bluuebunny/crossref_metadata_2025 huggingface dataset:
Invasion of human aortic endothelial cells by oral viridans group streptococci and induction of inflammatory cytokine production
Authors: Nagata E. , de Toledo A. , Oho T.
Published: December 2010

Oral viridans group streptococci are the major commensal bacteria of the supragingival oral biofilm and have been detected in human atheromatous plaque. Atherosclerosis involves an ongoing inflammatory response, reportedly involving chronic infection caused by multiple pathogens. The aim of this study was to examine the invasion of human aortic endothelial cells (HAECs) by oral viridans group streptococci and the subsequent cytokine production by viable invaded HAECs. The invasion of HAECs by bacteria was examined using antibiotic protection assays and was visualized by confocal scanning laser microscopy. The inhibitory effects of catalase and cytochalasin D on the invasion of HAECs were also examined. The production of cytokines by invaded or infected HAECs was determined using enzyme‐linked immunosorbent assays, and a real‐time polymerase chain reaction method was used to evaluate the expression of cytokine messenger RNA. The oral streptococci tested were capable of invading HAECs. The number of invasive bacteria increased with the length of the co‐culture period. After a certain co‐culture period, some organisms were cytotoxic to the HAECs. Catalase and cytochalasin D inhibited the invasion of HAECs by the organism. HAECs invaded by Streptococcus mutans Xc, Streptococcus gordonii DL1 (Challis), Streptococcus gordonii ATCC 10558 and Streptococcus salivarius ATCC 13419 produced more cytokine(s) (interleukin‐6, interleukin‐8, monocyte chemoattractant protein‐1) than non‐invaded HAECs. The HAECs invaded by S. mutans Xc produced the largest amounts of cytokines, and the messenger RNA expression of cytokines by invaded HAECs increased markedly compared with that by non‐invaded HAECs. These results suggest that oral streptococci may participate in the pathogenesis of atherosclerosis.
Forces and Surface Pressure on a Blade Moving in Front of the Admission Region
Authors: Cho Soo-Yong , Cho Chong-Hyun , Ahn Kook-Young , Kim Young-Cheol
Published: December 2010

The partial admission technique is widely used to control the output power of turbines. In some cases, it has more merits than full admission. However, additional losses, such as expansion, mixing, or pumping, are generated in partial admission as compared with full admission. Thus, an experiment was conducted in a linear cascade apparatus having a partial admission region in order to investigate the effect of partial admission on a blade row. The admission region was formed by a spouting nozzle installed at the inlet of the linear cascade apparatus. Its cross section was rectangular and its size is 200×200 mm2. The tested blade was axial-type and its chord was 200 mm. Nineteen identical blades were applied to the linear cascade for the partial admission experiment. The blades moved along the rotational direction in front of the admission region, and then operating forces and surface pressures on the blades were measured at the steady state. The experiment was conducted at a Reynolds number of 3×105 based on the chord. The nozzle flow angle was set to 65 deg with a solidity of 1.38 for performance test at the design point. In addition, another two different solidities of 1.25 and 1.67 were applied. From the experimental results, when the solidity was decreased, the maximum rotational force increased but the maximum axial force decreased.
Mechanics of Indentation into Micro- and Nanoscale Forests of Tubes, Rods, or Pillars
Authors: Wang Lifeng , Ortiz Christine , Boyce Mary C.
Published: December 2010

The force-depth behavior of indentation into fibrillar-structured surfaces such as those consisting of forests of micro- or nanoscale tubes or rods is a depth-dependent behavior governed by compression, bending, and buckling of the nanotubes. Using a micromechanical model of the indentation process, the effective elastic properties of the constituent tubes or rods as well as the effective properties of the forest can be deduced from load-depth curves of indentation into forests. These studies provide fundamental understanding of the mechanics of indentation of nanotube forests, showing the potential to use indentation to deduce individual nanotube or nanorod properties as well as the effective indentation properties of such nanostructured surface coatings. In particular, the indentation behavior can be engineered by tailoring various forest features, where the force-depth behavior scales linearly with tube areal density (m, number per unit area), tube moment of inertia (I), tube modulus (E), and indenter radius (R) and scales inversely with the square of tube length (L2), which provides guidelines for designing forests whether to meet indentation stiffness or for energy storage applications in microdevice designs.
Coupled Interfacial Energy and Temperature Effects on Size-Dependent Yield Strength and Strain Hardening of Small Metallic Volumes
Authors: Abu Al-Rub Rashid K. , Faruk Abu N. M.
Published: December 2010

Plasticity in heterogeneous metallic materials with small volumes is governed by the interactions of dislocations at interfaces. In particular, interfaces of a material confined in a small volume can strongly affect the mechanical properties of micro and nanosystems. In this paper, the framework of higher-order strain gradient plasticity theory with interfacial energy effect is used to investigate the coupling of interfacial energy with temperature and how it affects the initial yield strength (i.e., onset of plasticity) and the strain hardening rates of confined small metallic volumes. It is postulated that the interfacial energy decreases as temperature increases such that size effect decreases as temperature increases. As an application, the size effect of thermal loading of a film-substrate system is investigated. It is shown that the temperature at which the film starts to yield plastically is size-dependent, which is attributed to the size-dependent yield strength. Furthermore, the flow stress is more temperature sensitive as the size decreases.
Dynamic Characteristics of Aerostatic Porous Journal Bearings With a Surface-Restricted Layer
Authors: Otsu Yuta , Miyatake Masaaki , Yoshimoto Shigeka
Published: December 2010

