Impaired organic anion excretion and cholestasis caused by 1,3-bis-(2-chloroethyl)-1-nitrosourea (carmustine or BCNU) in rats

Previous investigation showed that 20 mg/kg BCNU caused inhibition of sulfobromophthalein (BSP) excretion and inhibited bile salt independent bile flow (BSIF) in rats by 48 h after treatment (Hoyt, 1984). The present investigation demonstrated that BCNU inhibited the canalicular step in the excretion of BSP. This was indicated by the inhibition of maximal excretion of BSP, inhibition of the biliary excretion of the non-metabolized dye, indocyanine green and the lack of inhibition of the conjugation of BSP with glutathione. Canalicular effects were also suggested because BCNU-pretreatment inhibited the excretion of endogenous reduced glutathione and oxidized glutathione. The inhibition of BSP excretion by BCNU did not appear to result from increased hepatic content of reduced or oxidized glutathione because these materials fell to normal levels at 72 h after 20 mg/kg BCNU. BSP excretion was inhibited by this dosage for at least 96 h (Hoyt, 1984). Inhibition of BSP excretion was not due to accumulation of bile salts because their depletion had no effect on BSP excretion in BCNU-treated rats. Pretreatment of rats with pentobarbital sodium prevented BCNU-induced cholestasis and inhibition of BSP excretion. Pentobarbital may have stimulated BSIF, altered the response of the liver to BCNU, changed the amount and/or types of interactions of BCNU with liver or reduced the amount of BCNU reaching sites of action. Theophylline and glucagon infusions stimulated bile flow in BCNU-treated rats. These agents may have increased intracellular cyclic adenosine monophosphate (cAMP) content. The research of others indicates that cAMP may stimulate sodium-coupled chloride transport in epithelia. Therefore, this transport or hepatocellular cAMP may be depressed in BCNU-treated rats. Theophylline and glucagon may have stimulated bile flow so that the effect of BCNU on other systems was masked. Analysis of biliary bile salt composition demonstrated that there was no increase of the more hydrophobic, toxic bile salts. No action of BCNU is related to the hypothesized accumulation. The opposite trend, a shift to hydrophilic bile salts, was observed. This shift is observed in cholestasis caused by alpha-napthyl isothiocyanate, ethinyl estradiol and bile duct ligation, suggesting that it is a result of cholestasis

Protein Never in Mitosis Gene A Interacting-1 regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells

© 2009 Liu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Self-concealment: Integrative review and working model

An extensive empirical literature has focused on the self-concealment (SC) construct. In this article, we review 137 studies that used the Self-Concealment Scale (SCS) with varied populations (e.g., adolescent; intercultural; international; lesbian, gay, and bisexual; and intimate partner). We propose a working model for the psychology of SC and the mechanisms of action for its effects on well-being. A dual-motive conflict between urges to conceal and reveal is seen to play a central role in these health effects. Meta-analytic techniques identify significant associations for SC with 18 constructs falling into six general categories: antecedents, disclosure and concealment, emotion regulation, social well-being, psychological and physical health, and psychotherapy. We interpret these findings with reference to current research and theory on secret keeping and health as well as emotion- and self-regulatory processes. This first integrative review supports the construct validity of the SCS and demonstrates the value of the SC construct for the study of psychological phenomena in which secret keeping is a recognized issue

Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet

<p>Abstract</p> <p>Background</p> <p>It was hypothesized that a pro-atherogenic, high saturated fat and cholesterol diet (HCD) would increase the inflammatory response to <it>E. coli </it>endotoxin (LPS) and increase its concentration in plasma after administration to mice.</p> <p>Methods</p> <p>C57Bl/6 mice were fed a HCD or a control diet (CD) for 4 weeks, and then treated with saline, 0.5, 1 or 2 mg LPS/kg, ip. Liver injury (alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, collagen staining), circulating cytokines (tumor necrosis factor-α, interleukin-6 and interferon-γ), factors that can bind LPS (serum amyloid A, apolipoprotein A1, LPS binding protein, and CD14), and plasma levels of LPS were measured. The hepatic response was assessed by measuring vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase (iNOS) and signal transducer and activator of transcription-1 proteins, and VCAM-1 and iNOS mRNAs. Hepatic mRNA encoding the LPS receptor, Toll like receptor 4, was also determined.</p> <p>Results</p> <p>Two mg LPS/kg killed 100% of mice fed HCD within 5 d, while no mice fed CD died. All mice treated with 0 to 1 mg LPS/kg survived 24 h. HCD increased plasma alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, and the enzymes were increased more by LPS in HCD than CD mice. Induction of plasma tumor necrosis factor-α, interleukin-6, and interferon-γ by LPS was greater with HCD than CD. Hepatic VCAM-1 and iNOS protein and mRNA were induced by LPS more in mice fed HCD than CD. Tyrosine phosphorylation of signal transducer and activator of transcription-1 caused by LPS was prolonged in HCD compared with CD mice. Despite the hepatic effects of HCD, diet had no effect on the LPS plasma concentration-time profile. HCD alone did not affect circulating levels of plasma apolipoprotein A1 or LPS binding protein. However, plasma concentrations of serum amyloid A and CD14, and hepatic toll-like receptor-4 mRNA were increased in mice fed HCD.</p> <p>Conclusion</p> <p>HCD increased the sensitivity of mice to LPS without affecting its plasma level. Although increased serum amyloid A and CD14 in the circulation may inhibit LPS actions, their overexpression, along with hepatic toll-like receptor-4 or other factors, may contribute to the heightened sensitivity to LPS.</p

