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Sample records for ppargamma induces profound

  1. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

    PubMed

    Yamauchi, T; Waki, H; Kamon, J; Murakami, K; Motojima, K; Komeda, K; Miki, H; Kubota, N; Terauchi, Y; Tsuchida, A; Tsuboyama-Kasaoka, N; Yamauchi, N; Ide, T; Hori, W; Kato, S; Fukayama, M; Akanuma, Y; Ezaki, O; Itai, A; Nagai, R; Kimura, S; Tobe, K; Kagechika, H; Shudo, K; Kadowaki, T

    2001-10-01

    PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

  2. Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer.

    PubMed

    Reddy, Raju C; Srirangam, Anjaiah; Reddy, Kaunteya; Chen, Jun; Gangireddy, Srinivasareddy; Kalemkerian, Gregory P; Standiford, Theodore J; Keshamouni, Venkateshwar G

    2008-06-01

    Preclinical studies have shown that peroxisome proliferator-activated receptor gamma (PPAR-gamma) ligands can exert antitumor effects against non-small cell lung cancer (NSCLC) and a variety of other cancers. In this study, we investigate the potential use of a PPAR-gamma ligand, troglitazone (Tro), in combination with either of two chemotherapeutic agents, cisplatin (Cis) or paclitaxel (Pac), for the treatment of NSCLC. In vitro, treatment of NSCLC cell lines with Tro potentiated Cis- or Pac-induced growth inhibition. The potentiation of growth inhibition was observed only when Cis or Pac treatment was followed by Tro and not vice versa, demonstrating a sequence-specific effect. Median effect analysis revealed a synergistic interaction between Tro and Cis in the inhibition of NSCLC cell growth and confirmed the sequence-specific effect. We also found that Cis or Pac up-regulated the expression of PPAR-gamma protein, accounting for the observed sequence-specific synergy. Similarly, experiments performed using a NSCLC xenograft model demonstrated enhanced effectiveness of combined treatment with Cis and PPAR-gamma ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-gamma expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-gamma ligands and chemotherapeutic agents for lung cancer treatment.

  3. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis.

    PubMed

    Milam, Jami E; Keshamouni, Venkateshwar G; Phan, Sem H; Hu, Biao; Gangireddy, Srinivasa R; Hogaboam, Cory M; Standiford, Theodore J; Thannickal, Victor J; Reddy, Raju C

    2008-05-01

    Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR-gamma as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-gamma in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-gamma agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-gamma agonists, including a constitutively active PPAR-gamma construct (VP16-PPAR-gamma), inhibit the ability of transforming growth factor-beta1 to induce myofibroblast differentiation and collagen secretion. PPAR-gamma agonists also inhibit fibrosis in a murine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR-gamma is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-gamma ligands as novel therapeutic agents for fibrotic lung diseases.

  4. PPAR-gamma knockout in pancreatic epithelial cells abolishes the inhibitory effect of rosiglitazone on caerulein-induced acute pancreatitis.

    PubMed

    Ivashchenko, C Y; Duan, S Z; Usher, M G; Mortensen, R M

    2007-07-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR-gamma agonists have been shown to exert some of their actions independent of PPAR-gamma, the role of PPAR-gamma in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR-gamma in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR-gamma in the endodermal derivatives, we created a cell-type specific knock out of PPAR-gamma in pancreatic acini, ducts, and islets. PPAR-gamma knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR-gamma knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR-gamma in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis.

  5. Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells

    SciTech Connect

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee; Koo, Hong Hoe; Sung, Ki Woong

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

  6. Bioassay for the identification of natural product-based activators of peroxisome proliferator-activated receptor-gamma (PPARgamma): the marine sponge metabolite psammaplin A activates PPARgamma and induces apoptosis in human breast tumor cells.

    PubMed

    Mora, Flor D; Jones, Deborah K; Desai, Prashant V; Patny, Akshay; Avery, Mitchell A; Feller, Dennis R; Smillie, Troy; Zhou, Yu-Dong; Nagle, Dale G

    2006-04-01

    Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor (NHR) family, are ligand-activated transcription factors. Ligands (agonists) of PPARgamma have been shown to inhibit growth, promote terminal differentiation, and induce apoptosis in human breast tumor cells. A cell-based reporter assay was developed to examine extracts of terrestrial and marine organisms for the ability to activate PPARgamma. Bioassay-guided fractionation and isolation of an active extract from Pseudoceratina rhax yielded the known histone deacetylase (HDAC) inhibitor psammaplin A (1). Compound 1 activates PPARgamma in a MCF-7 cell-based reporter assay and induces apoptosis in human breast tumor cells in vitro. Molecular modeling studies suggest that 1 may interact with binding sites within the PPARgamma ligand-binding pocket. Therefore, in addition to its known effects on HDAC-mediated processes, activation of PPARgamma-regulated gene expression may play a role in the ability of 1 to induce apoptosis.

  7. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    SciTech Connect

    Kim, Soyeon; Lee, Jae-Jung; Heo, Dae Seog

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands

  8. Albumin mediates PPAR-gamma or C/EBP-alpha-induced phenotypic changes in pancreatic stellate cells.

    PubMed

    Kim, Nayoung; Choi, Soyoung; Lim, Chaeseung; Lee, Hongsik; Oh, Junseo

    2010-01-01

    Activation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells is a key event of liver fibrosis, and adipogenic transcription factors, PPAR-gamma and C/EBP-alpha, reverse HSC activation. As albumin was reported to maintain the quiescent phenotype of stellate cells, we examined whether it plays a role in PPAR-gamma and C/EBP-alpha-mediated effects. Pancreatic stellate cells (PSCs) were isolated from rat pancreas and used in their culture-activated phenotype. Forced expression of PPAR-gamma or C/EBP-alpha in PSCs increased albumin mRNA and protein levels by >2.5-fold, which is accompanied with increased C/EBP-beta binding to albumin promoter. PPAR-gamma and C/EBP-alpha also induced a phenotypic switch from activated to quiescent cells and, interestingly, suppression of albumin using short-hairpin RNA (shRNA) blocked their effects. Therefore, our findings suggest that albumin may be a downstream effector of PPAR-gamma and C/EBP-alpha in PSCs and that it can be an attractive molecular target for anti-fibrotic therapies. Copyright 2009 Elsevier Inc. All rights reserved.

  9. Comparative gene expression profiles induced by PPAR{gamma} and PPAR{alpha}/{gamma} agonists in rat hepatocytes

    SciTech Connect

    Rogue, Alexandra; Renaud, Marie Pierre; Claude, Nancy; Guillouzo, Andre; Spire, Catherine

    2011-07-01

    Species-differential toxic effects have been described with PPAR{alpha} and PPAR{gamma} agonists between rodent and human liver. PPAR{alpha} agonists (fibrates) are potent hypocholesterolemic agents in humans while they induce peroxisome proliferation and tumors in rodent liver. By contrast, PPAR{gamma} agonists (glitazones) and even dual PPAR{alpha}/{gamma} agonists (glitazars) have caused idiosyncratic hepatic and nonhepatic toxicities in human without evidence of any damage in rodent during preclinical studies. The mechanisms involved in such differences remain largely unknown. Several studies have identified the major target genes of PPAR{alpha} agonists in rodent liver while no comprehensive analysis has been performed on gene expression changes induced by PPAR{gamma} and dual PPAR{alpha}/{gamma} agonists. Here, we investigated transcriptomes of rat hepatocytes after 24 h treatment with two PPAR{gamma} (troglitazone and rosiglitazone) and two PPAR{alpha}/{gamma} (muraglitazar and tesaglitazar) agonists. Although, hierarchical clustering revealed a gene expression profile characteristic of each PPAR agonist class, only a limited number of genes was specifically deregulated by glitazars. Functional analyses showed that many genes known as PPAR{alpha} targets were also modulated by both PPAR{gamma} and PPAR{alpha}/{gamma} agonists and quantitative differences in gene expression profiles were observed between these two classes. Moreover, most major genes modulated in rat hepatocytes were also found to be deregulated in rat liver after tesaglitazar treatment. Taken altogether, these results support the conclusion that differential toxic effects of PPAR{alpha} and PPAR{gamma} agonists in rodent liver do not result from transcriptional deregulation of major PPAR target genes but rather from qualitative and/or quantitative differential responses of a small subset of genes.

  10. Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study.

    PubMed

    Salam, Noeris K; Huang, Tom H-W; Kota, Bhavani P; Kim, Moon S; Li, Yuhao; Hibbs, David E

    2008-01-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays an essential role in lipid and glucose homeostasis. It is recognized as the receptor of the thiazolidinediones-a synthetic class of anti-diabetic drugs-and is the target of many drug discovery efforts because of its role in disease states, such as type II diabetes mellitus. In this study, structure-based virtual screening of the PPAR-gamma ligand binding domain against a natural product library has revealed 29 potential agonists. In vitro testing of this list identified six flavonoids to have stimulated PPAR-gamma transcriptional activity in a transcriptional factor assay. Of these, flavonoid-psi-baptigenin-was classed as the most potent PPAR-gamma agonist, possessing low micromolar affinity (EC(50) = 2.9 microM). Further in vitro testing using quantitative RT-PCR and immunoblotting experiments demonstrated that psi-baptigenin activated PPAR-gamma mRNA (4.1 +/- 0.2-fold) and protein levels (2.9 +/- 0.4-fold) in THP-1 macrophages. Moreover, psi-baptigenin's-induced PPAR-gamma enhancement was abolished in the presence of a selective PPAR-gamma antagonist, GW9662. Induced-fit docking investigations provide a detailed understanding on the ligands' mechanism of action, suggesting five of the active flavonoids induce significant conformational change in the receptor upon binding. Overall, these results offer insight into various naturally derived flavonoids as leads/templates for development of novel PPAR-gamma ligands.

  11. Effect of niacin on LXRalpha and PPARgamma expression and HDL-induced cholesterol efflux in adipocytes of hypercholesterolemic rabbits.

    PubMed

    Zhao, Shui-ping; Yang, Jun; Li, Jing; Dong, Shao-zhuang; Wu, Zhi-hong

    2008-02-29

    Adipose tissue contains a large amount of cholesterol and performs a buffer function for circulating cholesterol. Liver X receptors (LXR) alpha and peroxisome proliferator-activated receptor gamma (PPARgamma) might play a significant role in adipocyte cholesterol metabolism through mediation of cholesterol efflux. The aim of this study was to evaluate the effect of niacin on LXRalpha and PPARgamma expression and HDL-induced cholesterol efflux in adipocytes from hypercholesterolemic rabbits. Twelve rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n=6): maintained high cholesterol diet for 6 weeks; (2) niacin group (n=6): the same cholesterol diet plus niacin (200 mg/kg/d) for 6 weeks. Control group (n=6) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for adipocyte culture. Reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate adipocytes LXRalpha mRNA expressions. Cholesterol efflux rate was determined through measuring release of radioactivity from (3)H-cholesterol prelabeled cells into medium containing high-density lipoprotein (HDL). The direct effect of niacin on LXRalpha and PPARgamma mRNA expression in primary rabbit adipocytes was assayed. High cholesterol diet resulted in decreased LXRalpha mRNA expressions and reduced HDL-induced cholesterol efflux rate in adipocytes. Six weeks of niacin treatment significantly enhanced the cholesterol efflux from adipocytes, which was related to the increased mRNA expressions of LXRalpha (r=0.71, P<0.05). In in vitro study, niacin dose-dependently stimulated LXRalpha and PPARgamma mRNA expression in cultured adipocytes. And various doses of niacin-induced cholesterol efflux was positive correlation with LXRalpha and PPARgamma mRNA expression (r=0.83 P<0.01; r=0.76 P<0.05; respectively). Niacin can up-regulate LXRalpha and PPARgamma mRNA expression and promote the HDL-induced cholesterol efflux in

  12. Evodiamine might inhibit TGF-beta1-induced epithelial-mesenchymal transition in NRK52E cells via Smad and PPAR-gamma pathway.

