bluuebunny/crossref_metadata_2025 huggingface dataset:
mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes
Authors: Vollenbröker Beate , George Britta , Wolfgart Maria , Saleem Moin A. , Pavenstädt Hermann , Weide Thomas
Published: November 2008

The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors can cause proteinuria, especially in kidney and heart transplanted patients. Podocytes play a major role in establishing the selective permeability of the blood-urine filtration barrier. Damage of these cells leads to proteinuria, a hallmark of most glomerular diseases. Interestingly, podocyte damage and focal segmental glomerulosclerosis can occur after treatment with an mTOR inhibitor in some transplant patients. To investigate the mechanisms of mTOR inhibitor-induced podocyte damage, we analyzed the effect of rapamycin on mTOR signaling and cellular function in human podocytes. We found that prolonged rapamycin treatment reduced the expression of total mTOR, which correlates with diminished levels of mTOR phosphorylation at Ser2448and Ser2481. In addition, treatment with rapamycin reduced rictor expression and mTORC2 formation, resulting in a reduced phosphorylation of protein kinase B at Ser473. The expression level of the slit-diaphragm proteins nephrin and transient receptor potential cation channel 6 as well as the cytoskeletal adaptor protein Nck significantly decreased. Moreover, rapamycin reduced cell adhesion and cell motility, which was accompanied by an enhanced formation of dot-like actin-rich structures. Our data provide new molecular insights explaining which pathways and molecules are affected in podocytes by an imbalanced mTOR function because of rapamycin treatment.
PDGF receptor-β modulates metanephric mesenchyme chemotaxis induced by PDGF AA
Authors: Ricono Jill M. , Wagner Brent , Gorin Yves , Arar Mazen , Kazlauskas Andrius , Choudhury Goutam Ghosh , Abboud Hanna E.
Published: November 2008

PDGF B chain or PDGF receptor (PDGFR)-β-deficient (−/−) mice lack mesangial cells. To study responses of α- and β-receptor activation to PDGF ligands, metanephric mesenchymal cells (MMCs) were established from embryonic day E11.5 wild-type (+/+) and −/− mouse embryos. PDGF BB stimulated cell migration in +/+ cells, whereas PDGF AA did not. Conversely, PDGF AA was chemotactic for −/− MMCs. The mechanism by which PDGFR-β inhibited AA-induced migration was investigated. PDGF BB, but not PDGF AA, increased intracellular Ca2+and the production of reactive oxygen species (ROS) in +/+ cells. Transfection of −/− MMCs with the wild-type β-receptor restored cell migration and ROS generation in response to PDGF BB and inhibited AA-induced migration. Inhibition of Ca2+signaling facilitated PDGF AA-induced chemotaxis in the wild-type cells. The antioxidant N-acetyl-l-cysteine (NAC) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI) abolished the BB-induced increase in intracellular Ca2+concentration, suggesting that ROS act as upstream mediators of Ca2+in suppressing PDGF AA-induced migration. These data indicate that ROS and Ca2+generated by active PDGFR-β play an essential role in suppressing PDGF AA-induced migration in +/+ MMCs. During kidney development, PDGFR β-mediated ROS generation and Ca2+influx suppress PDGF AA-induced chemotaxis in metanephric mesenchyme.
Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase
Authors: Wei Xiao Fan , Zhou Qiu Gen , Hou Fan Fan , Liu Bei Yi , Liang Min
Published: November 2008

Mesangial deposition of extracellular matrix (ECM) is a hallmark of several glomerular diseases including diabetic nephropathy. Accumulation of advanced oxidation protein products (AOPPs) has been found in diabetes and chronic kidney disease and linked to mesangial ECM deposition and progressive glomerulosclerosis in these disorders. Although emerging evidence implicates AOPPs as the renal pathogenic factors, the underlying mechanisms have not been investigated. Here, using cultured rat mesangial cells (MCs) as a model, we identify AOPPs as the important mediators for activation of MC NADPH oxidase. Exposure of MCs to AOPPs, through membrane-associated phosphorylation of PKCα, induced rapid phosphorylation of cytosolic p47phoxand its membrane translocation, enhanced interaction of p47phoxwith the membrane components p22phoxand Nox4, and increased expression of these key regulatory subunits of NADPH oxidase. Challenge with AOPPs triggered cytosolic superoxide generation, resulting in upregulation of fibronectin and collagen IV genes and proteins and overexpression of TGF-β1 via a PKC-NADPH oxidase-dependent pathway, as these downstream events were blocked by the inhibitors of PKC, inhibitors of NADPH oxidase, or the cytosolic superoxide scavenger. These data provide new information for understanding the molecular basis underlying AOPP-induced MC perturbation and might be a central step toward development of new interventions.
FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?
Authors: Razzaque M. Shawkat
Published: November 2008