Aerostatic porous bearings have been successfully applied to various precision devices such as machine tools and measuring equipment to achieve a higher accuracy of motion. However, aerostatic porous bearings have a disadvantage in that they are prone to cause pneumatic hammer instability. Therefore, to avoid this instability, a surface-restricted layer that has permeability smaller than the bulk of the porous material is usually formed on the bearing surface. In this paper, the dynamic characteristics of aerostatic porous journal bearings that have a surface-restricted layer are investigated numerically and experimentally. The effects of permeability in bulk porous materials and of a surface-restricted layer on the bearing characteristics are discussed using two kinds of porous material: graphite and metal. It was confirmed that aerostatic porous metal bearings with relatively large permeability could achieve large values of dynamic stiffness and damping coefficients using a low permeability, surface-restricted layer.
Investigation of Effect of Creep Strain on Low-Cycle Fatigue of Lead-Free Solder by Cyclic Loading Using Stepped Ramp Waves
Authors: Ohguchi Ken-ichi , Sasaki Katsuhiko
Published: December 2010

The fatigue life of a material varies with the strain rate if it has time-dependent deformation. An interesting phenomenon related to the effect of the strain rate on the fatigue life can be observed when a cyclic tension-compression loading of which strain rate in the tensile region is different from that in the compressive region is employed for the fatigue test. Different fatigue lives due to different strain rates in the tensile and compression regions originate from the difference of development behaviors of creep strain generated in the cyclic loading. This paper investigates the effects of creep strain on the difference of fatigue life due to the different strain rate in the tensile and compression regions. The creep strain of the lead-free solder Sn–3.0Ag–0.5Cu subjected to a cyclic loading was investigated using stepped ramp wave loading. The experimental results reveal that the creep strain develops differently in the tensile and compression regions. A new parameter is proposed for estimating fatigue life when the strain rate varies in the loading direction.
Large Variations in Southern Hemisphere Biomass Burning During the Last 650 Years
Authors: Wang Z. , Chappellaz J. , Park K. , Mak J. E.
Published: December 2010

Burn, Baby, Burn

The atmospheric trace gas, carbon monoxide, has important effects on methane and on ozone, and is important both in atmospheric chemistry and for its indirect influence on climate. Little is known about the abundance and sources of CO prior to the industrial age, or about the importance of anthropogenic activities on its budget.

Wang
et al.

(p.
1663
, published online 2 December; see the Perspective by

Prentice

) present a 650-year-long record of CO atmospheric concentration and isotopic composition, using samples from Antarctic ice cores, in order to begin to reconstruct past CO variability and its causes. The concentration of CO decreased by ∼25% from the mid-1300s to the 1600s, and then recovered completely by the late 1800s. Large variations in the degree of biomass burning in the Southern Hemisphere are likely to have been primarily responsible for the observed changes.
A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus
Authors: Wolfe-Simon Felisa , Blum Jodi Switzer , Kulp Thomas R. , Gordon Gwyneth W. , Hoeft Shelley E. , Pett-Ridge Jennifer , Stolz John F. , Webb Samuel M. , Weber Peter K. , Davies Paul C. W. , Anbar Ariel D. , Oremland Ronald S.
Published: December 2010

Evidence is offered for arsenate replacing phosphate as a molecular building block in a Mono Lake, California, bacterium.
Vernalization-Mediated Epigenetic Silencing by a Long Intronic Noncoding RNA
Authors: Heo Jae Bok , Sung Sibum
Published: December 2010

Spring flowering enabled by a winter chill is regulated by interplay between protein-coding and noncoding RNA transcripts.
What is morally salient about enhancement technologies?
Authors: Pols Auke J K , Houkes Wybo
Published: December 2010

The human enhancement debate typically centres on moral issues regarding changes in human nature, not on the means for these changes. We argue that one cannot grasp what is morally salient about human enhancement without understanding how technologies affect human action and practical reasoning. We present a minimalist conception of human agents as bounded practical reasoners. Then, we categorise different effects of technologies on our possibilities for action and our evaluation of these possibilities. For each, we discuss whether enhancement technologies have morally salient effects; which technologies show these effects; and whether these differ significantly from those of other, non-enhancement technologies. We conclude that enhancement technologies are morally salient in several respects, that not all enhancement technologies share all those morally salient respects, and that continuities with traditional technologies may be found in all morally salient respects.
Changing attitudes towards euthanasia among medical students in Austria: Table 1
Authors: Stronegger Willibald J , Schmölzer Christin , Rásky Éva , Freidl Wolfgang
Published: December 2010

Background

In most European countries the attitudes regarding the acceptability of active euthanasia have clearly changed in the population since World War II. Therefore, it is interesting to know which trends in attitudes prevail among the physicians of the future.