Using Remotely Sensed Data and Watershed and Hydrodynamic Models to Evaluate the Effects of Land Cover Land Use Change on Aquatic Ecosystems in Mobile Bay, AL

Alabama coastal systems have been subjected to increasing pressure from a variety of activities including urban and rural development, shoreline modifications, industrial activities, and dredging of shipping and navigation channels. The impacts on coastal ecosystems are often observed through the use of indicator species. One such indicator species for aquatic ecosystem health is submerged aquatic vegetation (SAV). Watershed and hydrodynamic modeling has been performed to evaluate the impact of land cover land use (LCLU) change in the two counties surrounding Mobile Bay (Mobile and Baldwin) on SAV stressors and controlling factors (temperature, salinity, and sediment) in the Mobile Bay estuary. Watershed modeling using the Loading Simulation Package in C++ (LSPC) was performed for all watersheds contiguous to Mobile Bay for LCLU scenarios in 1948, 1992, 2001, and 2030. Remotely sensed Landsat-derived National Land Cover Data (NLCD) were used in the 1992 and 2001 simulations after having been reclassified to a common classification scheme. The Prescott Spatial Growth Model was used to project the 2030 LCLU scenario based on current trends. The LSPC model simulations provided output on changes in flow, temperature, and sediment for 22 discharge points into the estuary. These results were inputted in the Environmental Fluid Dynamics Computer Code (EFDC) hydrodynamic model to generate data on changes in temperature, salinity, and sediment on a grid throughout Mobile Bay and adjacent estuaries. The changes in the aquatic ecosystem were used to perform an ecological analysis to evaluate the impact on SAV habitat suitability. This is the key product benefiting the Mobile Bay coastal environmental managers that integrates the influences of temperature, salinity, and sediment due to LCLU driven flow changes with the restoration potential of SAVs. Data products and results are being integrated into NOAA s EcoWatch and Gulf of Mexico Data Atlas online systems for dissemination to coastal resource managers and stakeholders. Objective 1: Develop and utilize Land Use scenarios for Mobile and Baldwin Counties, AL as input to models to predict the affects on water properties (temperature,salinity,)for Mobile Bay through 2030. Objective 2: Evaluate the impact of land use change on seagrasses and SAV in Mobile Bay. Hypothesis: Urbanization will significantly increase surface flows and impact salinity and temperature variables that effect seagrasses and SAVs

The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity

Background: We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. Results: FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO). Conclusions: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy

Антикризисное управление

Учебно-методический комплекс (УМК) по учебной дисциплине «Ан-тикризисное управление» создан в соответствии с требованиями Положения об учебно-методическом комплексе на уровне высшего образования, утвер-жденного постановлением Министерства образования Республики Беларусь от 26.07.2011 № 167, предназначен для реализации содержания образова-тельной программы для обучающихся первой ступени высшего образования для студентов специальности 1-26 02-02 «Менеджмент». Содержание разделов УМК соответствует образовательному стандарту высшего образования данной специальности. Главная цель УМК – оказание методической помощи магистрантам в освоении и систематизации учебного материала в процессе обучения и под-готовки к аттестации по дисциплине «Антикризисное управление». УМК включает: 1. Теоретический раздел (конспект лекций, аннотированный перечень основных учебных и научно-практических изданий). 2. Практический раздел (тематика практических занятий по дисци-плине в соответствии с учебным планом и учебной программой). 3. Контроль работы обучающихся (материалы для текущей аттестации, позволяющие определить соответствие учебной деятельности обучающихся требованиям образовательного стандарта высшего образования и учебно-программной документации, в т.ч. вопросы для подготовки к зачету). 4. Вспомогательный раздел (содержание учебного материала учебной дисциплины; методические рекомендации по организации самостоятельной работы магистрантов; информационно-аналитические материалы: список ре-комендуемой литературы, перечень электронных ресурсов и их адреса; при-мерный перечень тем для написания рефератов). Работа с УМК должна включать на первом этапе ознакомление с со-держанием учебного материала учебной дисциплины, посредством которого можно получить информацию о тематике лекций и практических занятий, перечнях рассматриваемых вопросов и рекомендуемой для их изучения ли-тературы. Для подготовки к практическим занятиям необходимо использо-вать материалы, представленные в Теоретическом и Практическом разделах. В основу структуры программы легла учебная программа «Антикри-зисное управление» Белорусского государственного университета для выс-ших учебных заведений по специальности Э.01.03.00 «Экономика и управле-ния на предприятии» (регистрационный № ТД-182/баз.)