Understanding the physiological regulation of mineral ion metabolism is essential for determining the pathomechanisms of skeletal, vascular, and renal diseases associated with an abnormal regulation of calcium and phosphate homeostasis. Normal calcium and phosphate balance is delicately maintained by endocrine factors that coordinate to influence the functions of the intestine, bone, parathyroid gland, and kidney. Under physiological conditions, the kidneys play an important role in maintaining normal mineral ion balance by fine-tuning the amount of urinary excretion of calcium and phosphate according to the body's needs. Fibroblast growth factor (FGF)23 regulates urinary phosphate excretion to maintain systemic phosphate homeostasis. The exact mode of action of the phosphaturic effects of FGF23 is not fully understood and is an intense area of research. Studies suggest, however, that FGF23, by interacting with FGF receptors, can initiate downstream signaling events and that Klotho, a transmembrane protein, facilitates the interaction of FGF23 with its receptor. FGF23 can inhibit the activities of 1-α-hydroxylase and sodium-phosphate cotransporter in the kidney to influence the overall systemic phosphate balance. This article briefly summarizes how FGF23 might coordinately regulate systemic phosphate homeostasis and how Klotho is involved in such regulation.
Measuring partial body potassium in the legs of patients with spinal cord injury: a new approach
Authors: Wielopolski L. , Ramirez L. M. , Spungen A. M. , Swaby S. , Asselin P. , Bauman W. A.
Published: November 2008

Patients with acute spinal cord injury (SCI) with paralysis experience rapid and marked muscle atrophy below the level of the lesion. Muscle is lost above the lesion due to enforced bed rest associated with immobilization. Presently, there is no viable method to quantify muscle loss between the time of injury to the initiation of rehabilitation and remobilization. Furthermore, to assess the efficacy of any physical or pharmacological intervention necessitates the ability to accurately determine the impact of these treatments on muscle mass and function. Our results are presented from measurements of regional potassium (K) in the legs of persons with chronic SCI. The intracellular body K, comprising ∼97% of the total body K, is indicative of the metabolically active cell mass, of which over 50% is located in the skeletal muscle (SM). To assess regional variations in SM mass in the legs, a partial body K (PBK) system designed for this purpose was placed on a potentially mobile cart. The SM mass measured by PBK in an able-bodied control cohort ( n = 17) and in patients with chronic SCI ( n = 21) was 17.6 ± 0.86 and 11.0 ± 0.65 kg, respectively, a difference of ∼37.5%. However, the difference in the lean tissue mass of the legs obtained by dual-energy absorptiometry (DXA) in the same cohorts was 20.5 ± 0.86 and 15.5 ± 0.88 kg, respectively, or a difference of ∼24.4%. PBK offers a novel approach to obtain regional K measurements in the legs, thus allowing the potential for early and serial assessment of muscle loss in SCI subjects during the acute and subacute periods following paralysis. The basic characteristics and performance of our PBK system and our calibration procedure are described in this preliminary report.
Effects of head and body cooling on hemodynamics during immersed prone exercise at 1 ATA
Authors: Wester T. E. , Cherry A. D. , Pollock N. W. , Freiberger J. J. , Natoli M. J. , Schinazi E. A. , Doar P. O. , Boso A. E. , Alford E. L. , Walker A. J. , Uguccioni D. M. , Kernagis D. , Moon R. E.
Published: November 2008

Immersion pulmonary edema (IPE) is a condition with sudden onset in divers and swimmers suspected to be due to pulmonary arterial or venous hypertension induced by exercise in cold water, although it does occur even with adequate thermal protection. We tested the hypothesis that cold head immersion could facilitate IPE via a reflex rise in pulmonary vascular pressure due solely to cooling of the head. Ten volunteers were instrumented with ECG and radial and pulmonary artery catheters and studied at 1 atm absolute (ATA) during dry and immersed rest and exercise in thermoneutral (29–31°C) and cold (18–20°C) water. A head tent varied the temperature of the water surrounding the head independently of the trunk and limbs. Heart rate, Fick cardiac output (CO), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and central venous pressure (CVP) were measured. MPAP, PAWP, and CO were significantly higher in cold pool water ( P ≤ 0.004). Resting MPAP and PAWP values (means ± SD) were 20 ± 2.9/13 ± 3.9 (cold body/cold head), 21 ± 3.1/14 ± 5.2 (cold/warm), 14 ± 1.5/10 ± 2.2 (warm/warm), and 15 ± 1.6/10 ± 2.6 mmHg (warm/cold). Exercise values were higher; cold body immersion augmented the rise in MPAP during exercise. MAP increased during immersion, especially in cold water ( P < 0.0001). Except for a transient additive effect on MAP and MPAP during rapid head cooling, cold water on the head had no effect on vascular pressures. The results support a hemodynamic cause for IPE mediated in part by cooling of the trunk and extremities. This does not support the use of increased head insulation to prevent IPE.
Activation of δ-Opioid Receptors Reduces Excitatory Input to Putative Gustatory Cells Within the Nucleus of the Solitary Tract
Authors: Zhu Mingyan , Cho Young K. , Li Cheng-Shu
Published: November 2008