Methods

The present study analyses trends in the attitudes towards active euthanasia in medical students at the Medical University of Graz, Austria. The survey was conducted over a period of 9 years, enabling us to investigate trends regarding both attitudes and underlying motives.

Results

Acceptance of active euthanasia increased from 16.3% to 29.1% to 49.5% in the periods from 2001 to 2003/04 to 2008/09.

Conclusions

The survey period from 2001 to 2009 reveals a massive change in medical students' attitudes towards active euthanasia under medical supervision. Ethical convictions of medical doctors seem to fall back behind a higher valuation of the autonomy of the patient.
NUCLEAR PHYSICS IN A SUSY UNIVERSE
Authors: CLAVELLI L. , PEREVALOVA I.
Published: December 2010

We refine a previous zeroth-order analysis of the nuclear properties of a supersymmetric (SUSY) universe with standard model particle content plus degenerate SUSY partners. No assumptions are made concerning the Higgs structure except we assume that the degenerate fermion/sfermion masses are nonzero. This alternate universe has been dubbed Susyria and it has been proposed that such a world may exist with zero vacuum energy in the string landscape.
THE SCHWARZSCHILD'S BRANEWORLD SOLUTION
Authors: OVALLE J.
Published: December 2010

In the context of the Randall–Sundrum braneworld, the minimal geometric deformation approach, which has been successfully used to generate exact interior solutions to Einstein's field equations for static braneworld stars with local and nonlocal bulk terms, is used to obtain the braneworld version of the Schwarzschild's interior solution. Using this new solution, the behavior of the Weyl functions is elucidated in terms of the compactness for different stellar distributions.
CORRESPONDENCE BETWEEN JORDAN–EINSTEIN FRAMES AND PALATINI-METRIC FORMALISMS
Authors: CAPOZZIELLO SALVATORE , DARABI FARHAD , VERNIERI DANIELE
Published: December 2010

We discuss the conformal symmetry between Jordan and Einstein frames considering their relations with the metric and Palatini formalisms for modified gravity. Appropriate conformal transformations are taken into account leading to the evident connection between the gravitational actions in the two mentioned frames and the Hilbert–Einstein action with a cosmological constant. We show that the apparent differences between Palatini and metric formalisms strictly depend on the representation while the number of degrees of freedom is preserved. This means that the dynamical content of both formalism is identical.
Regulation of microsomal triglyceride transfer protein by apolipoprotein A-IV in newborn swine intestinal epithelial cells
Authors: Yao Ying , Lu Song , Huang Yue , Beeman-Black Casey C. , Lu Rena , Pan Xiaoyue , Hussain M. Mahmood , Black Dennis D.
Published: December 2010

Apolipoprotein (apo) A-IV overexpression enhances chylomicron (CM) assembly and secretion in newborn swine intestinal epithelial cells by producing larger particles (Lu S, Yao Y, Cheng X, Mitchell S, Leng S, Meng S, Gallagher JW, Shelness GS, Morris GS, Mahan J, Frase S, Mansbach CM, Weinberg RB, Black DD. J Biol Chem 281: 3473–3483, 2006). To determine the impact of apo A-IV on microsomal triglyceride transfer protein (MTTP), IPEC-1 cell lines containing a tetracycline-regulatable expression system were used to overexpress native swine apo A-IV and “piglike” human apo A-IV, a mutant human apo A-IV with deletion of the EQQQ-rich COOH-terminus, previously shown to upregulate basolateral triglyceride (TG) secretion 5-fold and 25-fold, respectively. Cells were incubated 24 h with and without doxycycline and oleic acid (OA, 0.8 mM). Overexpression of the native swine apo A-IV and piglike human apo A-IV increased MTTP lipid transfer activity by 39.7% ( P = 0.006) and 53.6% ( P = 0.0001), respectively, compared with controls. Changes in mRNA and protein levels generally paralleled changes in activity. Interestingly, native swine apo A-IV overexpression also increased MTTP large subunit mRNA, protein levels, and lipid transfer activity in the absence of OA, suggesting a mechanism not mediated by lipid absorption. Overexpression of piglike human apo A-IV significantly increased partitioning of radiolabeled OA from endoplasmic reticulum (ER) membrane to lumen, suggesting increased net transfer of membrane TG to luminal particles. These results suggest that the increased packaging of TG into nascent CMs in the ER lumen, induced by apo A-IV, is associated with upregulation of MTTP activity at the pretranslational level. Thus MTTP is regulated by apo A-IV in a manner to promote increased packaging of TG into the CM core, which may be important in neonatal fat absorption.
Quantitative imaging of alveolar recruitment with hyperpolarized gas MRI during mechanical ventilation
Authors: Cereda Maurizio , Emami Kiarash , Kadlecek Stephen , Xin Yi , Mongkolwisetwara Puttisarn , Profka Harrilla , Barulic Amy , Pickup Stephen , Månsson Sven , Wollmer Per , Ishii Masaru , Deutschman Clifford S. , Rizi Rahim R.
Published: December 2010

