis of Various Etiology
Authors: Gerolymos M. , Karagianni F. , Papasotiriou M. , Kalliakmani P. , Sotsiou F. , Charonis A. , Goumenos D.S.
Published: June 2011

Background/Aims: Activation of myofibroblasts occurs during kidney injury. Genomic and proteomic studies suggest that transgelin represents a protein that may be involved in renal injury. The purpose of this study was to estimate transgelin expression in the renal tissue of patients with glomerulonephritis. Methods: Transgelin was identified in biopsy sections of 67 patients by immunohistochemistry and immunofluorescence. Its distribution was compared to that of α-smooth muscle actin (α-SMA), a marker of myofibroblast activation in the kidney. Results: Transgelin and α-SMA expression was identified within glomeruli and interstitium. In patients with IgA nephropathy and focal segmental glomerulosclerosis, glomerular expression of transgelin was higher than that of α-SMA. The extent of transgelin immunostaining was related to mesangial proliferation (p = 0.034), glomerular sclerosis (p = 0.035), interstitial fibrosis (p = 0.047) and to the clinical course (p = 0.009). Colocalization studies showed that in some areas of kidney tissue both proteins were expressed with comparable intensity, whereas in other areas expression of either transgelin or α-SMA was predominant. Conclusion: Strong transgelin expression was observed in renal tissue of patients with glomerulonephritis. The observed differences in the pattern of transgelin and α-SMA expression suggest that either different subpopulations of myofibroblasts exist, or that these proteins are activated at different stages of renal injury/scarring.
Meta-Analysis of Homogeneous Subgroups Reveals Association between PDE4D Gene Variants and Ischemic Stroke
Authors: Yoon Dankyu , Park Sue K. , Kang Daehee , Park Taesung , Park Ji Wan
Published: June 2011

Background: An Icelandic study showed a significant positive association between phosphodiesterase 4D (PDE4D) gene variants and stroke. However, subsequent studies reported conflicting results, possibly due to small sample sizes and the heterogeneity of the studies. Method: We performed a meta-analysis on 6 SNPs of the PDE4D gene to investigate the association between this gene and ischemic stroke by integrating the results of previous studies, comprising 11,834 cases and 15,233 controls. A pooled genotypic odds ratio (OR) for each SNP was determined under 3 genetic models (i.e. dominant, recessive, and codominant) using both fixed- and random-effects models with consideration for heterogeneity and publication bias across studies. Results: Among the SNPs included in this study, SNP56 (rs702553) showed the most significant association with ischemic stroke in a meta-analysis comprised of 7 homogenous studies. The overall OR of the TT genotype compared to the AA genotype was 1.29 (95% CI 1.03–1.61; p = 0.022). For SNP83 (rs966221), a protective effect of the ancestral allele T was observed only in Asian populations (ORTT 0.79, 95% CI 0.69–0.90; p = 0.0005). This meta-analysis revealed a significant association of PDE4D gene variants with the risk of ischemic stroke, and further investigations are warranted to evaluate possible ethnic-specific effects.