The rostral nucleus of the solitary tract (NST) is the first central relay in the gustatory pathway and plays a key role in processing and modulation of gustatory information. Here, we investigated the effects of opioid receptor agonists and antagonists on synaptic responses of the gustatory parabrachial nuclei (PbN)-projecting neurons in the rostral NST to electrical stimulation of the solitary tract (ST) using whole cell recordings in the hamster brain stem slices. ST-evoked excitatory postsynaptic currents (EPSCs) were significantly reduced by met-enkephalin (MetE) in a concentration-dependent fashion and this effect was eliminated by naltrexone hydrochloride, a nonselective opioid receptor antagonist. Bath application of naltrindole hydrochloride, a selective δ-opioid receptor antagonist, eliminated MetE-induced reduction of EPSCs, whereas CTOP, a selective μ-opioid receptor antagonist had no effect, indicating that δ-opioid receptors are involved in the reduction of ST-evoked EPSCs induced by MetE. SNC80, a selective δ-opioid receptor agonist, mimicked the effect of MetE. The SNC80-induced reduction of ST-evoked EPSCs was eliminated by 7-benzylidenenaltrexone, a selective δ1-opioid receptor antagonist but not by naltriben mesylate, a selective δ2-opioid receptor antagonist, indicating that δ1-opioid receptors mediate the reduction of ST-evoked EPSCs induced by SNC80. Single-cell reverse transcriptase–polymerase chain reaction analysis revealed the presence of δ1-opioid receptor mRNA in cells that responded to SNC80 with a reduction in ST-evoked EPSCs. Moreover, Western blot analysis demonstrated the presence of 40-kDa δ-opioid receptor proteins in the rostral NST tissue. These results suggest that postsynaptic δ1-opioid receptors are involved in opioid-induced reduction of ST-evoked EPSCs of PbN-projecting rostral NST cells.
A “Gap Effect” on Stop Signal Reaction Times in a Human Saccadic Countermanding Task
Authors: Stevenson Scott A. , Elsley James K. , Corneil Brian D.
Published: November 2008

The “gap effect” describes a phenomenon whereby saccadic reaction times are expedited by the removal of a visible fixation point prior to target presentation. Here we investigated whether processes controlling saccade cancellation are also subjected to a gap effect. Human subjects performed a countermanding experiment that required them to try to cancel an impending saccade in the presence of an imperative visual stop signal, across different fixation conditions. We found that saccadic cancellation latencies, estimated via derivation of the stop signal reaction time (SSRT), were ∼40 ms shorter on trials with a 200-ms gap between fixation point removal and target presentation compared with when the fixation point remained illuminated. Follow-up experiments confirmed that the reduction in SSRTs were primarily due to removal of a foveal fixation point (as opposed to a generalized warning effect) and persisted with an auditory stop signal that controlled for potential differences in stop signal saliency across different fixation conditions. Saccadic RTs exhibited a gap effect in all experiments with reductions in RTs being due to both removal of a foveal fixation point and a generalized warning effect. Overall, our results demonstrate that processes controlling saccade cancellation can be expedited by a 200-ms gap. The simultaneous priming of both saccade cancellation and generation is of particular interest considering the mutually antagonistic relationship between the saccade fixation and generation networks in the oculomotor system.
Structural Characteristics and Crystallization of Metallic Glass Sputtered Films by Using Zr System Target
Authors: Kondoh Katsuyoshi , Kawabata Kenshi , Serikawa Tadashi , Kimura Hisamichi
Published: November 2008

Zr-Al-Ni-Cu thin films were deposited by the radio-frequency sputtering method at low substrate temperature using three kinds of targets:Zr55Al10Ni5Cu30bulk metallic glass target (α-BMG target), crystallized bulk metallic glass target (c-BMG target), and an elemental composite target composed of each Zr, Al, Ni chips, and Cu plate. XRD profiles of the films prepared when using these targets indicated that all of the films showed amorphous structures. While XRD profiles of the films usingα- and c-BMG targets revealed a broad peak of2θ=38degree in the same way as theα-BMG target indicating amorphous structures, that of the film using elemental composite targets showed a broad peak of2θ=42degree, which is higher compared to the latter material. As a result of annealing the films at various temperatures for 900 seconds, the film using theα-BMG target showed a crystallization temperature of 748 K, higher than that of BMG with 723 K, while the other films had lower crystallization temperatures below 723 K. XRD profiles also indicated that the crystallized compounds of the films were different from those of BMG target.
Climate Change over the Equatorial Indo-Pacific in Global Warming*
Authors: Ihara Chie , Kushnir Yochanan , Cane Mark A. , de la Peña Victor H.
Published: November 2008