The aim of this study was to assess the utility of 3He MRI to noninvasively probe the effects of positive end-expiratory pressure (PEEP) maneuvers on alveolar recruitment and atelectasis buildup in mechanically ventilated animals. Sprague-Dawley rats ( n = 13) were anesthetized, intubated, and ventilated in the supine position (4He-to-O2 ratio: 4:1; tidal volume: 10 ml/kg, 60 breaths/min, and inspiration-to-expiration ratio: 1:2). Recruitment maneuvers consisted of either a stepwise increase of PEEP to 9 cmH2O and back to zero end-expiratory pressure or alternating between these two PEEP levels. Diffusion MRI was performed to image 3He apparent diffusion coefficient (ADC) maps in the middle coronal slices of lungs ( n = 10). ADC was measured immediately before and after two recruitment maneuvers, which were separated from each other with a wait period (8–44 min). We detected a statistically significant decrease in mean ADC after each recruitment maneuver. The relative ADC change was −21.2 ± 4.1 % after the first maneuver and −9.7 ± 5.8 % after the second maneuver. A significant relative increase in mean ADC was observed over the wait period between the two recruitment maneuvers. The extent of this ADC buildup was time dependent, as it was significantly related to the duration of the wait period. The two postrecruitment ADC measurements were similar, suggesting that the lungs returned to the same state after the recruitment maneuvers were applied. No significant intrasubject differences in ADC were observed between the corresponding PEEP levels in two rats that underwent three repeat maneuvers. Airway pressure tracings were recorded in separate rats undergoing one PEEP maneuver ( n = 3) and showed a significant relative difference in peak inspiratory pressure between pre- and poststates. These observations support the hypothesis of redistribution of alveolar gas due to recruitment of collapsed alveoli in presence of atelectasis, which was also supported by the decrease in peak inspiratory pressure after recruitment maneuvers.
Acute effect of muscle stretching on the steadiness of sustained submaximal contractions of the plantar flexor muscles
Authors: Kato Emika , Vieillevoye Stéphanie , Balestra Costantino , Guissard Nathalie , Duchateau Jacques
Published: December 2010

This paper examines the acute effect of a bout of static stretches on torque fluctuation during an isometric torque-matching task that required subjects to sustain isometric contractions as steady as possible with the plantar flexor muscles at four intensities (5, 10, 15, and 20% of maximum) for 20 s. The stretching bout comprised five 60-s passive stretches, separated by 10-s rest. During the torque-matching tasks and muscle stretching, the torque (active and passive) and surface electromyogram (EMG) of the medial gastrocnemius (MG), soleus (Sol), and tibialis anterior (TA) were continuously recorded. Concurrently, changes in muscle architecture (fascicle length and pennation angle) of the MG were monitored by ultrasonography. The results showed that during stretching, passive torque decreased and fascicle length increased gradually. Changes in these two parameters were significantly associated ( r2= 0.46; P < 0.001). When data from the torque-matching tasks were collapsed across the four torque levels, stretches induced greater torque fluctuation ( P < 0.001) and enhanced EMG activity ( P < 0.05) in MG and TA muscles with no change in coactivation. Furthermore, stretching maneuvers produced a greater decrease (∼15%; P < 0.001) in fascicle length during the torque-matching tasks and change in torque fluctuation (CV) was positively associated with changes in fascicle length ( r2= 0.56; P < 0.001), MG and TA EMG activities, and coactivation ( r2= 0.35, 0.34, and 0.35, respectively; P < 0.001). In conclusion, these observations indicate that repeated stretches can decrease torque steadiness by increasing muscle compliance and EMG activity of muscles around the joint. The relative influence of such adaptations, however, may depend on the torque level during the torque-matching task.
Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions
Authors: Towle Murray J. , Salvato Kathleen A. , Wels Bruce F. , Aalfs Kimberley K. , Zheng Wanjun , Seletsky Boris M. , Zhu Xiaojie , Lewis Bryan M. , Kishi Yoshito , Yu Melvin J. , Littlefield Bruce A.
Published: December 2010

Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type–specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [3H]eribulin accumulates to lower intracellular levels than [3H]ER-076349, yet is retained longer and at higher levels. Similar findings occurred with irreversible vincristine and reversible vinblastine, pointing to persistent cellular retention as a component of irreversibility. Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496–505. ©2011 AACR.
ROS and CHOP Are Critical for Dibenzylideneacetone to Sensitize Tumor Cells to TRAIL through Induction of Death Receptors and Downregulation of Cell Survival Proteins
Authors: Prasad Sahdeo , Yadav Vivek R. , Ravindran Jayaraj , Aggarwal Bharat B.
Published: December 2010