    PubMed

    Wei, Jiali; Li, Zhuori; Yuan, Feng

    2014-07-01

    Epithelial-mesenchymal transition (EMT) is involved in renal tubulointerstitial fibrosis. Transforming growth factor (TGF)-beta1 is the main inducer of EMT. Phosphorylation of Smad proteins and PPAR-gamma activation are required for the process of TGF-beta1-induced EMT. Evodiamine possesses anti-inflammatory, anti-obesity, anti-cancer, and anti-nociceptive effects. We have examined the effects of evodiamine in EMT induced by TGF-beta1 and the role of Smad and PPAR-gamma signal pathway in rat renal proximal tubular epithelial (NRK52E) cells in vitro. E-cadherin, alpha-smooth muscle actin (SMA), Smad 2 and PPAR-gamma mRNA and protein expressions were detected by real-time PCR and Western blot, respectively. NRK52E treated with TGF-beta1 for 48 h induced EMT, as evidenced by loss of E-cadherin and de novo expression of alpha-SMA. EMT was almost completely blocked by evodiamine and rosiglitazone. TGF-beta1 significantly increased Smad 2 expression and decreased PPAR-gamma expression in NRK52E cells compared with the control group, while evodiamine and rosiglitazone almost reversed these effects. These observations suggest that evodiamine and rosiglitazone inhibit TGF-beta1-induced EMT in NRK52E cells. Smad 2 and PPAR-gamma signal pathway might participate in the effects of evodiamine and rosiglitazone in EMT induced by TGF-beta1. © 2014 International Federation for Cell Biology.

  13. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}

    SciTech Connect

    Kim, Kook Hwan; Hong, Sung Pyo; Kim, KyeongJin; Park, Min Jung; Kim, Kwang Jin; Cheong, JaeHun . E-mail: molecule85@pusan.ac.kr

    2007-04-20

    Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPAR{gamma} (peroxisome proliferators-activated receptor {gamma}) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPAR{gamma}. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfected with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPAR{gamma} transcriptional activity. However, HCV core protein had no effect on PPAR{gamma} gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.

  14. PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis.

    PubMed

    Burgess, Heather A; Daugherty, Louis Eugene; Thatcher, Thomas H; Lakatos, Heather F; Ray, Denise M; Redonnet, Michelle; Phipps, Richard P; Sime, Patricia J

    2005-06-01

    Pulmonary fibrosis is a progressive life-threatening disease for which no effective therapy exists. Myofibroblasts are one of the key effector cells in pulmonary fibrosis and are the primary source of extracellular matrix production. Drugs that inhibit the differentiation of fibroblasts to myofibroblasts have potential as antifibrotic therapies. Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor that upon ligation with PPARgamma agonists activates target genes containing PPAR response elements. PPARgamma agonists have anti-inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPARgamma agonists to block two of the most important profibrotic activities of TGF-beta on pulmonary fibroblasts: myofibroblast differentiation and production of excess collagen. Both natural (15d-PGJ2) and synthetic (ciglitazone and rosiglitazone) PPARgamma agonists inhibited TGF-beta-driven myofibroblast differentiation, as determined by alpha-smooth muscle actin-specific immunocytochemistry and Western blot analysis. PPARgamma agonists also potently attenuated TGF-beta-driven type I collagen protein production. A dominant-negative PPARgamma partially reversed the inhibition of myofibroblast differentiation by 15d-PGJ2 and rosiglitazone, but the irreversible PPARgamma antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPARgamma agonists are mediated through both PPARgamma-dependent and independent mechanisms. Thus PPARgamma agonists have novel and potent antifibrotic effects in human lung fibroblasts and may have potential for therapy of fibrotic diseases in the lung and other tissues.

  15. PPARgamma agonist induced cardiac enlargement is associated with reduced fatty acid and increased glucose utilization in myocardium of Wistar rats.

    PubMed

    Edgley, Amanda J; Thalén, Pia G; Dahllöf, Björn; Lanne, Boel; Ljung, Bengt; Oakes, Nicholas D

    2006-05-24

    In toxicological studies, high doses of peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists cause cardiac enlargement. To investigate whether this could be explained by a large shift from free fatty acid to glucose utilization by the heart, Wistar rats were treated for 2-3 weeks with a potent, selective PPARgamma agonist (X334, 3 micromol/kg/d), or vehicle. X334 treatment increased body-weight gain and ventricular mass. Treatment lowered plasma triglycerides by 61%, free fatty acid levels by 72%, insulin levels by 45%, and reduced total plasma protein concentration by 7% (indicating plasma volume expansion) compared to vehicle animals. Fasting plasma glucose levels were unaltered. To assess cardiac free fatty acid and glucose utilization in vivo we used simultaneous infusions of non-beta-oxidizable free fatty acid analogue, [9,10-(3)H](R)-2-bromopalmitate and [U-(14)C]2-deoxy-d-glucose tracers, which yield indices of local free fatty acid and glucose utilization. In anesthetized, 7 h fasted animals, left ventricular glucose utilization was increased to 182% while free fatty acid utilization was reduced by 28% (P<0.05) compared to vehicle. In separate studies we attempted to prevent the X334-induced hypolipidemia. Various dietary fat supplements were unsuccessful. By contrast, restricting the time during which the treated animals had access to food (promoting endogenous lipolysis), restored plasma free fatty acid from 27% to 72% of vehicle control levels and prevented the cardiac enlargement. Body-weight gain in these treated-food restricted rats was not different from vehicle controls. In conclusion, the cardiac enlargement caused by intense PPARgamma activation in normal animals is associated with marked changes in free fatty acid/glucose utilization and the enlargement can be prevented by restoring free fatty acid availability.

  16. Histones induce rapid and profound thrombocytopenia in mice

    PubMed Central

    Bhandari, Ashish A.

    2011-01-01

    Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage. PMID:21700775

  17. PPARgamma, Bioactive Lipids, and Cancer Progression

    PubMed Central

    Robbins, Gregory T.; Nie, Daotai

    2012-01-01

    In this article we review the evolution of cancer research involving PPARgamma, including mechanisms, target genes, and clinical applications. For the last thirteen years, the effects of PPARgamma activity on tumor biology have been studied intensely. Most of this research has focused upon the potential for employing agonists of this nuclear receptor in cancer treatment. As a monotherapy such agonists have shown little success in clinical trials, while they have shown promise as components of combination treatments both in culture and in animal models. Other investigations have explored a possible role for PPARgamma as a tumor suppressor, and as an inducer of differentiation of cancer stem cells. Whereas early studies have yielded variable conclusions regarding the prevalence of PPARgamma mutations in cancer, the protein level of this receptor has been more recently identified as a significant prognostic marker. We predict that indicators of PPARgamma activity may also serve as predictive markers for tailoring treatments. PMID:22201838

  18. A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

    PubMed

    Fukui, Y; Masui, S; Osada, S; Umesono, K; Motojima, K

    2000-05-01

    Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.

  19. Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism.

    PubMed

    Ferguson, Heather E; Thatcher, Thomas H; Olsen, Keith C; Garcia-Bates, Tatiana M; Baglole, Carolyn J; Kottmann, R M; Strong, Emily R; Phipps, Richard P; Sime, Patricia J

    2009-11-01

    Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPARgamma ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPARgamma independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an alpha/beta unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPARgamma ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPARgamma ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.

  20. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    SciTech Connect

    Oishi, Katsutaka; Uchida, Daisuke; Ohkura, Naoki; Horie, Shuichi

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  1. Acute stent thrombosis associated with heparin-induced thrombocytopenia and abciximab-induced profound thrombocytopenia.

    PubMed

    Dasari, Tarun W; Pappy, Reji; Hennebry, Thomas A

    2011-02-01

    Heparin-induced thrombocytopenia (HIT) is a wellknown complication after exposure to heparin products. Profound thrombocytopenia has also been reported with the use of abciximab, a glycoprotein IIb/IIIa receptor antagonist, which is used during percutaneous coronary intervention. Acute stent thrombosis is a rare but serious complication of HIT. We report an unusual case of acute stent thrombosis with concomitant heparin- and abciximab-induced profound thrombocytopenia and discuss the subsequent treatment strategies. Prompt identification and management of this disorder is critically important to avoid devastating complications.

  2. Activation of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) induces cell death through MAPK-dependent mechanism in osteoblastic cells

    SciTech Connect

    Kim, Sung Hun; Yoo, Chong Il; Kim, Hui Taek; Park, Ji Yeon; Kwon, Chae Hwa; Keun Kim, Yong . E-mail: kim430@pusan.ac.kr

    2006-09-01

    The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPAR{gamma} agonists in osteoblastic cells. Ciglitazone and troglitazone, PPAR{gamma} agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPAR{alpha} agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPAR{gamma} antagonist GW9662. Ciglitazone treatment caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis.

  3. Involvement of PPARgamma in oxidative stress-mediated prostaglandin E(2) production in SZ95 human sebaceous gland cells.

    PubMed

    Zhang, Qiwei; Seltmann, Holger; Zouboulis, Christos C; Konger, Raymond L

    2006-01-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is thought to play a role in sebaceous gland cell function. We previously demonstrated in human epidermoid carcinoma KB cells that UVB irradiation activates PPARgamma via the generation of multiple oxidized glycerophosphocholine species with PPARgamma ligand activity. UVB-induced cyclooxygenase 2 (COX-2) expression was also shown to be PPARgamma-dependent. We therefore reasoned that PPARgamma activation and PPARgamma-dependent COX-2 expression may occur as a general consequence of oxidative stress. The present studies were designed to examine the effects of the oxidant tert-butylhydroperoxide (TBH) on PPARgamma activation and COX-2 expression in SZ95 sebocytes. We first verified that functional PPARgamma is expressed and activated by UVB irradiation in these cells. We next demonstrated that TBH increased PPARgamma reporter activity in SZ95 sebocytes. Increased COX-2 protein, mRNA expression, and prostaglandin E(2) (PGE(2)) production was observed after TBH or PPARgamma agonist treatment. The ability of PPARgamma agonists and TBH to induce COX-2 expression and PGE(2) production was blocked by pretreatment with the specific PPARgamma antagonist GW9662. Finally, TBH and PPARgamma agonists failed to elicit a PGE(2) response in SZ95 sebocytes stably expressing a dominant-negative PPARgamma. This study illustrates the importance of the PPARgamma system in regulating cellular responses to oxidative stress.

  4. A PPAR-gamma agonist protects from radiation-induced intestinal toxicity

    PubMed Central

    Sottili, Mariangela; Gerini, Chiara; Desideri, Isacco; Bastida, Cinzia; Pallotta, Stefania; Castiglione, Francesca; Bonomo, Pierluigi; Meattini, Icro; Greto, Daniela; Cappelli, Sabrina; Di Brina, Lucia; Loi, Mauro; Biti, Giampaolo; Livi, Lorenzo

    2016-01-01

    Objective Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. Methods Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 µM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. Results Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfα and Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. Conclusion Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation. PMID:28344789

  5. A PPAR-gamma agonist attenuates pulmonary injury induced by irradiation in a murine model.

    PubMed

    Mangoni, Monica; Sottili, Mariangela; Gerini, Chiara; Bonomo, Pierluigi; Bottoncetti, Anna; Castiglione, Francesca; Franzese, Ciro; Cassani, Sara; Greto, Daniela; Masoni, Tatiana; Meattini, Icro; Pallotta, Stefania; Passeri, Alessandro; Pupi, Alberto; Vanzi, Eleonora; Biti, Giampaolo; Livi, Lorenzo

    2015-12-01

    Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR-γ agonist rosiglitazone is of interest in the prevention and therapy of radiation-induced pulmonary injury. We evaluated the radioprotective effects of rosiglitazone in a murine model of pulmonary damage to determine whether radioprotection was selective for normal and tumor tissues. Lungs in C57BL/6J mice were irradiated (19 Gy) with or without rosiglitazone (RGZ, 5mg/kg/day for 16 weeks, oral gavage). Computed tomography (CT) was performed and Hounsfield Units (HU) were determined during the observation period. Histological analysis and evaluation of fibrosis/inflammatory markers by western blot were performed at 16 weeks. A549 tumor-bearing CD1 mice were irradiated (16 Gy) with or without RGZ, and tumor volumes were measured at 35 days. Rosiglitazone reduced radiologic and histologic signs of fibrosis, inflammatory infiltrate, alterations to alveolar structures, and HU lung density that was increased due to irradiation. RGZ treatment also significantly decreased Col1, NF-kB and TGF-β expression and increased Bcl-2 protein expression compared to the irradiation group and reduced A549 clonogenic survival and xenograft tumor growth. Rosiglitazone exerted a protective effect on normal tissues in radiation-induced pulmonary injury, while irradiated lung cancer cells were not protected in vivo and in vitro. Thus, rosiglitazone could be proposed as a radioprotective agent in the treatment of lung cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation.