The response of the equatorial Indian Ocean climate to global warming is investigated using model outputs submitted to the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report. In all of the analyzed climate models, the SSTs in the western equatorial Indian Ocean warm more than the SSTs in the eastern equatorial Indian Ocean under global warming; the mean SST gradient across the equatorial Indian Ocean is anomalously positive to the west in a warmer twenty-first-century climate compared to the twentieth-century climate, and it is dynamically consistent with the anomalous westward zonal wind stress and anomalous positive zonal sea level pressure (SLP) gradient to the east at the equator. This change in the zonal SST gradient in the equatorial Indian Ocean is detected even in the lowest-emission scenario, and the size of the change is not necessarily larger in the higher-emission scenario.

With respect to the change over the equatorial Pacific in climate projections, the subsurface central Pacific displays the strongest cooling or weakest warming around the thermocline depth compared to that above and below in all of the climate models, whereas changes in the zonal SST gradient and zonal wind stress around the equator are model dependent and not straightforward.
The Skill of Probabilistic Precipitation Forecasts under Observational Uncertainties within the Generalized Likelihood Uncertainty Estimation Framework for Hydrological Applications
Authors: Pappenberger F. , Ghelli A. , Buizza R. , Bódis K.
Published: November 2008

A methodology for evaluating ensemble forecasts, taking into account observational uncertainties for catchment-based precipitation averages, is introduced. Probability distributions for mean catchment precipitation are derived with the Generalized Likelihood Uncertainty Estimation (GLUE) method. The observation uncertainty includes errors in the measurements, uncertainty as a result of the inhomogeneities in the rain gauge network, and representativeness errors introduced by the interpolation methods. The closeness of the forecast probability distribution to the observed fields is measured using the Brier skill score, rank histograms, relative entropy, and the ratio between the ensemble spread and the error of the ensemble-median forecast (spread–error ratio). Four different methods have been used to interpolate observations on the catchment regions. Results from a 43-day period (20 July–31 August 2002) show little sensitivity to the interpolation method used. The rank histograms and the relative entropy better show the effect of introducing observation uncertainty, although this effect on the Brier skill score and the spread–error ratio is not very large. The case study indicates that overall observation uncertainty should be taken into account when evaluating forecast skill.
A Diagnostic Model for Mixed Layer Depth Estimation with Application to Ocean Station P in the Northeast Pacific
Authors: Thomson Richard E. , Fine Isaac V.
Published: November 2008

This paper presents a simple diagnostic model for estimating mixed layer depth based solely on the one-dimensional heat balance equation, the surface heat flux, and the sea surface temperature. The surface fluxes drive heating or cooling of the upper layer whereas the surface temperature acts as a “thermostat” that regulates the vertical extent of the layer. Daily mixed layer depth estimates from the diagnostic model (and two standard bulk mixed layer models) are compared with depths obtained from oceanic profiles collected during the 1956–80 Canadian Weathership program at Station P and more recent (2001–07) profiles from the vicinity of this station from Argo drifters. Summer mixed layer depths from the diagnostic model agree more closely with observed depths and are less sensitive to heat flux errors than those from bulk models. For the Weathership monitoring period, the root-mean-square difference between modeled and observed monthly mean mixed layer depths is ∼6 m for the diagnostic model and ∼10 m for the bulk models. The diagnostic model is simpler to apply than bulk models and sidesteps the need for wind data and turbulence parameterization required by these models. Mixed layer depths obtained from the diagnostic model using NCEP–NCAR reanalysis data reveal that—contrary to reports for late winter—there has been no significant trend in the summer mixed layer depth in the central northeast Pacific over the past 52 yr.
Is There Evidence-based Hypolipidemic Treatment with Clinical Benefit beyond Statins?
Authors: Goumas Georgios S.
Published: November 2008