Because tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is being tested in cancer patients. Unfortunately, patients develop resistance to the cytokine, therefore, agents that can sensitize cells to TRAIL are urgently needed. In this study, we investigated whether dibenzylideneacetone (DBA) can sensitize cancer cells to TRAIL and potentiates TRAIL-induced apoptosis. As indicated by accumulation of the membrane phospholipid phosphatidylserine, DNA breaks, intracellular esterase activity, and activation of caspase-8, -9, and -3, we concluded that DBA potentiated TRAIL-induced apoptosis in colon cancer cells. DBA also converted TRAIL resistant-cells to TRAIL-sensitive. When examined for the mechanism, we found that DBA decreased the expression of antiapoptotic proteins and decoy recptor-2 and increased proapoptotic proteins. DBA also induced both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 by small interfering RNA (SiRNA) reduced the sensitizing effect of DBA on TRAIL-induced apoptosis. In addition, DBA increased the expression of CHOP proteins. Knockdown of CHOP by siRNA decreased the induction of DBA-induced DR5 expression and apoptosis. Induction of receptors by DBA, however, was p53-independent, as deletion of p53 had no effect on receptor induction. We observed that DBA-induced induction of DR5 and DR4 was mediated through generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of death receptors and suppression of cell survival proteins by DBA. Overall, our results show that DBA potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of ROS and CHOP mediated pathways. Cancer Res; 71(2); 538–49. ©2010 AACR.
The Tumor Suppressor Protein Menin Inhibits AKT Activation by Regulating Its Cellular Localization
Authors: Wang Yan , Ozawa Atsushi , Zaman Shadia , Prasad Nijaguna B. , Chandrasekharappa Settara C. , Agarwal Sunita K. , Marx Stephen J.
Published: December 2010

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here, we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity. Cancer Res; 71(2); 371–82. ©2010 AACR.
Evaluation of Novel Aminomethyl Indole Derivatives as Src Kinase Inhibitors and Antioxidant Agents
Authors: Ölgen Süreyya , Kılıç-Kurt Zühal , Şener Fatma , İşgör Yasemin G. , Çoban Tülay
Published: December 2010

Background: Oxidative stress has been implicated in aging and in a variety of diseases affecting the nervous, respiratory, cardiovascular and gastrointestinal system in humans. Reactive oxygen species (ROS) have been associated with mechanisms to activate kinases, such as protein tyrosine kinases, which may initiate malignant transformation. Significant evidences of the activation of protein kinases by oxidative stress brought increased attention to the role of antioxidants in these mechanisms. Therefore, recent efforts have focused on revealing the relationship between protein kinase inhibition and the levels of ROS production. Methods: Antioxidant properties of aminomethyl indole derivatives were investigated by employing various in vitro systems, microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl and scavenging of superoxide anion radical by virtue of superoxide dismutase inhibitory activity. In vitro tyrosine kinase assays of the aminomethyl indole derivatives were evaluated by changes in the enzymatic activity of pp60c-Src tyrosine kinase through alterations in the phosphorylation level of immobilized kinase substrate. Results: Analysis of the antioxidant effects of indole 1a–c, bromo indole 2a–c and phenyl indole 3a–c derivatives revealed almost equal inhibition against LP for 5-bromo indole 2a–c and phenyl indole 3a–c derivatives and slight inhibition against superoxide dismutase only for 1a and 1c. Nonsubstituted compounds at position 5 showed half-inhibition of LP. Compound 1a has tyrosine kinase inhibition with an IC50 of 102.6 ± 1.16 µM. Conclusion: The substitution feature at position 5 of the indole ring certainly plays an important role in both tyrosine kinase inhibition and antioxidant capacity. While certain lipophilicity of this substitution is important for antioxidant activity, it may, on the other hand, have a negative impact on the inhibition of Src kinase.
Effectiveness of Nonpharmacological Approaches in Patients with Mild Cognitive Impairment
Authors: Tsolaki Magda , Kounti Fotini , Agogiatou Christina , Poptsi Eleni , Bakoglidou Evangelia , Zafeiropoulou Myrto , Soumbourou Aikaterini , Nikolaidou Evdokia , Batsila Georgia , Siambani Aikaterini , Nakou Stella , Mouzakidis Christos , Tsiakiri Anna , Zafeiropoulos Stavros , Karagiozi Konstantina , Messini Chaido , Diamantidou Alexandra , Vasiloglou Maria
Published: December 2010

Background: Mild cognitive impairment (MCI) patients are at increased risk of developing dementia. There is a conflict if cognitive interventions can improve cognitive and functional performances in order to delay the development of dementia. Objectives: This study aimed to examine the effectiveness of a holistic cognitive rehabilitation program on patients with MCI. Methods: The participants, 176 MCI patients with Mini-Mental State Examination = 27.89 (1.73), were classified into 2 groups matched for age, gender, education and cognitive abilities: (1) patients (104) on nonpharmacological therapy and (2) patients (72) on no therapy at all. The effectiveness of the interventions was assessed by neuropsychological evaluation performed at baseline and at the end of the interventions. Results: Between-group difference in benefit of the experimental group was demonstrated in abilities of executive function (p = 0.004), verbal memory (p = 0.003), praxis (p ≤ 0.012), daily function (p = 0.001) and general cognitive ability (p ≤ 0.005). The experimental patients improved cognitive and functional performances, while the control patients demonstrated deterioration in daily function (p = 0.004). Conclusions: Our findings indicate that nonpharmacological therapy of the holistic approach can improve MCI patients’ cognitive and functional performances.
Isoniazid Blood Levels in Patients with Pulmonary Tuberculosis at a Tuberculosis Referral Center
Authors: Fahimi Fanak , Kobarfard Farzad , Tabarsi Payam , Hemmati Shabnam , Salamzadeh Jamshid , Baniasadi Shadi
Published: December 2010