    PubMed

    Ishibashi, Yuji; Matsui, Takanori; Ohta, Keisuke; Tanoue, Ryuichiro; Takeuchi, Masayoshi; Asanuma, Katsuhiko; Fukami, Kei; Okuda, Seiya; Nakamura, Kei-ichiro; Yamagishi, Sho-ichi

    2013-01-01

    Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE-elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up-regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). Further, although PEDF did not affect protein expression levels of PPARγ, it significantly restored the PPARγ transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy.

  7. Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats.

    PubMed

    Sánchez-Hidalgo, Marina; Martín, Antonio Ramon; Villegas, Isabel; de la Lastra, Catalina Alarcón

    2007-05-21

    Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a highly nuclear receptor expressed in the colon, may participate in the control of inflammation, especially in regulating the production of immunomodulatory and inflammatory mediators, cellular proliferation and apoptosis. In order to delve into the anti-inflammatory mechanisms and signalling pathways of PPARgamma agonists, we have studied the effects of rosiglitazone, a PPARgamma agonist on the extent and severity of acute ulcerative colitis caused by intracolonic administration of 2,4,6-trinitribenzene sulfonic acid (TNBS) in rats. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-alpha) levels and a histological study of the lesions. We determined prostaglandin E2 production as well as the cyclooxygenases (COX)-1 and -2 expressions by immunohistochemistry and Western blotting. The nuclear factor kappa (NF-kappaB) p65 and p38 mitogen-activated protein kinase (MAPK) expression levels were also measured by Western blotting. Finally, since PPARgamma agonists modulate apoptosis, we tried to clarify its effects under early acute inflammatory conditions. Inflammation following TNBS induction was characterized by increased colonic wall thickness, edema, diffuse inflammatory cells infiltration, necrosis reaching an ulcer index (UI) of 9.66+/-0.66 cm(2) and increased MPO activity and TNF-alpha colonic levels. Rosiglitazone treatment significantly reduced the morphological alteration associated with TNBS administration and the UI with the highest dose. In addition, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Rosiglitazone significantly reduced the rise in the prostaglandin (PG) E(2) generation compared with TNBS group. The COX-1 levels remained stable throughout the treatment in all groups. The COX-2 expression was elevated in TNBS group; however

  8. Short-term fasting induces profound neuronal autophagy

    PubMed Central

    Flynn, Claudia T.; Wood, Malcolm R.; Kiosses, William B.

    2010-01-01

    Disruption of autophagy—a key homeostatic process in which cytosolic components are degraded and recycled through lysosomes—can cause neurodegeneration in tissue culture and in vivo. Upregulation of this pathway may be neuroprotective, and much effort is being invested in developing drugs that cross the blood brain barrier and increase neuronal autophagy. One well-recognized way of inducing autophagy is by food restriction, which upregulates autophagy in many organs including the liver; but current dogma holds that the brain escapes this effect, perhaps because it is a metabolically privileged site. Here, we have re-evaluated this tenet using a novel approach that allows us to detect, enumerate and characterize autophagosomes in vivo. We first validate the approach by showing that it allows the identification and characterization of autophagosomes in the livers of food-restricted mice. We use the method to identify constitutive autophagosomes in cortical neurons and Purkinje cells, and we show that short-term fasting leads to a dramatic upregulation in neuronal autophagy. The increased neuronal autophagy is revealed by changes in autophagosome abundance and characteristics, and by diminished neuronal mTOR activity in vivo, demonstrated by a reduction in levels of phosphorylated S6 ribosomal protein in Purkinje cells. The increased abundance of autophagosomes in Purkinje cells was confirmed using transmission electron microscopy. Our data lead us to speculate that sporadic fasting might represent a simple, safe and inexpensive means to promote this potentially therapeutic neuronal response. PMID:20534972

  9. Glibenclamide-induced profound hypoglycaemic crisis: a case report

    PubMed Central

    Hussain, Arshad; Ali, Iftikhar; Khan, Aziz Ullah; Khan, Tahir Mehmood

    2016-01-01

    The value of sulphonylureas in the long-term treatment of type II diabetes has been questioned. The potential benefits of an antidiabetic drug must be carefully weighed against the risk of developing hazardous adverse effects like hypoglycaemia. We present drug-induced hypoglycaemia in a 77-year-old Pakistani male who had hypertension, type II diabetes and renal parenchymal disease (grade I), presented to the emergency department complaining of a 1-day history of fever, loose motions and drowsiness. His fever was low grade, intermittent, and not associated with rigors and chills. He had four episodes of watery stools for 1 day, with no associated vomiting but with drowsiness. He was aphasic, unable to walk and did not recognize his family members. The patient was taken to his local doctor who found him to be hypoglycaemic, with a blood sugar of 45 mg/dl. He was managed with intravenous (IV) dextrose and referred to the hospital. Hypoglycaemia is perhaps the most widespread and underreported complication of oral hypoglycaemic agents and may lead to overwhelming morbidity and mortality. Patient evaluation and proper counselling may help in identifying patients at greatest risk and avoid complications associated with these commonly prescribed drugs. PMID:27092233

  10. Expression of peroxisome proliferator-activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPARgamma agonists.

    PubMed

    Sato, H; Ishihara, S; Kawashima, K; Moriyama, N; Suetsugu, H; Kazumori, H; Okuyama, T; Rumi, M A; Fukuda, R; Nagasue, N; Kinoshita, Y

    2000-11-01

    Peroxisome proliferator-activated receptor (PPAR) gamma is expressed in human colon cancer, prostate cancer and breast cancer cells, and PPARgamma activation induces growth inhibition in these cells. PPARgamma expression in human gastric cancer cells, however, has not been fully investigated. We report the PPARgamma expression in human gastric cancer, and the effect of PPARgamma ligands on proliferation of gastric carcinoma cell lines. Immunohistochemistry was used to demonstrate the presence of PPARgamma protein in surgically resected specimens from well differentiated, moderately differentiated and poorly differentiated adenocarcinoma. We used reverse transcription-polymerase chain reaction and Northern and Western blot analyses to demonstrate PPARgamma expression in four human gastric cancer cell lines. PPARgamma agonists (troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J2) showed dose-dependent inhibitory effects on the proliferation of the gastric cancer cells, and their effect was augmented by the simultaneous addition of 9- cis retinoic acid, a ligand of RXRalpha. Flow cytometry demonstrated G1 cell cycle arrest and a significant increase of annexin V-positive cells after treatment with troglitazone. These results suggest that induction of apoptosis together with G1 cell cycle arrest may be one of the mechanisms of the antiproliferative effect of PPARgamma activation in human gastric cancer cells. Copyright 2000 Cancer Research Campaign.

  11. Zinc modulates PPARgamma signaling and activation of porcine endothelial cells.

    PubMed

    Meerarani, Purushothaman; Reiterer, Gudrun; Toborek, Michal; Hennig, Bernhard

    2003-10-01

    Dietary zinc has potent antioxidant and anti-inflammatory properties and is a critical component of peroxisome proliferator-activated receptor (PPAR) gene expression and regulation. To assess the protective mechanisms of PPARgamma in endothelial cell dysfunction and the role of zinc in the modulation of PPARgamma signaling, cultured porcine pulmonary artery endothelial cells were exposed to the membrane-permeable zinc chelator N,N,N'N'-tetrakis (2-pyridylmethyl)-ethylene diamine (TPEN), thiazolidinedione (TZD; PPARgamma agonist) or bisphenol A diglycidyl ether (BADGE; PPARgamma antagonist). Subsequently, endothelial cells were activated by treatment with linoleic acid (90 micro mol/L) for 6 h. Zinc chelation by TPEN increased the DNA binding activity of nuclear factor (NF)-kappaB and activator protein (AP)-1, decreased PPARgamma expression and activation as well as up-regulated interleukin (IL)-6 expression and production. These effects were fully reversed by zinc supplementation. In addition, exposure to TZD down-regulated linoleic acid-induced DNA binding activity of NF-kappaB and AP-1, whereas BADGE further induced activation of these oxidative stress-sensitive transcription factors. Most importantly, the TZD-mediated down-regulation of NF-kappaB and AP-1 and reduced inflammatory response were impaired during zinc chelation. These data suggest that zinc plays a critical role in PPARgamma signaling in linoleic acid-induced endothelial cell activation and indicate that PPARgamma signaling is impaired during zinc deficiency.

  12. gamma-secretase inhibitor induces adipogenesis of adipose-derived stem cells by regulation of Notch and PPAR-gamma.

    PubMed

    Huang, Y; Yang, X; Wu, Y; Jing, W; Cai, X; Tang, W; Liu, L; Liu, Y; Grottkau, B E; Lin, Y

    2010-04-01

    To determine the inhibitory effect and mechanism of Notch signalling on adipogenesis of mouse adipose-derived stem cells (mASCs). Varied concentrations of N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT) were added to mASCs 3 days before adipogenic induction with insulin-containing differentiation medium. The process of adipogenesis and ability of lipid droplet accumulation were analysed using oil red-O staining. The Notch signalling pathway (Notch-1, -2, -3, -4, Hes-1 and Hey-1) and adipogenesis-related factors (PPAR-gamma, DLK-1/Pref-1 and Acrp) were tested using real-time PCR, Western blot analysis and immunofluorescence staining assays. We demonstrated that Notch-2-Hes-1 signalling pathway was inhibited dose-dependently by DAPT in mASCs. In addition, transcription of PPAR-gamma was promoted by DAPT before adipogenic induction, while inhibitor of adipogenesis DLK-1/Pref-1 was further depressed. At early stages of differentiation (2-4 days), adipogenesis in mASCs was advanced and significantly enhanced in 5 and 10 mum DAPT pre-treated cases. On day 4, in differentiated mASCs cases with DAPT pre-treatment, we also found promotion of activation of de-PPAR-gamma and depression of HES-1, DLK-1/Pref-1 mRNA and protein expression. We conclude that blocking Notch signalling with DAPT enhances adipogenesis of differentiated mASCs at an early stage. It may be due to depression of DLK-1/Pref-1 and promotion of de-PPAR-gamma activation, which work through inhibition of Notch-2-Hes-1 pathway by DAPT.

  13. HER2 regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression and sensitivity of breast cancer cells to PPARgamma ligand therapy.