Aggressive therapy with statins to lower the low density lipoprotein cholesterol decreases cardiovascular events. Nevertheless, administration of the highest approved statin dose only offers limited additional benefit at the expense of an increased incidence of side effects. Therefore, novel compounds that further reduce the low-density lipoprotein cholesterol and at the same time have beneficial effects on other lipid parameters when added to statin therapy are under investigation. Nicotinic acid lowers the levels of the low-density lipoprotein cholesterol and triglycerides while raising the concentration of the protective high-density lipoprotein cholesterol. A significant inverse association exists between long-term intake of ω-3 fatty acids and cardiovascular mortality; these fish oils lower serum triglycerides levels. Fibrates substantially decrease triglycerides, increase high density lipoprotein cholesterol, and modestly decrease low-density lipoprotein cholesterol levels. Ezetimibe selectively inhibits cholesterol absorption in the gut. Combined therapy with ezetimibe and a statin provides an incremental reduction in the low-density lipoprotein cholesterol levels.
Genetic Differences in Sensitivity to Alterations of Mandible Structure Caused by the Teratogen 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Authors: Keller James M. , Zelditch Miriam L. , Huet Yvette M. , Leamy Larry J.
Published: November 2008

The contaminant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is an environmental pollutant and teratogen that has been shown to alter craniofacial development. Differences in sensitivity to TCDD are attributed primarily to differences in alleles at the Ahr locus coding for the aryl–hydrocarbon receptor (AHR) that binds TCDD and mediates its effects by altering gene expression. The authors used geometric morphometric methods to evaluate differences in the effects of small in utero exposures of TCDD on adult mandible size and shape in five different inbred mouse strains with the same Ahr alleles. Because of the known effects of this toxicant on bone and craniofacial structures, the authors hypothesized that TCDD would decrease mandible size and alter mandible shape, but that the effects of TCDD exposure would differ among the inbred strains. The authors found that TCDD did alter mandible size and shape, but these effects were limited to specific strains and also differed between the sexes. The relative sensitivity to TCDD’s effects on mandibles did not correspond with the previously reported sensitivity to TCDD’s effects on molars. The authors hypothesize that beyond Ahr-related effects, variation in response to TCDD reflects differences in the genetic architecture controlling the trait being evaluated, thus explaining the species, strain, and trait specificity of TCDD.
Fidelity to Theory in PA Intervention Research
Authors: Keller Colleen , Fleury Julie , Sidani Souraya , Ainsworth Barbara
Published: November 2008

Research using theory-based interventions to promote regular physical activity (PA) has increased substantially over the past decade. The purpose of this article is to provide a review and summary of PA intervention research specific to fidelity to intervention theory, providing an overview of the concept of fidelity to intervention theory, defining the evaluative components of fidelity: (a) conceptualization of the problem, (b) operationalization of the theory, (c) specification of mediating processes, and (d) specification of outcome variables. Using journal scans and computerized literature database searches, the authors identified 470 PA activity intervention studies that incorporated a theoretical perspective. A validity framework explicated by was used to summarize intervention research in light of fidelity to intervention theory. In all, 15 intervention studies met the inclusion criteria and were incorporated into the review. Theoretical models for health behavior change, including social cognitive theory (SCT), cognitive behavioral theory (CBT), the transtheoretical model (TTM, the TTM combined with SCT), the reversal theory (theory of psychological reversals), and the disconnected values theory, were used as a basis for intervention design and evaluation.
Differential oxidative stress and DNA damage in rat brain regions and blood following chronic arsenic exposure
Authors: Mishra D , Flora SJS
Published: November 2008

Chronic arsenic poisoning caused by contaminated drinking water is a wide spread and worldwide problem particularly in India and Bangladesh. One of the possible mechanisms suggested for arsenic toxicity is the generation of reactive oxygen species (ROS). The present study was planned 1) to evaluate if chronic exposure to arsenic leads to oxidative stress in blood and brain – parts of male Wistar rats and 2) to evaluate which brain region of the exposed animals was more sensitive to oxidative injury. Male Wistar rats were exposed to arsenic (50 ppm sodium arsenite in drinking water) for 10 months. The brain was dissected into five major parts, pons medulla, corpus striatum, cortex, hippocampus, and cerebellum. A number of biochemical variables indicative of oxidative stress were studied in blood and different brain regions. Single-strand DNA damage using comet assay was also assessed in lymphocytes. We observed a significant increase in blood and brain ROS levels accompanied by the depletion of GSH/GSSG ratio and glucose-6-phosphate dehydrogenase (G6PD) activity in different brain regions of arsenic-exposed rats. Chronic arsenic exposure also caused significant single-strand DNA damage in lymphocytes as depicted by comet with a tail in arsenic-exposed cells compared with the control cells. On the basis of results, we concluded that the cortex region of the brain was more sensitive to oxidative injury compared with the other regions studied. The present study, thus, leads us to suggest that arsenic induces differential oxidative stress in brain regions with cortex followed by hippocampus and causes single-strand DNA damage in lymphocytes.
Inhibition of carbon tetrachloride–mediated apoptosis and oxidative stress by melatonin in experimental liver fibrosis
Authors: Ogeturk M , Kus I , Pekmez H , Yekeler H , Sahin S , Sarsilmaz M
Published: November 2008