Background: Serum concentrations of isoniazid (INH) were evaluated in Iranian patients admitted to the Tuberculosis Ward of Masih Daneshvari Hospital, Tehran, Iran. Factors correlated to plasma INH levels were determined. Methods: Blood samples were obtained 2 h after ingestion of 5 mg/kg INH in 82 patients (1 sample/patient) on days 3–15 of treatment. The following variables were investigated: INH plasma level, duration of therapy, age, sex, weight, dose of INH administered and smoking status. Results: The average (±SD) age and weight of patients were 60.68 ± 18.53 years and 74.96 ± 7.15 kg, respectively. INH concentrations were low in 14.63% and high in 23.17% of the patients (INH reference range: 3–5 µg/ml). Plasma INH was statistically correlated with duration of INH administration (Kendall’s rank correlation, r = 0.66, p < 0.001) but not with other variables. Conclusion: Based on the result of this study, plasma INH concentrations were not within the therapeutic range for 37.80% of the patients on conventional therapy. Therefore therapeutic drug monitoring may be needed to optimize INH dosage, especially in patients with inadequate clinical response or toxicity to INH.
TDP-43-Based Animal Models of Neurodegeneration: New Insights into ALS Pathology and Pathophysiology
Authors: Wegorzewska Iga , Baloh Robert H.
Published: December 2010

The clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) suggests these diseases share common underlying mechanisms, a suggestion underscored by the discovery that TDP-43 inclusions are a key pathologic feature in both ALS and FTLD. This finding, combined with the identification of TDP-43 mutations in ALS, directly implicates this DNA/RNA binding protein in disease pathogenesis in ALS and FTLD. However, many key questions remain, including what is the normal function of TDP-43, and whether disease-associated mutations produce toxicity in the nucleus, cytoplasm or both. Furthermore, although pathologic TDP-43 inclusions are clearly associated with many forms of neurodegeneration, whether TDP-43 aggregation is a key step in the pathogenesis in ALS, FTLD and other disorders remains to be proven. This review will compare the features of numerous recently developed animal models of TDP-43-related neurodegeneration, and discuss how they contribute to our understanding of the pathogenesis of human ALS and FTLD.
Spatial Navigation and APOE in Amnestic Mild Cognitive Impairment
Authors: Laczó Jan , Andel Ross , Vlček Kamil , Macoška Václav , Vyhnálek Martin , Tolar Martin , Bojar Martin , Hort Jakub
Published: December 2010

Background: The effect of APOE Ε4 allele (Ε4) on spatial navigation in amnestic mild cognitive impairment (aMCI) is unknown. Objective: Our purpose was to examine the characteristics of spatial navigation impairment in Ε4-positive (Ε4+) and Ε4-negative (Ε4–) aMCI subgroups. Methods: Blood samples were collected to determine the APOE genotype. A total of 34 aMCI patients were stratified into aMCI-Ε4– (n = 23) and aMCI-Ε4+ (n = 11) groups. Control (n = 28) and mild Alzheimer’s disease (AD; n = 16) groups were also used. We used a human analogue of the Morris water maze (enclosed arena 2.9 m in diameter) to examine body-centered (egocentric) and world-centered (allocentric) spatial navigation. Results: The aMCI-Ε4+ group performed poorer on spatial navigation than the aMCI-Ε4– group in both egocentric and allocentric tasks even though these 2 groups did not differ in global cognitive functioning or neuropsychological tests. The aMCI-Ε4+ and mild AD groups performed similarly on all Morris Water Maze tasks and were outperformed by the aMCI-Ε4– group, which also resembled the control group in performance on the egocentric tasks. The aMCI groups showed poor spatial navigation learning regardless of their Ε4 positivity. Conclusion: We found more profound deficits in spatial navigation in aMCI-Ε4+ relative to aMCI-Ε4– patients. The aMCI-Ε4+ group resembled the mild AD group in spatial navigation performance. Although the Ε4 genotype was indicative of spatial navigation performance, it was not indicative of the aMCI patients’ ability to learn the tasks. Spatial navigation testing represents a promising area with respect to identifying individuals at higher risk for AD among the heterogeneous MCI population.
Using the WHOQOL-DIS to Measure Quality of Life in Persons with Physical Disabilities Caused by Neurodegenerative Disorders
Authors: Lucas-Carrasco Ramona , Pascual-Sedano Berta , Galán Ingrid , Kulisevsky Jaime , Sastre-Garriga Jaume , Gómez-Benito Juana
Published: December 2010