    PubMed

    Yang, Zhibo; Bagheri-Yarmand, Rozita; Balasenthil, Seetharaman; Hortobagyi, Gabriel; Sahin, Aysegul A; Barnes, Christopher J; Kumar, Rakesh

    2003-08-01

    Induction of terminal differentiation of cancer cells is an evolving novel therapeutic approach, and accordingly, peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-stimulated transcription factor with differentiation-promoting activity and overexpressed in a variety of cancers, has emerged as one of the promising therapeutic targets. Because c-erbB family growth factor receptor 2 (HER2) overexpression is one of the most recognizable molecular dysfunctions in breast tumors, in the studies presented here, we explored the effect of HER2 overexpression on the status of PPARgamma expression and on the sensitivity of breast cancer cells to PPARgamma-ligand troglitazone-induced growth inhibition. We show that HER2 overexpression in MCF7 breast cancer cells enhanced the expression of PPARgamma-mRNA and -protein. Furthermore, PPARgamma expression was dramatically increased in 11 of 16 breast tumors as compared with the adjacent normal tissue. In addition, HER2 up-regulation resulted in a partial inhibition of transcriptional activity of the endogenous PPARgamma, stimulation to differentiation, and resistance to troglitazone-mediated inhibition of anchorage-independent growth of breast cancer cells. Conversely, down-regulation of HER2 by anti-HER2 monoclonal antibody Herceptin led to a decreased level of PPARgamma protein and sensitization of breast cancer cells to the inhibitory effects of troglitazone. In summary, these findings show for the first time that HER2 up-regulates PPARgamma expression and modulates the sensitivity of breast cancer cells to PPARgamma ligand therapy.

  14. Fenofibrate vs pioglitazone: Comparative study of the anti-arthritic potencies of PPAR-alpha and PPAR-gamma agonists in rat adjuvant-induced arthritis.

    PubMed

    Koufany, Meriem; Jouzeau, Jean-Yves; Moulin, David

    2014-01-01

    Rheumatoid arthritis is characterized by synovial hyperplasia, inflammatory infiltration, cartilage destruction and juxta-articular as well as generalized bone demineralization. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily which behave as ligand-activated transcription factors in response to endogenous fatty acids and eicosanoids or isotype selective synthetic compounds as fibrates and thiazolidinediones. Beyond their key role in lipid metabolism, increased evidence has shown a role of the three isotypes in inflammatory modulation. We and others demonstrated previously that PPAR-gamma agonists reduced the severity of experimental polyarthritis and the overall inflammatory-induced bone loss. To compare the anti-arthritic potencies of a PPAR-alpha agonist (fenofibrate, a lipid lowering drug) and a PPAR-gamma agonist (pioglitazone, formerly used as an antidiabetic drug) in rat adjuvant-induced arthritis. Male Lewis rats were sensitized by an intra-dermal injection of 1 mg complete Freund's adjuvant at the basis of the tail and were treated orally for 21 days with fenofibrate 100 mg/kg/day (FENO) or pioglitazone 30 mg/kg/day (PIO), or with vehicle only. Arthritis severity was evaluated by clinical observations (oedema, clinical score, body weight). Global and femoral bone mineral density (BMD), femoral bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (DEXA) before sensitization and at day 20. Synovial mRNA levels of IL-1beta and IL-6 were determined by real-time RT-PCR. Administration of fenofibrate (100mg/kg/d) and pioglitazone (30 mg/kg/d) significantly reduced hindpaw oedema and arthritis score. Treatment with fenofibrate exerted a better effect on clinical scoring. DEXA analysis revealed that pioglitazone and fenofibrate treatment to a greater extent, reduced inflammatory-bone loss and increased BMD versus vehicle-treated rats. Finally, we demonstrated that both agonists

  15. Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine.

    PubMed Central

    2010-01-01

    Background Acetylcholinesterase inhibitors cannot rapidly reverse profound neuromuscular block. Sugammadex, a selective relaxant binding agent, reverses the effects of rocuronium and vecuronium by encapsulation. This study assessed the efficacy of sugammadex compared with neostigmine in reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia. Methods Patients aged ≥18 years, American Society of Anesthesiologists class 1-4, scheduled to undergo surgery under general anesthesia were enrolled in this phase III, multicenter, randomized, safety-assessor blinded study. Sevoflurane anesthetized patients received vecuronium 0.1 mg/kg for intubation, with maintenance doses of 0.015 mg/kg as required. Patients were randomized to receive sugammadex 4 mg/kg or neostigmine 70 μg/kg with glycopyrrolate 14 μg/kg at 1-2 post-tetanic counts. The primary efficacy variable was time from start of study drug administration to recovery of the train-of-four ratio to 0.9. Safety assessments included physical examination, laboratory data, vital signs, and adverse events. Results Eighty three patients were included in the intent-to-treat population (sugammadex, n = 47; neostigmine, n = 36). Geometric mean time to recovery of the train-of-four ratio to 0.9 was 15-fold faster with sugammadex (4.5 minutes) compared with neostigmine (66.2 minutes; p < 0.0001) (median, 3.3 minutes with sugammadex versus 49.9 minutes with neostigmine). No serious drug-related adverse events occurred in either group. Conclusions Recovery from profound vecuronium-induced block is significantly faster with sugammadex, compared with neostigmine. Neostigmine did not rapidly reverse profound neuromuscular block (Trial registration number: NCT00473694). PMID:20809967

  16. PPAR{gamma} activation abolishes LDL-induced proliferation of human aortic smooth muscle cells via SOD-mediated down-regulation of superoxide

    SciTech Connect

    Heo, Kyung-Sun; Kim, Dong-Uk; Ryoo, Sungwoo; Nam, Miyoung; Baek, Seung Tae; Kim, Lila; Park, Song-Kyu; Myung, Chang-Seon; Hoe, Kwang-Lae . E-mail: kwanghoe@kribb.re.kr

    2007-08-10

    Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred. In previous studies, our group investigated the molecular mechanisms by which LDL induces IL-8 production and by which PPAR{alpha} activation abolishes LDL effects in human aortic SMCs (hAoSMCs). Herein is the first report of PPAR{gamma} activation by troglitazone (TG) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H{sub 2}O{sub 2}, but of O2?-, and the subsequent activation of Erk1/2 in hAoSMCs. Moreover, in this study TG abolished the LDL-accelerated G{sub 1}-S progression to control levels via down-regulation of active cyclinD1/CDK4 and cyclinE/CDK2 complexes and up-regulation of p21{sup Cip1} expression. TG exerted its anti-proliferative effects through the up-regulation of basal superoxide dismutase (SOD) expression. This data suggests that the regulation of O2?- is located at the crossroads between LDL signaling and cell proliferation.

  17. A novel PPAR{gamma} agonist, KR62776, suppresses RANKL-induced osteoclast differentiation and activity by inhibiting MAP kinase pathways

    SciTech Connect

    Park, Ju-Young; Bae, Myung-Ae; Cheon, Hyae Gyeong; Kim, Sung Soo; Hong, Jung-Min; Kim, Tae-Ho; Choi, Je-Yong; Kim, Sang-Hyun; Lim, Jiwon; Choi, Chang-Hyuk; Shin, Hong-In; Kim, Shin-Yoon Park, Eui Kyun

    2009-01-16

    We investigated the effects of a novel peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, KR62776, on osteoclast differentiation and function, and on the underlying signaling pathways. KR62776 markedly suppressed differentiation into osteoclasts in various osteoclast model systems, including bone marrow mononuclear (BMM) cells and a co-culture of calvarial osteoblasts and BMM cells. KR62776 suppressed the activation of tartrate-resistant acid phosphatase (TRAP) and the expression of genes associated with osteoclast differentiation, such as TRAP, dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-associated receptor (OSCAR). Furthermore, KR62776 reduced resorption pit formation in osteoclasts, and down-regulated genes essential for osteoclast activity, such as Src and {alpha}v{beta}3 integrin. An analysis of a signaling pathway showed that KR62776 inhibited the receptor activator of nuclear factor-{kappa}B ligand (RANKL)-induced activation of p38 mitogen-activated protein kinase (p38MAPK), extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor-{kappa}B (NF-{kappa}B). Together, these results demonstrate that KR62776 negatively affects osteoclast differentiation and activity by inhibiting the RANKL-induced activation of MAP kinases and NF-{kappa}B.

  18. Antiplatelet drug induced isolated profound thrombocytopenia in interventional cardiology: a review based on individual case reports.

    PubMed

    Höchtl, Thomas; Pachinger, Linda; Unger, Gerhard; Geppert, Alexander; Wojta, Johann; Harenberg, Job; Huber, Kurt

    2007-08-01

    A combination antithrombotic and antiplatelet therapy with clopidogrel, aspirin, glycoprotein IIb/IIIa receptor inhibitors and heparins is routinely used as adjunct therapy in patients undergoing percutaneous coronary intervention (PCI). As all substances inhibit platelet function, bleeding and thrombocytopenia may occur. We report on three patients who developed isolated profound thrombocytopenia (platelet count of < 20,000/mm(3)) within 24 h after initiation of combination antiplatelet and antithrombotic therapy during a 1 year observation period in 443 consecutive patients undergoing PCI and stent implantation. The data from our cardiology unit revealed an incidence of an isolated profound thrombocytopenia in 0.7% of all patients on combination antithrombotic therapy and in 1.5% of patients with GPIIb/IIIa-blockers. In all three cases with isolated profound thrombocytopenia GPIIb/IIIa-blockers were found to be the causative agents. Negative results of HIT-assays excluded heparin induced thrombocytopenia type II. Despite the extremely low platelet count no severe bleeding was observed and in all cases platelet counts normalized within 3-4 days without specific interventions except discontinuation of the responsible agent. These findings are discussed in conjunct with an overview of the recent literature.

  19. PPAR{gamma} regulates the expression of cholesterol metabolism genes in alveolar macrophages

    SciTech Connect

    Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S.; Malur, Achut G.; Thomassen, Mary Jane

    2010-03-19

    Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.

  20. Recovery of laryngeal nerve function with sugammadex after rocuronium-induced profound neuromuscular block.

    PubMed

    Pavoni, Vittorio; Gianesello, Lara; Martinelli, Cristiana; Horton, Andrew; Nella, Alessandra; Gori, Gabriele; Simonelli, Martina; De Scisciolo, Giuseppe

    2016-09-01

    The aim of this study was to evaluate the efficacy of sugammadex in reversing profound rocuronium-induced neuromuscular block at the laryngeal adductor muscles using motor-evoked potentials (mMEPs). A prospective observational study. University surgical center. Twenty patients with American Society of Anesthesiologists physical class I-II status who underwent propofol-remifentanil anesthesia for the surgery of the thyroid gland. Patients were enrolled for reversal of profound neuromuscular block (sugammadex 16 mg/kg, 3 minutes after rocuronium 1.2 mg/kg). To prevent laryngeal nerve injury during the surgical procedures, all patients underwent neurophysiologic monitoring using mMEPs from vocal muscles. At the same time, the registration of TOF-Watch acceleromyograph at the adductor pollicis muscle response to ulnar nerve stimulation was performed; recovery was defined as a train-of-four (TOF) ratio ≥0.9. After injection of 16 mg/kg of sugammadex, the mean time to recovery of the basal mMEPs response at the laryngeal adductor muscles was 70 ± 18.2 seconds. The mean time to recovery of the TOF ratio to 0.9 was 118 ± 80 seconds. In the postoperative period, 12 patients received follow-up evaluation of the vocal cords and no lesions caused by the surface laryngeal electrode during electrophysiological monitoring were noted. Recovery from profound rocuronium-induced block on the larynx is fast and complete with sugammadex. In urgent scenarios, "early" extubation can be performed, even with a TOF ratio ≤0.9. However, all procedures to prevent postoperative residual curarization should still be immediately undertaken. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies.

    PubMed

    Siersbaek, Rasmus; Nielsen, Ronni; Mandrup, Susanne

    2010-08-04

    Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review the roles of PPARgamma and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARgamma and C/EBPalpha. Interestingly, these analyses show that PPARgamma and C/EBPalpha binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPalpha and PPARgamma cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors. Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. Bitter gourd seed fatty acid rich in 9c,11t,13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPARgamma in human colon cancer Caco-2 cells.