Melatonin, the principal secretory product of the pineal gland, functions as a potent antioxidant and free radical scavenger. Additionally, the antiapoptotic effect of melatonin has been observed both in vivo and in vitro. The aim of this experimental study was to investigate the protective effects of melatonin against carbon tetrachloride (CCl4)–induced apoptosis and oxidative stress in rat liver. Twenty-four male Wistar rats were divided in three equal groups. Group I was used as control. Rats in group II were injected every other day with CCl4 (0.5 mL/kg BW) for a month, whereas rats in group III were treated every other day with the same dose of CCl4 plus melatonin (25 mg/kg BW). At the end of the experiment, all animals were killed by decapitation and the livers were rapidly removed. Some of the liver tissue specimens were used for determination of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. The remaining tissue specimens were processed for immunohistochemical assessment, and the percentage rates of apoptotic liver cells stained with immunoreactive Bax were determined. Chronic administration of CCl4 significantly increased liver MDA contents, as an end product of lipid peroxidation, and also significantly decreased SOD and GSH-Px activities, emphasizing the generation of increased oxidative stress. Moreover, it caused an evident increase in apoptotic cells. Melatonin treatment significantly reduced MDA levels and elevated SOD and GSH-Px activities in rats received CCl4 plus melatonin. Furthermore, apoptotic changes caused by CCl4 were considerably decreased in these animals. The results of the present study indicate that melatonin treatment substantially prevents CCl4-induced apoptosis and oxidative damage in the liver. Thus, melatonin may serve as a drug for treating many clinical conditions that arise from inappropriate apoptosis.
JP-8 jet fuel exposure suppresses the immune response to viral infections
Authors: Harris DT , Sakiestewa D , Titone D , He X , Hyde J , Witten M
Published: November 2008

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents, namely, interleukin-10 and prostaglandin E2. Thus, it was of interest to determine if jet fuel exposure might alter the immune response to infectious agents. The Hong Kong influenza model was used for these studies. Mice were exposed to 1000 mg/m3 JP-8 (1 h/day) for 7 days before influenza viral infection. Animals were infected intra-nasally with virus and followed in terms of overall survival as well as immune responses. All surviving animals were killed 14 days after viral infection. In the present study, JP-8 exposure increased the severity of the viral infection by suppressing the anti-viral immune responses. That is, exposure of mice to JP-8 for 1 h/day for 7 days before infection resulted in decreased immune cell viability after exposure and infection, a greater than fourfold decrease in immune proliferative responses to mitogens, as well as an overall loss of CD3+, CD4+, and CD8+ T cells from the lymph nodes, but not the spleens, of infected animals. These changes resulted in decreased survival of the exposed and infected mice, with only 33% of animals surviving as compared with 50% of mice infected but not jet fuel–exposed (and 100% of mice exposed only to JP-8). Thus, short-term, low-concentration JP-8 jet fuel exposures have significant suppressive effects on the immune system which can result in increased severity of viral infections.
Arsenic in food and water – a brief history
Authors: Sambu S , Wilson R
Published: November 2008

Arsenic has been used for millenia. Although it has been known for many years that arsenic is soon fatal when ingested at high doses, the effects of low dosages became apparent in the 1980s. The full societal implications are only now becoming clear. It is now known to pose the highest calculated risk of any substance regulated by the US Environmental Protection Agency (EPA); high concentrations have been found in drinking water in many countries. In Bangladesh, in particular, the number of people suffering from over exposure vastly exceeds the number affected by the catastrophic accident at Chernobyl. This article shows the development of the human understanding about chronic arsenic poisoning with Bangladesh as a particular example.
Ethyl benzene should be considered ototoxic at occupationally relevant exposure concentrations
Authors: Vyskocil A , Leroux T , Truchon G , Lemay F , Gendron M , Gagnon F , El Majidi N , Viau C
Published: November 2008

Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the Time-Weighed Average Exposure Value for 8 h (TWAEV) is 100 ppm (434 mg/m3) and the Short-Term Exposure Value for 15 min (STEV) is 125 ppm (543 mg/m3). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as an ototoxic agent.
Chelation of bismuth by combining desferrioxamine and deferiprone in rats
Authors: Tubafard S , Fatemi SJ
Published: November 2008