Background/Aims: Neurodegenerative disorders (ND) have a major impact on quality of life (QoL) and place a substantial burden on patients, their families and carers; they are the second leading cause of disability. The objective of this study was to examine QoL in persons with ND. Methods: A battery of subjective assessments was used, including the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the World Health Organization Quality of Life – Disability (WHOQOL-DIS). Psychometric properties of the WHOQOL-BREF and WHOQOL-DIS were investigated using classical psychometric methods. Results: Participants (n = 149) were recruited and interviewed at two specialized centers to obtain information on health and disability perceptions, depressive symptoms (Hospital Anxiety and Depression Scale – Depression, HADS-D), Fatigue Assessment Scale (FAS), Satisfaction with Life (SWL), generic QoL (WHOQOL-BREF, WHOQOL-DIS), specific QoL (Multiple Sclerosis Impact Scale, MSIS-29; Parkinson’s Disease Questionnaire, PDQ-39) and sociodemographics. Internal consistency was acceptable, except for the WHOQOL-BREF social (0.67). Associations, using Pearson’s and Spearman’s rho correlations, were confirmed between WHOQOL-BREF and WHOQOL-DIS with MSIS-29, PDQ-39, HADS-D, FAS and SWL. Regarding ‘known group’ differences, Student’s t tests showed that WHOQOL-BREF and WHOQOL-DIS scores significantly discriminated between depressed and nondepressed and those perceiving a more severe impact of the disability on their lives. Conclusion: This study is the first to report on use of the WHOQOL-BREF and WHOQOL-DIS in Spanish persons with ND; they are promising useful tools in assessing persons with ND through the continuum of care, as they include important dimensions commonly omitted from other QoL measures.
Impaired Brain Creatine Kinase Activity in Huntington’s Disease
Authors: Zhang S.F. , Hennessey T. , Yang L. , Starkova N.N. , Beal M.F. , Starkov A.A.
Published: December 2010

Background: Huntington’s disease (HD) is associated with impaired energy metabolism in the brain. Creatine kinase (CK) catalyzes ATP-dependent phosphorylation of creatine (Cr) into phosphocreatine (PCr), thereby serving as readily available high-capacity spatial and temporal ATP buffering. Objective: Substantial evidence supports a specific role of the Cr/PCr system in neurodegenerative diseases. In the brain, the Cr/PCr ATP-buffering system is established by a concerted operation of the brain-specific cytosolic enzyme BB-CK and ubiquitous mitochondrial uMt-CK. It is not yet established whether the activity of these CK isoenzymes is impaired in HD. Methods: We measured PCr, Cr, ATP and ADP in brain extracts of 3 mouse models of HD – R6/2 mice, N171-82Q and HdhQ111 mice – and the activity of CK in cytosolic and mitochondrial brain fractions from the same mice. Results: The PCr was significantly increased in mouse HD brain extracts as compared to nontransgenic littermates. We also found an approximately 27% decrease in CK activity in both cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice, and an approximately 25% decrease in the mitochondria from HdhQ111 mice. Moreover, uMt-CK and BB-CK activities were approximately 63% lower in HD human brain samples as compared to nondiseased controls. Conclusion: Our findings lend strong support to the role of impaired energy metabolism in HD, and point out the potential importance of impairment of the CK-catalyzed ATP-buffering system in the etiology of HD.
The Relationship of Accentuated Lines in Enamel to Weaning Stress in Juvenile Baboons (Papio hamadryas anubis)
Authors: Dirks Wendy , Humphrey Louise T. , Dean M. Christopher , Jeffries Teresa E.
Published: December 2010

Weaning conflict may represent an evolutionary conflict of interest between parent and offspring, an honest signal of need on the part of a weanling, or both. Accentuated lines visible in histological sections of teeth are indicators of stress during enamel formation and have been hypothesised to form in baboon teeth during weaning. We analysed growth increments in 5 tooth sections from 2 Ugandan baboons (Papio hamadryas anubis), using polarised light microscopy, to determine when stresses occurred during the weaning process. Dietary transitions were reconstructed using normalised strontium intensities (Sr/Ca) in enamel. Accentuated lines were cross-matched between teeth from the same animal and plotted by month. The highest frequency of stress was experienced at around 6 months in 1 baboon, coinciding with an inferred reduction in suckling frequency, and at 11 months in another, coinciding with the inferred cessation of suckling. Because accentuated lines appear to indicate weaning stress at dietary transitions, weaning conflict may represent an honest signal of need on the part of the weanling.
Influence of Erythropoiesis-Stimulating Agents on Glycated Hemoglobin in Nondiabetic Kidney Diseases at the Start of Dialysis
Authors: Cordeiro Antonio Carlos , Carrero Juan Jesús , Bárány Peter , Qureshi Abdul Rashid , Heimbürger Olof , Lindholm Bengt , Stenvinkel Peter
Published: December 2010