    PubMed

    Yasui, Yumiko; Hosokawa, Masashi; Sahara, Takehiko; Suzuki, Rikako; Ohgiya, Satoru; Kohno, Hiroyuki; Tanaka, Takuji; Miyashita, Kazuo

    2005-08-01

    Bitter gourd (Momordica charantia) seed oil (BGO) is a unique oil which contains 9cis, 11trans, 13trans-conjugated linolenic acid (9c,11t,13t-CLN) at a high level of more than 60%. In this study, we investigated the anti-proliferative and apoptosis-inducing effects of free fatty acids prepared from BGO (BGO-FFA) using colon cancer Caco-2 cells. BGO-FFA and purified 9c,11t,13t-CLN remarkably reduced the cell viability of Caco-2. In Caco-2 cells treated with BGO-FFA, DNA fragmentation of apoptosis indicators was observed in a dose-dependent manner. The expression level of apoptosis suppressor Bcl-2 protein was also decreased by BGO-FFA treatment. The GADD45 and p53, which play an important role in apoptosis-inducing pathways, were remarkably up-regulated by BGO-FFA treatment in Caco-2 cells. Up-regulation of PPARgamma mRNA and protein were also observed during apoptosis induced by BGO-FFA. These results suggest that BGO-FFA rich in 9c,11t,13t-CLN may induce apoptosis in Caco-2 cells through up-regulation of GADD45, p53 and PPARgamma.

  3. Mild Lipid Stress Induces Profound Loss of MC4R Protein Abundance and Function

    PubMed Central

    Cragle, Faith K.

    2014-01-01

    Food intake is controlled at the central level by the melanocortin pathway in which the agonist α-MSH binds to melanocortin 4 receptor (MC4R), a Gs-coupled G protein-coupled receptor expressed by neurons in the paraventricular nuclei of the hypothalamus, which signals to reduce appetite. Consumption of a high-fat diet induces hypothalamic accumulation of palmitate, endoplasmic reticulum (ER) stress, apoptosis, and unresponsiveness to prolonged treatment with MC4R agonists. Here we have modeled effects of lipid stress on MC4R by using mHypoE-42 immortalized hypothalamic neurons expressing endogenous MC4R and Neuro2A cells expressing a tagged MC4R reporter, HA-MC4R-GFP. In the hypothalamic neurons, exposure to elevated palmitate in the physiological range induced splicing of X-box binding protein 1, but it did not activate C/EBP-homologous protein or induce increased levels of cleaved caspase-3, indicating mild ER stress. Such mild ER stress coexisted with a minimal loss of MC4R mRNA and yet a profound loss of cAMP signaling in response to incubation with the agonist. These findings were mirrored in the Neuro2A cells expressing HA-MC4R-GFP, in which protein abundance of the tagged receptor was decreased, whereas the activity per receptor number was maintained. The loss of cAMP signaling in response to α-MSH by elevated palmitate was corrected by treatment with a chemical chaperone, 4-phenylbutyrate in both mHypoE-42 hypothalamic neurons and in Neuro2A cells in which protein abundance of HA-MC4R-GFP was increased. The data indicate that posttranscriptional decrease of MC4R protein contribute to lower the response to α-MSH in hypothalamic neurons exposed to even a mild level of lipid stress and that a chemical chaperone corrects such a defect. PMID:24506538

  4. Surface-induced profound hypothermia in infant cardiac operations: a new system.

    PubMed

    Vidne, B A; Subramanian, S

    1976-12-01

    A new system of surface-induced profound hypothermia for infant cardiac operations has been developed in order to overcome problems inherent in the current techniques using crushed ice, water baths, and similar methods. The hypothermic chamber consists of two parts: a lower part, containing a refrigeration unit and a blower fan capable of lowering the air temperature in the chamber to -6 degrees C, and an upper part made of Plexiglas that has a completely detachable end to allow easy access to cannulas, the anesthesia hose, and the infant. A temperature panel recorder to monitor the infant's esophageal and rectal temperatures and the ambient chamber temperature is incorporated into the unit. Following evaluation in the animal laboratory, the hypothermic chamber has been successfully used in 10 infants without any complications attributable to the technique. This method provides a rapid and uniform drop of the body temperature and even skin cooling, eliminates the possibility of contact skin lesions, saves medical and paramedical personnel time in preparation of the infant and equipment, and allows observation of the child during the cooling phase. This hypothermic chamber has facilitated infant hypothermic operations.

  5. A novel peroxisome proliferator-activated receptor (PPAR)gamma agonist, NIP-222, reduces urinary albumin excretion in streptozotocin-diabetic mice independent of PPARgamma activation.

    PubMed

    Yotsumoto, Takashi; Naitoh, Takeshi; Kanaki, Tatsuro; Matsuda, Maho; Tsuruzoe, Nobutomo

    2003-12-01

    NIP-222 is a novel peroxisome proliferator-activated receptor (PPAR)gamma agonist. This study provides evidence that NIP-222 decreases urinary albumin excretion (UAE) in diabetic mice independent of its PPARgamma activation. We compared the effect of NIP-222 and another PPARgamma agonist, troglitazone, on UAE, plasma glucose level, blood pressure, and creatinine clearance (C(cr)) in streptozotocin (STZ)-induced diabetic mice. Treatment for 3 weeks with NIP-222 (30 mg/kg) was associated with a significant decrease in UAE without any change in blood pressure, creatinine clearance, or plasma glucose level. In contrast, UAE did not decrease in mice treated with troglitazone (300 mg/kg). These results indicate that NIP-222 has PPARgamma independent effects on UAE in diabetic mice and suggest that this agent may have potential to minimize the development and progression of diabetic nephropathy.

  6. The PPARgamma ligand rosiglitazone influences triacylglycerol metabolism in non-obese males, without increasing the transcriptional activity of PPARgamma in the subcutaneous adipose tissue.

    PubMed

    Joosen, Annemiek M C P; Bakker, Arjen H F; Kersten, Sander; Westerterp, Klaas R

    2008-03-01

    PPARgamma is obligatory for fat mass generation and is thought to determine the amount of TAG stored per fat cell. We investigated whether ligand availability for PPARgamma is rate limiting in fat mass generation and substrate metabolism. Twenty healthy men (20-29 years) were randomly assigned to receive the PPARgamma ligand rosiglitazone (RSG) (8 mg/d) (n 10) or a placebo (n 10) during a stay of 7 d in a respiration chamber. Food intake was ad libitum, resulting in positive energy balances of 32.2 MJ (placebo) and 44.7 MJ (RSG). Fat cell size and expression of PPARgamma, adipocyte fatty acid-binding protein (aP2), adipsin, adiponectin and fasting-induced adipose factor (FIAF) were determined in subcutaneous abdominal fat biopsies. The total amount of fat stored and the amount of TAG per fat cell were not different between groups. For the entire group, fat cell size was decreased after overeating (P = 0.02). FIAF mRNA levels were decreased after overeating in the RSG group (P = 0.01), with a trend towards a decrease in the placebo group. Unexpectedly, RSG treatment did not influence the expression levels of PPARgamma and of the PPARgamma responsive genes aP2, adiponectin and adipsin. In addition, RSG resulted in a larger increase in plasma TAG during overeating than placebo treatment. These results suggest that in healthy, non-obese males the PPARgamma ligand RSG influences TAG metabolism, independent of its PPARgamma transcriptional activity in the subcutaneous adipose tissue.

  7. A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro.

    PubMed

    Burgermeister, Elke; Schnoebelen, Astride; Flament, Angele; Benz, Jörg; Stihle, Martine; Gsell, Bernard; Rufer, Arne; Ruf, Armin; Kuhn, Bernd; Märki, Hans Peter; Mizrahi, Jacques; Sebokova, Elena; Niesor, Eric; Meyer, Markus

    2006-04-01

    Partial agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), also termed selective PPARgamma modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPARgamma ligands. In a cocrystal with PPARgamma it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPARgamma-coactivator-1alpha (PGC1alpha) to the receptor, a feature shared with other selective PPARgamma modulators. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wild-type PGC1alpha but not its LXXLL-deficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative cross-talk of TNFalpha on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1alpha is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1alpha to favorable PPARgamma-target genes provides a possible molecular mechanism whereby partial PPARgamma agonists dissociate TG accumulation from insulin signaling.

  8. Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice.

    PubMed

    Saika, Shizuya; Yamanaka, Osamu; Okada, Yuka; Miyamoto, Takeshi; Kitano, Ai; Flanders, Kathleen C; Ohnishi, Yoshitaka; Nakajima, Yuji; Kao, Winston W-Y; Ikeda, Kazuo

    2007-07-01

    Wound healing involves both local cells and inflammatory cells. Alkali burn of ocular surface tissue is a serious clinical problem often leading to permanent visual impairment resulting from ulceration, scarring and neovascularization during healing. Behaviors of corneal cells and inflammatory cells are orchestrated by growth factor signaling networks that have not been fully uncovered. Here we showed that adenoviral gene introduction of peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits activation of ocular fibroblasts and macrophages in vitro and also induced anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. PPARgamma overexpression suppressed upregulation of inflammation/scarring-related growth factors and matrix metalloproteinases (MMPs) in macrophages. It also suppressed expression of such growth factors and collagen Ialpha2 and myofibroblast generation upon exposure to TGFbeta1. Exogenous PPARgamma did not alter phosphorylation of Smad2, but inhibited its nuclear translocation. PPARgamma overexpression enhanced proliferation of corneal epithelial cells, but not of fibroblasts in vitro. Epithelial cell expression of MMP-2/-9 and TGFbeta1 and its migration were suppressed by PPARgamma overexpression. In vivo experiments showed that PPARgamma gene introduction suppressed monocytes/macrophages invasion and suppressed the generation of myofibroblasts, as well as upregulation of cytokines/growth factors and MMPs in a healing cornea. In vivo re-epitheliazation with basement membrane reconstruction in the healing, burned, cornea was accelerated by PPARgamma-Ad expression, although PPARgamma overexpression was considered to be unfavorable for cell migration. Together, these data suggest that overexpression of PPARgamma may represent an effective new strategy for treatment of ocular surface burns.

  9. PPAR-{gamma} agonist protects against intestinal injury during necrotizing enterocolitis

    SciTech Connect

    Baregamian, Naira; Mourot, Joshua M.; Ballard, Amie R.; Evers, B. Mark; Chung, Dai H.

    2009-02-06

    Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-{gamma} in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-{gamma} agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-{gamma} expression and activation of NF-{kappa}B in small intestine. Pretreatment with PPAR-{gamma} agonist, 15d-PGJ{sub 2}, attenuated intestinal NF-{kappa}B response and I/R-induced gut injury. Activation of PPAR-{gamma} demonstrated a protective effect on small bowel during I/R-induced gut injury.

  10. Different clinical characteristics of aminoglycoside-induced profound deafness with and without the 1555 A-->G mitochondrial mutation.

    PubMed

    Tono, T; Kiyomizu, K; Matsuda, K; Komune, S; Usami, S; Abe, S; Shinkawa, H

    2001-01-01

    Recent genetic studies have shown that hereditary susceptibility to aminoglycoside antibiotics is caused by the 1555 A-->G mitochondrial mutation. We found the 1555 mutation in 4 out of 68 postlingual deaf patients who were candidates for cochlear implantation. All 4 patients developed bilateral profound hearing loss following administration of aminoglycosides. The pedigree of the family shows exclusively maternal transmission of hearing impairment in each case. On comparison with neuro-otological findings from aminoglycoside-induced deaf patients without the 1555 mutation, four distinct characteristics were noted: (1) a progressive nature of hearing loss; (2) better residual pure-tone thresholds; (3) lower thresholds for electrical promontory stimulation, and (4) well-preserved vestibular function. Although other factors such as differing dosages and/or administration routes may also be involved, profound hearing loss associated with the 1555 mutation may be due to a different pathogenic mechanism, i.e., strial dysfunction rather than a direct insult to the hair cells.