Industrial Relations Experiments in China: Balancing Equity and Efficiency the Chinese Way

China should build socialism by "crossing the river by feeling for stones" (Deng Xiaoping). Chinese industrial relations are changing accordingly. Local union experiments have implemented local-level changes experimenting with institutional reforms that address efficiency and equity imbalances. Local union leaders have exercised autonomy to develop multi-employer “community unions” in Changchun’s Chaoyang District to represent peasant migrant workers employed by small firms by targeting small geographic zones and hiring union presidents as organizers, aggregating union members into amalgamated units. While the union’s role still includes social harmonization, unions have undertaken an additional representative role. Similar efforts elsewhere have given the union representation experience. Unions have organized multi-employer federations across industries. Unions also have collaborated with local governments on innovative structures to ensure that companies in some industries, such as construction, post a “bond” to guarantee end-of-year compensation. Finally, this paper discusses the role of the new Labor Contract Law in institutionalizing these changes. The LCL defines more precisely employment relationships and workers’ legal rights and seems to increase unions’ legal authority to ensure that employers respect individual workers’ rights, supports the extension of collective contracts to more enterprises, and appears to give unions greater authority to represent workers within the employment relationship and before legal authorities. These changes may provide a material basis for balancing efficiency with equity. We think these experiments have political foundations, whether it is “harmonious society” or simply to extend the union’s organizing maintain political status. Further research will determine whether these experiments are successful

Characterization of cholestasis induced by 1,3-bis-(2-chloroethyl)-1-nitrosourea in rats

BCNU caused severe cholestasis in rats after a single intraperitoneal injection. The cholestasis was characterized by a selective reduction of the bile salt independent bile flow to 11% of control. Decreased food or water consumption by the treated rats apparently did not contribute to cholestasis. Measurements of plasma Na⁺ and K⁺ concentrations were consistent with current concepts regarding the role of Na⁺/K⁺ ATPase in the formation of bile salt independent bile flow. Nevertheless, the possibility that the permeability of water to the canalicular space may be reduced in treated rats remains to be evaluated. Although bile salt excretion rates were slightly reduced in treated rats during cholestasis, bile salt concentrations in bile were elevated. Therefore, bile salt excretion was limited by cholestasis, not by a defect in concentrative transport. This increase in biliary bile salt concentration and increases in bile:plasma osmolality ratios tend to discount a breakdown of the bile:plasma permeability barrier as a cause of cholestasis in BCNU treated rats. In contrast to the effect of BCNU on bile salt excretion, treated rats failed to concentrate the xenobiotic organic anion, sulfobromophthalein (BSP), in bile to a normal extent. This was evident prior to the onset of cholestasis and, therefore, may be reflective of the lesion that causes cholestasis. Because BSP excretion depends largely upon conjugation of the dye with glutathione (GSH), hepatic GSH and BSP metabolites in bile were monitored. BCNU caused an increase in hepatic GSH before its effects on BSP excretion and bile flow were evident. The effect on GSH may be a result of stimulated synthesis, inhibited enzymatic degradation, inhibited efflux from the hepatocyte, or a combination of these. In any case, the decreased BSP excretion was not due to a lack of substrate for conjugation. BCNU, besides inhibiting BSP excretion, produced a qualitative change in BSP metabolites found in bile. This effect may be due to an alteration of GSH-S-transferase activity in treated rats. However, decreased canalicular excretion or bisolateral uptake may acount for the results

Grief counseling efficacy: What have we learned?

The growing debate within the bereavement field about the efficacy of grief counselling offers two contrasting viewpoints. At one extreme is Neimeyer\u27s claim that ‘such interventions are typically ineffective, and perhaps even deleterious, at least for persons experiencing a normal bereavement’. At the other is the more cautiously optimistic position of Larson and Hoyt, who argue that studies of grief counselling as typically practised demonstrate levels of effectiveness similar to those found for traditional psychotherapy, and that there is no empirical evidence to support claims of harmful effects. This article summarises the key findings and claims in this debate, explores factors that might have contributed to an uncritical acceptance of the claim that grief counselling is harmful, and recapitulates the authors’ view that the empirical data on outcomes from grief counselling give cause for cautious optimism