Consumption and production of bismuth compounds are increasing, however, a little information on the toxic effect and also the effective method in removal of bismuth compounds are available. The present research aimed to characterize the potential efficiency of two chelators after bismuth administration for 55 days following two dose levels of 20 and 40 mg/kg body weight daily to male rats. However, we found abnormalities after bismuth administration in clinical signs, such as body weight, kidneys and liver damages, a black line on gums and skin reactions. Furthermore, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing bismuth from the body was considered. Along this line, two known chelators deferiprone (1, 2-dimethy1-3-hydroxypyride-4-one, L1) and desferrioxamine (DFO) were chosen and tested in the acute rat model. Chelators were given orally (L1) or intraperitoneally (DFO) as a single or combined therapy for the period of a week. Doses of L1 and DFO were 110 mg/kg body weight in experiments. Bismuth and iron concentrations in various tissues were determined by graphite furnace and flame atomic absorption spectrometry, respectively. The combined chelation therapy results show that DFO and L1 are able to remove bismuth ions from the body, whereas iron concentration returned to the normal level and symptoms are also decreased. DFO was more effective than L1 in reducing bismuth concentration in tissues. The efficiency of DFO + L1 is more than DFO or L1 in removing bismuth from organs. Our results are indicative that the design procedure might be useful for preliminary in-vivo testing of the efficiency of chelating agents. Results of combined chelators’ treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for efficiency of chelating agents in bismuth toxicity.
The Utility of the Clinical Pulmonary Infection Score
Authors: Rosbolt Margaret Bonnie , Sterling Emily S. , Fahy Brenda G.
Published: November 2008

The most common infectious complication in critically ill patients is ventilator-associated pneumonia. Ventilator-associated pneumonia has significant morbidity and mortality, prolongs mechanical ventilation, and extends length of hospitalization. Despite its prevalence and impact, uniform diagnostic standards are lacking. The Centers for Disease Control, American Thoracic Society, and Infectious Diseases Society of America have recommended focus on improving preventive measures, establishing widely available and accurate diagnostic tools, and improving ventilator-associated pneumonia management with length of therapy guidelines. The purpose of this article is to review the evidence supporting the clinical pulmonary infection score as an adjunct to distinguish and detect clinically relevant ventilator-associated pneumonia and its use to guide length of therapy. This score combines clinical diagnostic criteria (tracheal secretion quantification and body temperature) with routinely obtained laboratory data (white blood cell count and oxygenation parameters), radiographic data, and bacteriological culture results. Limitations of clinical pulmonary infection score will be discussed.
Reentry for Serious and Violent Offenders
Authors: Listwan Shelley Johnson
Published: November 2008

With approximately 650,000 prisoners returning home each year, the discussion surrounding how to best plan for their transition home has increased. Traditional supervision-focused parole services have a limited ability to adequately address all of the exprisoners needs and issues. As such, in 2003, the federal government established the Serious and Violent Offender Reentry Initiative (SVORI). The SVORI is a large-scale program that provided states with federal funding to develop or enhance existing reentry services. The current study builds on the previous research by examining factors associated with program failure for both the institutional and community phases of a SVORI-funded reentry program. The results indicate that those individuals who were unemployed, who did not reside with family members, and who were higher risk were significantly more likely to fail the program during the community reentry phase.
Breastfeeding Rates in Baby-Friendly and Non-Baby-Friendly Hospitals in the Czech Republic From 2000 to 2006
Authors: Mydlilova Anna , Sipek Antonin , Vignerova Jana
Published: November 2008

The type of infant feeding at hospital discharge was compared in Baby-Friendly (BF), non-BF hospitals, neonatal intermediate care units (NICU), and perinatal centres (PC) in the Czech Republic. Data from 660 355 infants born from 2000 to 2006 was collected retrospectively from newborn reports. The exclusive breastfeeding rates decreased in BF hospitals from 92.9% in 2000 to 90.3% in 2006, whereas in non-BF hospitals from 89.4% in 2000 to 87.6% in 2006. Partial breastfeeding in BF hospitals increased from 3.6% in 2000 to 5.7% in 2006, whereas in non-BF hospitals from 4.9% in 2000 to 6.8% in 2006. Exclusive formula feeding rates changed only slightly. The risk of not being exclusively breastfed was higher in non-BF than in BF hospitals (unadjusted OR = 1.57, 95% CI 1.47-1, 68 for year 2000, OR = 1.6, 95% CI 1.53-1.68 for year 2004, and OR = 1.36, 95% CI 1.3-1.42 for year 2006). In hospitals with PC and NICU the exclusive breastfeeding rates were lower than in hospitals without those departments. J Hum Lact . 25(1):73-78.
Foundation Impact on Environmental Nongovernmental Organizations
Authors: Delfin Francisco G. , Tang Shui-Yan
Published: November 2008