  11. Troglitazone acts by PPARgamma and PPARgamma-independent pathways on LLC-PK1-F+ acid-base metabolism.

    PubMed

    Welbourne, Tomas; Friday, Ellen; Fowler, Rocky; Turturro, Francesco; Nissim, Itzhak

    2004-01-01

    Troglitazone was studied in pH-sensitive LLC-PK1-F+ cells to determine the effect on pHi and glutamine metabolism as well as the role of peroxisome proliferator-activated receptor (PPARgamma)-dependent and PPARgamma-independent signaling pathways. Troglitazone induces a dose-dependent cellular acidosis that occurs within 4 min and persists over 18 h as a result of inhibiting Na+/H+ exchanger-mediated acid extrusion. Cellular acidosis was associated with glutamine-dependent augmented [15N]ammonium production and decreased [15N]alanine formation from 15N-labeled glutamine. The shift in glutamine metabolism from alanine to ammoniagenesis appears within 3 h and is associated after 18 h with both a reduction in assayable alanine aminotransferase (ALT) activity as well as cellular acidosis. The relative contribution of troglitazone-induced cellular acidosis vs. the decrease in assayable ALT activity to alanine production could be demonstrated. The PPARgamma antagonist bisphenol A diglycide ether (BADGE) reversed both the troglitazone-induced cellular acidosis and ammoniagenesis but enhanced the troglitazone reduction of assayable ALT activity; BADGE also blocked troglitazone induction of peroxisome proliferator response element-driven firefly luciferase activity. The protein kinase C (PKC) inhibitor chelerythrine mimics troglitazone effects, whereas phorbol ester reverses the effects on ammoniagenesis consistent with troglitazone negatively regulating the DAG/PKC/ERK pathway. Although functional PPARgamma signaling occurs in this cell line, the major troglitazone-induced acid-base responses appear to be mediated by pathway(s) involving PKC/ERK.

  12. The PPAR{gamma} coding region and its role in visceral obesity

    SciTech Connect

    Boon Yin, Khoo Najimudin, Nazalan; Muhammad, Tengku Sifzizul Tengku

    2008-06-27

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a ligand activated transcription factor, plays many essential roles of biological function in higher organisms. The PPAR{gamma} is mainly expressed in adipose tissue. It regulates the transcriptional activity of genes by binding with other transcription factor. The PPAR{gamma} coding region has been found to be closest to that of monkey in ours and other research groups. Thus, monkey is a more suitable animal model for future PPAR{gamma} studying, although mice and rat are frequently being used. The PPAR{gamma} is involved in regulating alterations of adipose tissue masses result from changes in mature adipocyte size and/or number through a complex interplay process called adipogenesis. However, the role of PPAR{gamma} in negatively regulating the process of adipogenesis remains unclear. This review may help we investigate the differential expression of key transcription factor in adipose tissue in response to visceral obesity-induced diet in vivo. The study may also provide valuable information to define a more appropriate physiological condition in adipogenesis which may help to prevent diseases cause by negative regulation of the transcription factors in adipose tissue.

  13. Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

    SciTech Connect

    Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.

    2009-05-28

    Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

  14. Smoking Cessation Induces Profound Changes in the Composition of the Intestinal Microbiota in Humans

    PubMed Central

    Biedermann, Luc; Zeitz, Jonas; Mwinyi, Jessica; Sutter-Minder, Eveline; Rehman, Ateequr; Ott, Stephan J.; Steurer-Stey, Claudia; Frei, Anja; Frei, Pascal; Scharl, Michael; Loessner, Martin J.; Vavricka, Stephan R.; Fried, Michael; Schreiber, Stefan; Schuppler, Markus; Rogler, Gerhard

    2013-01-01

    Background The human intestinal microbiota is a crucial factor in the pathogenesis of various diseases, such as metabolic syndrome or inflammatory bowel disease (IBD). Yet, knowledge about the role of environmental factors such as smoking (which is known to influence theses aforementioned disease states) on the complex microbial composition is sparse. We aimed to investigate the role of smoking cessation on intestinal microbial composition in 10 healthy smoking subjects undergoing controlled smoking cessation. Methods During the observational period of 9 weeks repetitive stool samples were collected. Based on abundance of 16S rRNA genes bacterial composition was analysed and compared to 10 control subjects (5 continuing smokers and 5 non-smokers) by means of Terminal Restriction Fragment Length Polymorphism analysis and high-throughput sequencing. Results Profound shifts in the microbial composition after smoking cessation were observed with an increase of Firmicutes and Actinobacteria and a lower proportion of Bacteroidetes and Proteobacteria on the phylum level. In addition, after smoking cessation there was an increase in microbial diversity. Conclusions These results indicate that smoking is an environmental factor modulating the composition of human gut microbiota. The observed changes after smoking cessation revealed to be similar to the previously reported differences in obese compared to lean humans and mice respectively, suggesting a potential pathogenetic link between weight gain and smoking cessation. In addition they give rise to a potential association of smoking status and the course of IBD. PMID:23516617

  15. Inhibition of Protein Farnesylation Arrests Adipogenesis and Affects PPARgamma Expression and Activation in Differentiating Mesenchymal Stem Cells.

    PubMed

    Rivas, Daniel; Akter, Rahima; Duque, Gustavo

    2007-01-01

    Protein farnesylation is required for the activation of multiple proteins involved in cell differentiation and function. In white adipose tissue protein, farnesylation has shown to be essential for the successful differentiation of preadipocytes into adipocytes. We hypothesize that protein farnesylation is required for PPARgamma2 expression and activation, and therefore for the differentiation of human mesenchymal stem cells (MSCs) into adipocytes. MSCs were plated and induced to differentiate into adipocytes for three weeks. Differentiating cells were treated with either an inhibitor of farnesylation (FTI-277) or vehicle alone. The effect of inhibition of farnesylation in differentiating adipocytes was determined by oil red O staining. Cell survival was quantified using MTS Formazan. Additionally, nuclear extracts were obtained and prelamin A, chaperon protein HDJ-2, PPARgamma, and SREBP-1 were determined by western blot. Finally, DNA binding PPARgamma activity was determined using an ELISA-based PPARgamma activation quantification method. Treatment with an inhibitor of farnesylation (FTI-277) arrests adipogenesis without affecting cell survival. This effect was concomitant with lower levels of PPARgamma expression and activity. Finally, accumulation of prelamin A induced an increased proportion of mature SREBP-1 which is known to affect PPARgamma activity. In summary, inhibition of protein farnesylation arrests the adipogenic differentiation of MSCs and affects PPARgamma expression and activity.

  16. PPAR-gamma in the Cardiovascular System.

    PubMed

    Duan, Sheng Zhong; Ivashchenko, Christine Y; Usher, Michael G; Mortensen, Richard M

    2008-01-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-gamma agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-gamma have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-gamma agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

  17. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists

    USDA-ARS?s Scientific Manuscript database

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid red...

  18. PPAR{gamma} transcriptionally regulates the expression of insulin-degrading enzyme in primary neurons

    SciTech Connect

    Du, Jing; Zhang, Lang; Liu, Shubo; Zhang, Chi; Huang, Xiuqing; Li, Jian; Zhao, Nanming; Wang, Zhao

    2009-06-12

    Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both A{beta} and insulin and deficient in IDE function is associated with Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) pathology. However, little is known about the cellular and molecular regulation of IDE expression. Here we show IDE levels are markedly decreased in DM2 patients and positively correlated with the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) levels. Further studies show that PPAR{gamma} plays an important role in regulating IDE expression in rat primary neurons through binding to a functional peroxisome proliferator-response element (PPRE) in IDE promoter and promoting IDE gene transcription. Finally, we demonstrate that PPAR{gamma} participates in the insulin-induced IDE expression in neurons. These results suggest that PPAR{gamma} transcriptionally induces IDE expression which provides a novel mechanism for the use of PPAR{gamma} agonists in both DM2 and AD therapies.

  19. Suppression of prostaglandin E2 receptor subtype EP2 by PPARgamma ligands inhibits human lung carcinoma cell growth.

    PubMed

    Han, ShouWei; Roman, Jesse

    2004-02-20

    Prostaglandin E(2) (PGE(2)), a major cyclooxygenase (COX-2) metabolite, plays important roles in tumor biology and its functions are mediated through one or more of its receptors EP1, EP2, EP3, and EP4. We have shown that the matrix glycoprotein fibronectin stimulates lung carcinoma cell proliferation via induction of COX-2 expression with subsequent PGE(2) protein biosynthesis. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibited this effect and induced cellular apoptosis. Here, we explore the role of the PGE(2) receptor EP2 in this process and whether the inhibition observed with PPARgamma ligands is related to effects on this receptor. We found that human non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by PPARgamma ligands (GW1929, PGJ2, ciglitazone, troglitazone, and rosiglitazone [also known as BRL49653]) was associated with a significant decrease in EP2 mRNA and protein levels. The inhibitory effects of BRL49653 and ciglitazone, but not PGJ2, were reversed by a specific PPARgamma antagonist GW9662, suggesting the involvement of PPARgamma-dependent and -independent mechanisms. PPARgamma ligand treatment was associated with phosphorylation of extracellular regulated kinase (Erk), and inhibition of EP2 receptor expression by PPARgamma ligands was prevented by PD98095, an inhibitor of the MEK-1/Erk pathway. Butaprost, an EP2 agonist, like exogenous PGE(2) (dmPGE(2)), increased lung carcinoma cell growth, however, GW1929 and troglitazone blocked their effects. Our studies reveal a novel role for EP2 in mediating the proliferative effects of PGE(2) on lung carcinoma cells. PPARgamma ligands inhibit human lung carcinoma cell growth by decreasing the expression of EP2 receptors through Erk signaling and PPARgamma-dependent and -independent pathways.

  20. Profound and Rapid Reduction in Body Temperature Induced by the Melanocortin Receptor Agonists

    PubMed Central

    Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2014-01-01

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. PMID:25065745

  1. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists.

    PubMed

    Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2014-08-22

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Regulation of PPAR{gamma} function by TNF-{alpha}

    SciTech Connect

    Ye Jianping

    2008-09-26

    The nuclear receptor PPAR{gamma} is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPAR{gamma} activity by TNF-{alpha} is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPAR{gamma} activity is regulated by TNF-{alpha} at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPAR{gamma}. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPAR{gamma}. IKK acts through at least two mechanisms: inhibition of PPAR{gamma} expression and activation of PPAR{gamma} corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPAR{gamma} inhibition by TNF-{alpha}.

  3. A safety evaluation of profound hypothermia-induced suspended animation for delayed resuscitation at 90 or 120 min.

    PubMed

    Liu, Yu; Li, Shu; Li, Zhi; Zhang, Jian; Han, Jin-Song; Zhang, Yong; Yin, Zong-Tao; Wang, Hui-Shan

    2017-01-01

    The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia-induced suspended animation for delayed resuscitation (SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest (CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals. Sixteen male BAMA minipigs were randomized into two groups: CA90 group (90 min, n = 8) and CA120 group (120 min, n = 8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution (OPS), cardioplegia and profound hypothermia (15 °C) were induced. After CA, cardiopumonary bypass (CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CR), lactic dehydrogenase (LDH) and troponin T (TnT)] and survival were observed from pre-operation to 7 days post-operation. Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation (ALT 84.43 ± 18.65 U/L; AST 88.99 ± 23.19 U/L; Cr 87.90 ± 24.49 μmol/L; LDH 1894.13 ± 322.26 U/L; TnT 0.849 ± 0.135 ng/ml) but decreased to normal

  4. Molecular recognition of nitrated fatty acids by PPAR[gamma

    SciTech Connect

    Li, Yong; Zhang, Jifeng; Schopfer, Francisco J.; Martynowski, Dariusz; Garcia-Barrio, Minerva T.; Kovach, Amanda; Suino-Powell, Kelly; Baker, Paul R.S.; Freeman, Bruce A.; Chen, Y. Eugene; Xu, H. Eric

    2010-03-08

    Peroxisome proliferator activated receptor-{gamma} (PPAR{gamma}) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPAR{gamma} ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPAR{gamma}. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR{gamma} discrimination of various naturally occurring fatty acid derivatives.