Background: Although glycated hemoglobin (HbA1C) is a practical tool to assess long-term glucose control in the general population, it may underestimate glycemic control in chronic kidney disease (CKD) patients – especially those undergoing treatment with erythropoiesis-stimulating agents (ESA). We evaluated the association of HbA1C with other parameters of glucose homeostasis and tested its association with ESA use and mortality in nondiabetic incident dialysis patients. Methods: We studied 270 nondiabetic CKD stage 5 patients referred to initiate dialysis therapy [median age: 54 years (43–63), 154 males]. Patients were followed for up to 5 years for survival analysis. Results: HbA1C was positively correlated with age (Rho = 0.13; p = 0.031), C-reactive protein (Rho = 0.14; p = 0.024), total cholesterol (Rho = 0.19; p = 0.001), triglycerides (Rho = 0.21; p < 0.001) and glucose (Rho = 0.21; p = 0.001), but it was negatively correlated with HDL-cholesterol (Rho = –0.22; p < 0.001) and ESA dose (Rho = –0.27; p < 0.001). Across increasing HbA1C tertiles, increased glucose levels and reduced use of ESA and dose of ESA were observed (p < 0.001), but there were no differences in insulin and HOMA index. In a stepwise multivariate linear regression analysis, ESA dose was negatively associated with logHbA1C. HbA1C did not predict mortality. Conclusion: In nondiabetic CKD stage 5 patients, HbA1C levels were associated with ESA dose. HbA1C was not independently associated with surrogate markers of insulin resistance or mortality.
Role of Shear Stress in Endothelial Cell Morphology and Expression of Cyclooxygenase Isoforms
Authors: Potter Claire M.F. , Lundberg Martina H. , Harrington Louise S. , Warboys Christina M. , Warner Timothy D. , Berson R. Eric , Moshkov Alexey V. , Gorelik Julia , Weinberg Peter D. , Mitchell Jane A.
Published: December 2010

Objective—

The goal of this study was to examine the effect of chronic heterogeneous shear stress, applied using an orbital shaker, on endothelial cell morphology and the expression of cyclooxygenases 1 and 2.

Methods and Results—

Porcine aortic endothelial cells were plated on fibronectin-coated Transwell plates. Cells were cultured for up to 7 days either under static conditions or on an orbital shaker that generated a wave of medium inducing shear stress over the cells. Cells were fixed and stained for the endothelial surface marker CD31 or cyclooxygenases 1 and 2.En faceconfocal microscopy and scanning ion conductance microscopy were used to show that endothelial cells were randomly oriented at the center of the well, aligned with shear stress nearer the periphery, and expressed cyclooxygenase-1 under all conditions. Lipopolysaccharide induced cyclooxygenase-2 and the production of 6-keto-prostaglandin F1αin all cells.

Conclusion—

Cyclooxygenase-1 is expressed in endothelial cells cultured under chronic shear stress of high or low directionality.
Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease
Authors: Shimizu Chisato , Jain Sonia , Davila Sonia , Hibberd Martin L. , Lin Kevin O. , Molkara Delaram , Frazer Jeffrey R. , Sun Shelly , Baker Annette L. , Newburger Jane W. , Rowley Anne H. , Shulman Stanford T. , Davila Sonia , Burgner David , Breunis Willemijn B. , Kuijpers Taco W. , Wright Victoria J. , Levin Michael , Eleftherohorinou Hariklia , Coin Lachlan , Popper Stephen J. , Relman David A. , Fury Wen , Lin Calvin , Mellis Scott , Tremoulet Adriana H. , Burns Jane C.
Published: December 2010

Background—

Transforming growth factor (TGF)-β is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-β signaling might be important in KD susceptibility and disease outcome.

Methods and Results—

We investigated genetic variation in 15 genes belonging to the TGF-β pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-β2 protein levels in plasma. Genetic variants in
TGFB2
,
TGFBR2
, and
SMAD3
and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A
SMAD3
haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (
P
=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-β pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-β2 plasma protein levels changed dynamically over the course of the illness.

Conclusions—

These studies suggest that genetic variation in the TGF-β pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery
Z
scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.
Endothelial Nitric Oxide Modulates Expression and Processing of Amyloid Precursor Protein
Authors: Austin Susan A. , Santhanam Anantha V. , Katusic Zvonimir S.
Published: December 2010

Rationale:

The exact etiology of sporadic Alzheimer disease (AD) is unclear, but it is interesting that several cardiovascular risk factors are associated with higher incidence of AD. The link between these risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of nitric oxide (NO).

Objective:

To determine the relationship between endothelial derived NO and the expression and processing of amyloid precursor protein (APP).

Methods and Results:

We used human brain microvascular endothelial cells to examine the role of NO in modulating APP expression and processing in vitro. Inhibition of endothelial nitric oxide synthase (eNOS) with the specific NOS inhibitor L-NAME (
N
G
-nitro-
l
-arginine methyl ester) led to increased APP and BACE1 (β-site APP-cleaving enzyme1) protein levels, as well as increased secretion of the amyloidogenic peptide amyloid β (Aβ) (control 10.93±0.70 pg/mL; L-NAME 168.21±27.38 pg/mL;
P
<0.001). To examine the role of NO in modulation of APP expression and processing in vivo, we used brain and cerebral microvessels from eNOS-deficient (eNOS
−/−
) mice. Brain tissue from eNOS
−/−
mice had statistically higher APP and BACE1 protein levels, as well as increased BACE1 enzyme activity and Aβ (Aβ
1
-
42
wild-type control, 0.737pg/mg; eNOS
−/−
, 1.475 pg/mg;
P
<0.05), compared with wild-type controls (n=6 to 8 animals per background). Brain microvessels from eNOS
−/−
mice also showed statistically higher BACE1 protein levels as compared with wild-type control.

Conclusions:

Our data suggest that endothelial NO plays an important role in modulating APP expression and processing within the brain and cerebrovasculature. The NO/cGMP pathway may be an important therapeutic target in preventing and treating mild cognitive impairment, as well as AD.