The non-genomic effects of high doses of Rosiglitazone on cell growth and apoptosis in cultured monocytic cells

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a ligand-activated transcription factor which belongs to the nuclear hormone superfamily and has multiple pharmacological ligands called Thiazolidinediones (TZDs). TZDs are a class of drugs used in the treatment of type 2 diabetic patients. Rosiglitazone is one such TZD, and is used clinically to treat type 2 diabetes. In this study, the effect of Rosiglitazone on cell growth and apoptosis in cultured monocytic monomac 6 (MM6) cells was investigated. Over a 14 day period, MM6 cells were cultured in vitro and treated with 1μM and 10μM Rosiglitazone. Cell viability and proliferation were evaluated by Haemocytometer cell count and MTS assay respectively. Turbidity due to cell density was assessed spectrophotometrically. Apoptosis was determined by Caspase-Glo 3/7 assay. Expression of the endoplasmic reticulum (ER) stress-inducible protein sarco-endoplasmic reticulum Ca2+ATPase-2b (SERCA2b) was determined by Western blot. Neither 1μM nor 10μM Rosiglitazone exerted statistically significant inhibitory effects on cell proliferation, turbidity due to cell density, or cell viability (p > 0.05 in all cases). In contrast, Rosiglitazone induced increased apoptosis, but a significant difference was only observed in 10μM-treated cells compared with control cells (3.04 ± 0.52 control; p < 0.05) while 1μM-treated cells showed a non-significant increase (1.50 ± .06 control; p > 0.05). Meanwhile the expression of SERCA2b was up-regulated significantly in cells treated for >4hrs (e.g 2.45 ± 0.06 control at 24 hrs; p < 0.05) with 10μM Rosiglitazone. It was concluded that high doses (10μM) of Rosiglitazone up-regulate SERCA2b expression and induce apoptosis of MM6 cells by activating an ER stress response via a PPARγ-independent mechanism. The therapeutic relevance of these observations is a matter for further investigations. Key words: Rosiglitazone, PPARγ, Monocytes, ER Stress, SERCA2b, Apoptosi

Millennial-scale perspective on biodiversity conservation of the forest-steppe ecotone in Europe

Paleoecological studies document that grasslands with a high conservation value in the European forest-steppe ecotone are often anthropogenically derived, requiring management to avoid woodland recovery. Nevertheless, naturally open areas often persisted within this ecotone, explaining the high richness of these grassland

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

Conditional statistics of electron transport in interacting nanoscale conductors

Interactions between nanoscale semiconductor structures form the basis for charge detectors in the solid state. Recent experimental advances have demonstrated the on-chip detection of single electron transport through a quantum dot (QD). The discreteness of charge in units of e leads to intrinsic fluctuations in the electrical current, known as shot noise. To measure these single-electron fluctuations a nearby coherent conductor, called a quantum point contact (QPC), interacts with the QD and acts as a detector. An important property of the QPC charge detector is noninvasiveness: the system physically affects the detector, not visa-versa. Here we predict that even for ideal noninvasive detectors such as the QPC, when a particular detector result is observed, the system suffers an informational backaction, radically altering the statistics of transport through the QD as compared to the unconditional shot noise. We develop a theoretical model to make predictions about the joint current probability distributions and conditional transport statistics. The experimental findings reported here demonstrate the reality of informational backaction in nanoscale systems as well as a variety of new effects, such as conditional noise enhancement, which are in essentially perfect agreement with our model calculations. This type of switching telegraph process occurs abundantly in nature, indicating that these results are applicable to a wide variety of systems.Comment: 16 pages, 3 figures, to appear in Nature Physic

Gene mobility promotes the spread of resistance in bacterial populations

Theory predicts that horizontal gene transfer (HGT) expands the selective conditions under which genes spread in bacterial populations. Whereas vertically inherited genes can only spread by positively selected clonal expansion, mobile genetic elements can drive fixation of genes by infectious HGT. We tested this using populations of Pseudomonas fluorescens and the conjugative mercury resistance (Hg R) plasmid pQBR57. HGT expanded the selective conditions allowing the spread of Hg R: Chromosomal Hg R only increased in frequency under positive selection, whereas plasmid-encoded Hg R reached fixation with or without positive selection. Tracking plasmid dynamics over time revealed that the mode of Hg R inheritance varied across mercury environments. Under mercury selection, the spread of Hg R was driven primarily by clonal expansion while in the absence of mercury Hg R dynamics were dominated by infectious transfer. Thus, HGT is most likely to drive the spread of resistance genes in environments where resistance is useless

Prescription Drugs Associated with Reports of Violence Towards Others

CONTEXT: Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others. OBJECTIVE: To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association. METHODOLOGY: From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms. MAIN OUTCOME MEASURES: Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a χ2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01). RESULTS: We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs. CONCLUSIONS: Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features