  5. PPAR{gamma} agonists prevent TGF{beta}1/Smad3-signaling in human hepatic stellate cells

    SciTech Connect

    Zhao Caiyan; Chen, Wei; Yang Liu; Chen Lihong; Stimpson, Stephen A.; Diehl, Anna Mae . E-mail: annamae.diehl@duke.edu

    2006-11-17

    PPAR{gamma} agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPAR{gamma} agonists inhibit transforming growth factor (TGF){beta}1-activation of TGF{beta} receptor (TGF{beta}R)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1{alpha}I. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPAR{gamma} expression and transcriptional activity. These adipocytic HSC were then treated with TGF{beta}1 {+-} a TGF{beta}R-1 kinase inhibitor (SB431542) or a PPAR{gamma} agonist (GW7845). TGF{beta}1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGF{beta}R-1 kinase inhibitor, the PPAR{gamma} agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPAR{gamma} agonists reflect their ability to inhibit TGF{beta}1-TGF{beta}R1 signaling that initiates ECM gene expression in quiescent HSC.

  6. Selective modulation of promoter recruitment and transcriptional activity of PPAR{gamma}

    SciTech Connect

    Sears, Dorothy D. Hsiao, Albert; Ofrecio, Jachelle M.; Chapman, Justin; He, Weimin; Olefsky, Jerrold M.

    2007-12-21

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a nuclear receptor regulated by the insulin-sensitizing thiazolidinediones (TZDs). We studied selective modulation of endogenous genes by PPAR{gamma} ligands using microarray, RNA expression kinetics, and chromatin immunoprecipitation (ChIP) in 3T3-L1 adipocytes. We found over 300 genes that were significantly regulated the TZDs pioglitazone, rosiglitazone, and troglitazone. TZD-mediated expression profiles were unique but overlapping. Ninety-one genes were commonly regulated by all three ligands. TZD time course and dose-response studies revealed gene- and TZD-specific expression kinetics. PEPCK expression was induced rapidly but PDK4 expression was induced gradually. Troglitazone EC{sub 50} values for PEPCK, PDK4, and RGS2 regulation were greater than those for pioglitazone and rosiglitazone. TZDs differentially induced histone acetylation of and PPAR{gamma} recruitment to target gene promoters. Selective modulation of PPAR{gamma} by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes.

  7. Odor-Induced Neuronal Rhythms in the Olfactory Bulb Are Profoundly Modified in ob/ob Obese Mice

    PubMed Central

    Chelminski, Yan; Magnan, Christophe; Luquet, Serge H.; Everard, Amandine; Meunier, Nicolas; Gurden, Hirac; Martin, Claire

    2017-01-01

    Leptin, the product of the Ob(Lep) gene, is a peptide hormone that plays a major role in maintaining the balance between food intake and energy expenditure. In the brain, leptin receptors are expressed by hypothalamic cells but also in the olfactory bulb, the first central structure coding for odors, suggesting a precise function of this hormone in odor-evoked activities. Although olfaction plays a key role in feeding behavior, the ability of the olfactory bulb to integrate the energy-related signal leptin is still missing. Therefore, we studied the fate of odor-induced activity in the olfactory bulb in the genetic context of leptin deficiency using the obese ob/ob mice. By means of an odor discrimination task with concomitant local field potential recordings, we showed that ob/ob mice perform better than wild-type (WT) mice in the early stage of the task. This behavioral gain of function was associated in parallel with profound changes in neuronal oscillations in the olfactory bulb. The distribution of the peaks in the gamma frequency range was shifted toward higher frequencies in ob/ob mice compared to WT mice before learning. More notably, beta oscillatory activity, which has been shown previously to be correlated with olfactory discrimination learning, was longer and stronger in expert ob/ob mice after learning. Since oscillations in the olfactory bulb emerge from mitral to granule cell interactions, our results suggest that cellular dynamics in the olfactory bulb are deeply modified in ob/ob mice in the context of olfactory learning. PMID:28154537

  8. Gsalpha signalling suppresses PPARgamma2 generation and inhibits 3T3L1 adipogenesis.

    PubMed

    Zhang, Lei; Paddon, Carol; Lewis, Mark D; Grennan-Jones, Fiona; Ludgate, Marian

    2009-08-01

    Since TSH receptor (TSHR) expression increases during adipogenesis and signals via cAMP/phospho-cAMP-response element binding protein (CREB), reported to be necessary and sufficient for adipogenesis, we hypothesised that TSHR activation would induce preadipocyte differentiation. Retroviral vectors introduced constitutively active TSHR (TSHR*) into 3T3L1 preadipocytes; despite increased cAMP (RIA) and phospho-CREB (western blot) there was no spontaneous adipogenesis (assessed morphologically, using oil red O and QPCR measurement of adipogenesis markers). We speculated that Gbetagamma signalling may be inhibitory but failed to induce adipogenesis using activated Gsalpha (gsp*). Inhibition of phosphodiesterases did not promote adipogenesis in TSHR* or gsp* populations. Furthermore, differentiation induced by adipogenic medium with pioglitazone was reduced in TSHR* and abolished in gsp* expressing 3T3L1 cells. TSHR* and gsp* did not inactivate PPARgamma (PPARG as listed in the HUGO database) by phosphorylation but expression of PPARgamma1 was reduced and PPARgamma2 undetectable in gsp*. FOXO1 phosphorylation (required to inactivate this repressor of adipogenesis) was lowest in gsp* despite the activation of AKT by phosphorylation. PROF is a mediator that facilitates FOXO1 phosphorylation by phospho-Akt. Its transcript levels remained constantly low in the gsp* population. In most measurements, the TSHR* cells were between the gsp* and control 3T3L1 preadipocytes. The enhanced down-regulation of PREF1 (adipogenesis inhibitor) permits retention of some adipogenic potential in the TSHR* population. We conclude that Gsalpha signalling impedes FOXO1 phosphorylation and thus inhibits PPARgamma transcription and the alternative promoter usage required to generate PPARgamma2, the fat-specific transcription factor necessary for adipogenesis.

  9. Telmisartan prevented cognitive decline partly due to PPAR-{gamma} activation

    SciTech Connect

    Mogi, Masaki; Li Jianmei; Tsukuda, Kana; Iwanami, Jun; Min, Li-Juan; Sakata, Akiko; Fujita, Teppei; Iwai, Masaru; Horiuchi, Masatsugu

    2008-10-24

    Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-{gamma}. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of A{beta} 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-{gamma} antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-{gamma} agonistic effect, also inhibited A{beta}-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was not affected by GW9662. Immunohistochemical staining for A{beta} showed the reduced A{beta} deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-{gamma} activation, could exert a stronger effect.

  10. Effect of peroxisome proliferator activated receptor (PPAR)gamma agonists on prostaglandins cascade in joint cells.

    PubMed

    Moulin, David; Poleni, Paul-Emile; Kirchmeyer, Mélanie; Sebillaud, Sylvie; Koufany, Meriem; Netter, Patrick; Terlain, Bernard; Bianchi, Arnaud; Jouzeau, Jean-Yves

    2006-01-01

    In response to inflammatory cytokines, chondrocytes and synovial fibroblasts produce high amounts of prostaglandins (PG) which self-perpetuate locally the inflammatory reaction. Prostaglandins act primarily through membrane receptors coupled to G proteins but also bind to nuclear Peroxisome Proliferator-Activated Receptors (PPARs). Amongst fatty acids, the cyclopentenone metabolite of PGD2, 15-deoxy-Delta12,14PGJ2 (15d-PGJ2), was shown to be a potent ligand of the PPARgamma isotype prone to inhibit the production of inflammatory mediators. As the stimulated synthesis of PGE2 originates from the preferential coupling of inducible enzymes, cyclooxygenase-2 (COX-2) and membrane PGE synthase-1 (mPGES-1), we investigated the potency of 15d-PGJ2 to regulate prostaglandins synthesis in rat chondrocytes stimulated with interleukin-1beta (IL-1beta). We demonstrated that 15d-PGJ2, but not the high-affinity PPARgamma ligand rosiglitazone, decreased almost completely PGE2 synthesis and mPGES-1 expression. The inhibitory potency of 15d-PGJ2 was unaffected by changes in PPARgamma expression and resulted from inhibition of NF-kappaB nuclear binding and IkappaBalpha sparing, secondary to reduced phosphorylation of IKKbeta. Consistently with 15d-PGJ2 being a putative endogenous regulator of the inflammatory reaction if synthesized in sufficient amounts, the present data confirm the variable PPARgamma-dependency of its effects in joint cells while underlining possible species and cell types specificities.

  11. Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: possible involvement of PPAR-gamma receptor and nitric oxide.

    PubMed

    Shafizadeh, Milad; Rajaba, Armin; Imran khan, Muhammad; Ostadhadi, Sattar; Rastegar, Hosein; Dehpour, Ahmadreza

    2014-12-05

    Pioglitazone is a member of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, particularly used in management of type II diabetes. However it also has effects in some dermatological disorders. The current study was designed to investigate the effects of oral administration of pioglitazone and the association of nitric oxide, in serotonin-induced scratching in mice. In order to produce the scratching activity, serotonin (141 nm/site) was administered intradermally in the nape of the neck. Pioglitazone in concentrations of 10, 20, 40 and 80 mg/kg, was peroral administered (p.o) as a single dose, 4 h before the serotonin injection. PPAR-γ antagonist, GW9662 (2 mg/kg, i.p); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg, i.p); or a nitric oxide precursor, L-arginine (100 mg/kg, i.p.); adminstrated 15 min before pioglitazone were analyzed for anti-scratching activity. Results obtained showed that pioglitazone (40 and 80 mg/kg, p.o) reduced the scratching in a dose-dependent manner. GW9662 inverted the anti-scratching effect of pioglitazone (80 mg/kg). Acute dose of L-NAME (1 mg/kg, i.p) also prevented the anti-scratching property of pioglitazone (80 mg/kg, p.o); although L-arginine was used in sub-effective dose (100 mg/kg, i.p), however it potentiated the anti-scratching behavior when co-injected with pioglitazone (20 mg/kg, p.o). The results indicate that acute pioglitazone has an anti-scratching effect on serotonin-induced scratching in mice. It is concluded that anti-scratching outcome of acute pioglitazone is initiated via activation of PPAR-γ receptor and to some extent by the NO pathway.

  12. Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

    SciTech Connect

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi; Nakaoka, Hirotomo; Moritani, Tomozo; Horiuchi, Masatsugu

    2011-03-04

    Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.

  13. HtrA3 is regulated by 15-deoxy-{Delta}12,14-prostaglandin J2 independently of PPAR{gamma} in clear cell renal cell carcinomas

    SciTech Connect

    Theoleyre, Sandrine; Mottier, Stephanie; Masson, Damien; Denis, Marc G.