A survey of U.S. environmental nongovernmental organizations (NGOs) receiving grants in 2000 from private California foundations allowed the authors to evaluate conflicting claims on the impact of foundation funding on nonprofit grantees. Different from the view of elitist critics that foundations co-opt their grant recipients, these NGO respondents view foundations as mildly constructive across several organizational domains. These results are more consistent with pluralist and resource dependency arguments that view foundation donors as supportive of NGO capacity building. Whether the funding impact is cooptation or capacity building has less to do with NGOs' degree of dependency on philanthropic funds and more with grant types received and their organizational traits. Multiyear programmatic grants are associated with capacity-building, whereas 1-year program grants are associated with cooptation. A simplistic interpretation of elitist theory may underestimate the diversity of motivations among funders and the tremendous administrative costs associated with a rigid supervision of grantees.
Cell Discohesion and Multifocality of Carcinoma In situ of the Bladder: New Insight From the Adhesion Molecule Profile (e-Cadherin, Ep-CAM, and MUC1)
Authors: Patriarca Carlo , Colombo Piergiuseppe , Pio Taronna Angelo , Wesseling Jelle , Franchi Giada , Guddo Francesca , Naspro Richard , Macchi Roberto Maria , Giunta Paolo , Di Pasquale Marcello , Parente Michele , Arizzi Carmelo , Roncalli Massimo , Campo Biagio
Published: November 2008

Urothelial cell carcinoma in situ (CIS) of the bladder is a superficially diffusive and highly discohesive disease. The authors analyzed the expression of some adhesion molecules (e-cadherin and Ep-CAM) and MUC1 in 32 unifocal and multifocal bladder urothelial cell CIS in an attempt to clarify this discohesion. E-cadherin was strongly expressed, in more than 75% of the cases. The presence of methylation of the CDH1 e-cadherin promoter gene was also investigated, but methylation was found in only one case. Ep-CAM was present in all the cases with a heterogeneous staining pattern. Similarly, MUC1/episialin was variously present in 94% of the cases without a polarized staining pattern and was expressed more strongly in cases with multifocal disease. Because loss of MUC1 polarization leads to interference with cell—cell adhesion mechanisms mediated by cadherins, these findings help explain why bladder urothelial cell CIS often shows a discohesive morphology and multifocality despite a strongly expressed adhesion molecule profile. Finally, Ep-CAM expression might provide some support for future target therapy trials.
Race, Retrospective Voting, and Disasters
Authors: Lay J. Celeste
Published: November 2008

The 2006 New Orleans mayoral election provides a unique opportunity to examine the influence of a natural disaster on voting behavior. Theories of retrospective voting presume that voters will punish incumbents whose performance they deem unacceptable. To many Americans, Ray Nagin had done a poor job in handling Katrina. Theories of racial conflict and accommodation, however, contend that voters in urban elections base their choice primarily on racial group interests. This study shows that racial identity was a critical factor in vote choice. Although judgments of Nagin's performance were important, many voters placed greater responsibility on the federal government for the response.
Answering the critics
Authors: Jakimow Tanya
Published: November 2008

Post-development critiques and subsequent debates have sparked revision in the development sector, influencing recent approaches to knowledge in development. This article examines the extent to which the ‘knowledge strategies’ applied to development agencies are compatible with the normative characteristics of ‘reflexive development’. It argues that although development agencies are seemingly in a process of transforming thinking and practice, reflexivity has not gone far enough in the evaluation of development strategies. This has resulted in several deficiencies in the knowledge agenda: a concentration on organizations rather than the development sector; an emphasis on larger organizations while ignoring smaller development actors; and inadequate conceptualizations of ‘learning’.
The millennium village project and African development
Authors: Carr Edward R.
Published: November 2008

The Millennium Village Project (MVP) has come to embody hope for a new development path that might succeed where previous efforts have failed. A closer consideration of this project, however, suggests that this hope might be misplaced. Because of a general dearth of critical thought in key areas of project conceptualization, the MVP risks reproducing the problems of previous top-down, expert-driven development efforts. This article examines the conceptual issues raised by this absence of critical thought, and the reasons why project supporters have generally overlooked these issues. It then presents a critical grassroots framework which, if incorporated into existing MVP practices, might allow for the creation of a realistic, sustainable development path in Africa.
Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia
Authors: de Jonge Robert , Tissing Wim J. E. , Hooijberg Jan Hendrik , Jansen Gerrit , Kaspers Gertjan J. L. , Lindemans Jan , Peters Godefridus J. , Pieters Rob
Published: November 2008

Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS −151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P < .05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G>A and NNMT IVS −151C>T variants to an increased ALL susceptibility.
Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks
Authors: Ocio Enrique M. , Maiso Patricia , Chen Xi , Garayoa Mercedes , Álvarez-Fernández Stela , San-Segundo Laura , Vilanova David , López-Corral Lucía , Montero Juan C. , Hernández-Iglesias Teresa , de Álava Enrique , Galmarini Carlos , Avilés Pablo , Cuevas Carmen , San-Miguel Jesús F. , Pandiella Atanasio
Published: November 2008

Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50 values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.