Processes controlling the net carbon consumption of inorganic carbon in the North Sea

Data on dissolved inorganic carbon (DIC), partial pressure of CO2 (pCO2) and nutrients have been collected during four cruises carried out in the whole North Sea, each cruise covering one month of each season between 2001 and 2002. The impact of biological activity, air-sea exchange and physical mixing processes on the monthly variations of DIC have been determined for each regions of the North Sea using the International Commission for the Exploration of the Seas (ICES) boxes separation. For the February-July period, the biological activity was the main factor controlling the DIC variations in the upper layer of the whole North Sea and was responsible for a loss of 20 to 50 mmol m-3 month-1. The concomitant atmospheric input increased DIC by 8 to 12 mmol m-3, whereas the mixing term was low, except in the north-western North Sea, where it increased DIC concentrations by approximately 10 mmol m-3.We computed the Net Community Production based on Carbon (DIC) data (NCPC) for the North Sea. For the productive period, the NCPC was higher in the upper layer of the northern and central North Sea than in the coastal and southern areas. Maximum values of 1.0 to 1.5 mol C m-2 month-1 were observed inMay in the northern and central North Sea, whereas maximum of 0.5-0.7 mol C m-2 month-1 were observed in April in the southern and coastal areas of the North Sea.We compared the NCPC to the NCP calculated from nitrogen data from the same cruises and converted into moles of carbon using the Redfield ratios (NCPN). Results showed that in areas where nitrate was depleted by April, i.e. mainly in the central and northern North Sea, DIC consumption continues until July, leading to a large difference between NCPC and NCPN. On the other hand, in coastal areas where nitrate were available during the complete productive period, NCPC and NCPN were very similar. For the whole year in the upper layer of the North Sea, the NCPC of 2.3 mol C m-2 yr-1 was a factor two higher than NCPN and higher than previous calculation of the net carbon production in the North Sea based on nutrient data. We argue that NCP based on nutrient data converted to moles of carbon using the Redfield ratios, leads to underestimation of the net carbon production for the North Sea because of the preferential recycling of nutrients

Pregnant women with bronchial asthma benefit from progressive muscle relaxation: A randomized, prospective, controlled trial

Background: Asthma is a serious medical problem in pregnancy and is often associated with stress, anger and poor quality of life. The aim of this study was to determine the efficacy of progressive muscle relaxation (PMR) on change in blood pressure, lung parameters, heart rate, anger and health-related quality of life in pregnant women with bronchial asthma. Methods: We treated a sample of 64 pregnant women with bronchial asthma from the local population in an 8-week randomized, prospective, controlled trial. Thirty-two were selected for PMR, and 32 received a placebo intervention. The systolic blood pressure, forced expiratory volume in the first second, peak expiratory flow and heart rate were tested, and the State-Trait Anger Expression Inventory and Health Survey (SF-36) were employed. Results: According to the intend-to-treat principle, a significant reduction in systolic blood pressure and a significant increase in both forced expiratory volume in the first second and peak expiratory flow were observed after PMR. The heart rate showed a significant increase in the coefficient of variation, root mean square of successive differences and high frequency ranges, in addition to a significant reduction in low and middle frequency ranges. A significant reduction on three of five State-Trait Anger Expression Inventory scales, and a significant increase on seven of eight SF-36 scales were observed. Conclusions: PMR appears to be an effective method to improve blood pressure, lung parameters and heart rate, and to decrease anger levels, thus enhancing health-related quality of life in pregnant women with bronchial asthma. Copyright (c) 2006 S. Karger AG, Basel

Climate change adaptation, flood risks and policy coherence in integrated water resources management in England

Integrated water resources management (IWRM) assumes coherence between cognate aspects of water governance at the river basin scale, for example water quality, energy production and agriculture objectives. But critics argue that IWRM is often less ‘integrated’ in practice, raising concerns over inter-sectoral coherence between implementing institutions. One increasingly significant aspect of IWRM is adaptation to climate change-related risks, including threats from flooding, which are particularly salient in England. Although multiple institutional mechanisms exist for flood risk management (FRM), their coherence remains a critical question for national adaptation. This paper therefore (1) maps the multi-level institutional frameworks determining both IWRM and FRM in England; (2) examines their interaction via various inter-institutional coordinating mechanisms; and (3) assesses the degree of coherence. The analysis suggests that cognate EU strategic objectives for flood risk assessment demonstrate relatively high vertical and horizontal coherence with river basin planning. However, there is less coherence with flood risk requirements for land-use planning and national flood protection objectives. Overall, this complex governance arrangement actually demonstrates de-coherence over time due to ongoing institutional fragmentation. Recommendations for increasing IWRM coherence in England or re-coherence based on greater spatial planning and coordination of water-use and land-use strategies are proposed