    2010-04-09

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligands have been shown to possess anti-proliferative effects in many types of cancer. In clear cell renal cell carcinoma (CCRCC), the targets involved in these effects are not known. In this study, we demonstrated that, in CCRCC cell lines, the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) induces the expression, both at the mRNA and the protein levels, of the HtrA3 gene. This gene belongs to the High-Temperature Requirement Factor A family of serine proteases that repress signaling by TGF-{beta} family members and inhibit cell migration. Rosiglitazone or ciglitazone, synthetic PPAR{gamma} agonists, did not induce HtrA3 expression, and the PPAR{gamma} antagonist GW9662 did not prevent 15dPGJ2 induction, suggesting that the up-regulation of HtrA3 by 15dPGJ2 is independent of PPAR{gamma}. The MEK/ERK inhibitor PD98059 dramatically repressed HtrA3 induction. Altogether, these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPAR{gamma}. Our results provide a better understanding of the mechanisms involved in the regulation of HtrA3, a potential tumor suppressor gene.

  14. A new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes.

    PubMed

    Qin, Chunhua; Morrow, Derek; Stewart, Jessica; Spencer, Kyle; Porter, Weston; Smith, Roger; Phillips, Timothy; Abdelrahim, Maen; Samudio, Ismael; Safe, Stephen

    2004-03-01

    1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF(3)) and several p-substituted phenyl analogues have been investigated as a new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Structure-activity studies in PPARgamma-dependent transactivation assays in MCF-7 breast cancer cells show that 5-20 micro M concentrations of compounds containing p-trifluoromethyl, t-butyl, cyano, dimethylamino, and phenyl groups were active, whereas p-methyl, hydrogen, methoxy, hydroxyl, or halogen groups were inactive as PPARgamma agonists. Induction of PPARgamma-dependent transactivation by 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2) and DIM-C-pPhCF(3) was inhibited in MCF-7 cells cotreated with the PPARgamma-specific antagonist N-(4'-aminopyridyl)-2-chloro-5-nitrobenzamide. In mammalian two-hybrid assays, DIM-C-pPhCF(3) and PGJ2 (5-20 micro M) induced interactions of PPARgamma with steroid receptor coactivator (SRC) 1, SRC2 (TIFII), and thyroid hormone receptor-associated protein 220 but not with SRC3 (AIB1). In contrast, DIM-C-pPhCF(3), but not PGJ2, induced interactions of PPARgamma with PPARgamma coactivator-1. C-substituted diindolylmethanes inhibit carcinogen-induced rat mammary tumor growth, induce differentiation in 3T3-L1 preadipocytes, inhibit MCF-7 cell growth and G(0)/G(1)-S phase progression, induce apoptosis, and down-regulate cyclin D1 protein and estrogen receptor alpha in breast cancer cells. These compounds are a novel class of synthetic PPARgamma agonists that induce responses in MCF-7 cells similar to those observed for PGJ2.

  15. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.

    PubMed

    Keohane, Clodagh; Kordasti, Shahram; Seidl, Thomas; Perez Abellan, Pilar; Thomas, Nicholas S B; Harrison, Claire N; McLornan, Donal P; Mufti, Ghulam J

    2015-10-01

    CD4(+) T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.

  16. Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

    PubMed

    Park, Jun-Young; Kawada, Teruo; Han, In-Seob; Kim, Byung-Sam; Goto, Tsuyoshi; Takahashi, Nobuyuki; Fushiki, Tohru; Kurata, Tadao; Yu, Rina

    2004-08-13

    Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

  17. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.

    PubMed

    Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc

    2003-11-13

    Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

  18. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway.

    PubMed

    Huang, Cheng; Zhang, Yuebo; Gong, Zhenwei; Sheng, Xiaoyan; Li, Zongmeng; Zhang, Wei; Qin, Ying

    2006-09-22

    Berberine (BBR), a compound purified from Cortidis rhizoma, reduces serum cholesterol, triglycerides, and LDL-cholesterol of hypercholesterolemic patients and high fat diet fed animals, and increases hepatic LDLR mRNA and protein levels through a post-transcriptional mechanism. BBR also enhances the hypoglycemic action of insulin in diabetic animal models. Here, we show that BBR inhibits the differentiation of 3T3-L1 preadipocytes induced by DM and suppresses the mitotic clonal expansion of 3T3-L1 preadipocytes in a time- and dose-dependent manner. Gene expression analysis and Western blot analysis reveal that the BBR inhibits the mRNA and protein levels of adipogenesis related transcription factors PPARgamma and C/EBPalpha and their upstream regulator, C/EBPbeta. Reporter gene assays demonstrate that the full-length PPARgamma and alpha transcription activities are inhibited by BBR. Using real-time PCR, we have also found that the PPAR target genes that are involved in adipocyte differentiation, such as aP2, CD36, ACO, LPL, and other adipocyte markers, are suppressed by BBR. These studies suggest that BBR works on multiple molecular targets as an inhibitor of PPARgamma and alpha, and is a potential weight reducing, hypolipidemic, and hypoglycemic drug.

  19. Combined low doses of PPARgamma and RXR ligands trigger an intrinsic apoptotic pathway in human breast cancer cells.

    PubMed

    Bonofiglio, Daniela; Cione, Erika; Qi, Hongyan; Pingitore, Attilio; Perri, Mariarita; Catalano, Stefania; Vizza, Donatella; Panno, Maria Luisa; Genchi, Giuseppe; Fuqua, Suzanne A W; Andò, Sebastiano

    2009-09-01

    Ligand activation of peroxisome proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPARgamma ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor p53 and its effector p21(WAF1/Cip1). Functional experiments indicate that the nuclear factor-kappaB site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of p53 in PPARgamma/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPARgamma and RXR ligands may provide a therapeutic advantage in breast cancer treatment.

  20. PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts.

    PubMed

    Simonin, Marie-Agnès; Bordji, Karim; Boyault, Sandrine; Bianchi, Arnaud; Gouze, Elvire; Bécuwe, Philippe; Dauça, Michel; Netter, Patrick; Terlain, Bernard

    2002-01-01

    This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-gamma expression induced by 10 microg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 microM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ(2) decreased LPS-induced interleukin (IL)-1 beta (-25%) and tumor necrosis factor (TNF)-alpha (-40%) expression. Interestingly, troglitazone strongly decreased TNF-alpha expression (-50%) but had no significant effect on IL-1 beta expression. 15d-PGJ(2) was able to inhibit DNA-binding activity of both nuclear factor (NF)-kappa B and AP-1. Troglitazone had no effect on NF-kappa B activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ(2) and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-alpha and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-gamma ligands and underline different mechanisms of action of 15d-PGJ(2) and troglitazone in synovial fibroblasts.

  1. Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency.

    PubMed

    Ballantyne, Laurel L; Sin, Yuan Yan; Al-Dirbashi, Osama Y; Li, Xinzhi; Hurlbut, David J; Funk, Colin D

    2016-12-01

    Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype. Liver-selective Arg1 deletion was induced by using an adeno-associated viral (AAV)-thyroxine binding globulin (TBG) promoter-Cre recombinase vector administered to Arg1 "floxed" mice; Arg1(fl/fl) ). An AAV vector expressing an Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes after partial hepatectomy was used for cell delivery to "rescue" tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout of Arg1 with lethality ≈ 3 weeks after Cre-induced gene disruption. Delivery of Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival > 4 months) but a significant proportion still succumb to the enzyme deficiency even though liver expression and enzyme activity of the fusion protein reach levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT hepatocytes into knockout livers can be achieved but not sufficient for rescuing the lethal phenotype. This raises a conundrum relating to liver-specific expression of Arg1. On the one hand, loss of expression in this organ appears to be both necessary and sufficient to explain the lethal phenotype of the genetic disorder in mice. On the other hand, gene and cell-directed therapies suggest that rescue of extra-hepatic Arg1

  2. Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARgamma and Identification of TUSC5 Coding Variants in Lean and Obese Humans.

    PubMed

    Knotts, Trina A; Lee, Hyun Woo; Kim, Jae Bum; Oort, Pieter J; McPherson, Ruth; Dent, Robert; Tachibana, Keisuke; Doi, Takefumi; Yu, Songtao; Reddy, Janardan K; Uno, Kenji; Katagiri, Hideki; Pasarica, Magdalena; Smith, Steven R; Sears, Dorothy D; Grino, Michel; Adams, Sean H

    2009-01-01

    Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor gamma (PPARgamma) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARgamma target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARgamma. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds a approximately -1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARgamma responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARgamma target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARgamma agonists in humans remains equivocal.

  3. Profound perturbation induced by triclosan exposure in mouse gut microbiome: a less resilient microbial community with elevated antibiotic and metal resistomes.

    PubMed

    Gao, Bei; Tu, Pengcheng; Bian, Xiaoming; Chi, Liang; Ru, Hongyu; Lu, Kun

    2017-06-12

    Environmental chemical-induced perturbations of gut microbiome are associated with a series of adverse health outcomes. The effects of triclosan on human health have been controversial in recent years. The purpose of this study is to investigate the functional impact of triclosan on the mouse gut microbiome and the link between triclosan exposure and resistomes in gut bacteria. We combined 16S rRNA gene sequencing and shotgun metagenomics sequencing to examine the compositional and functional impact of triclosan exposure on the gut microbiota of C57BL/6 mice. 16S rRNA sequencing results revealed that 13-week triclosan exposure in drinking water induced significant perturbations in mouse gut bacterial assemblages with distinct trajectories compared to controls. Metagenomics sequencing results indicated a remarkable enrichment of gut bacterial genes related to triclosan resistance, stress response, antibiotic resistance and heavy metal resistance. Triclosan exposure has a profound impact on the mouse gut microbiome by inducing perturbations at both compositional and functional levels. To our best knowledge, this is the first evidence regarding the functional alterations of gut microbiome induced by triclosan exposure, which may provide novel mechanistic insights into triclosan exposure and associated diseases.

  4. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1).

    PubMed

    Medina-Gomez, Gema; Gray, Sarah; Vidal-Puig, Antonio

    2007-10-01

    Obesity is characterised by an increase in the adipose deposits, resulting from an imbalance between food intake and energy expenditure. When expansion of the adipose tissue reaches its maximum limit, as in obesity, fat accumulates in non-adipose tissues such as liver, heart, muscle and pancreas, developing a toxic response known as lipotoxicity, a condition that promotes the development of insulin resistance and other metabolic complications. Thus, the lipotoxic state may contribute to the increased risk of insulin resistance, diabetes, fatty liver and cardiovascular complications associated with obesity. We are interested in studying adipose tissue, specifically how mechanisms of adipogenesis and remodelling of adipose tissue, in terms of size and function of the adipocytes, could be considered a strategy to increase the capacity for lipid storage and prevent lipotoxicity. The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that regulate energy balance by promoting either energy deposition or energy dissipation. Under normal physiological conditions, PPARgamma is mainly expressed in adipose tissue and regulates diverse functions such as the development of fat cells and their capacity to store lipids. The generation of PPARgamma knockout mice, either tissue specific or isoform specific, has provided new models to study PPARgamma's role in adipose tissue differentiation and function and have highlighted the essential role of PPARgamma in adipogenesis and lipogenesis.A second strategy to prevent lipotoxicity is to increase the capacity of tissues to oxidise fatty acids. PPARgammacoactivator-1alpha is a coactivator of PPARgamma that induces the expression of genes that promote the differentiation of preadipocytes to brown adipocytes. Recently, it has been implicated in increasing the oxidation of fatty acids via increasing mitochondrial capacity and function, making this co-factor a key candidate for the treatment of

  5. Profound Childhood Religious Experience.

    ERIC Educational Resources Information Center

    Armstrong, Thomas

    Recent research into the religious lives of children has been influenced by various contemporary theories of child development including Fowler's (1981) "stages of faith" model. Profound religious states among children seem to have been neglected, yet the literature in this field attests to the existence of these states. The presence of…

  6. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    SciTech Connect

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  7. Transforming growth factor-{beta} inhibits CCAAT/enhancer-binding protein expression and PPAR{gamma} activity in unloaded bone marrow stromal cells

    SciTech Connect

    Ahdjoudj, S.; Kaabeche, K.; Holy, X.; Fromigue, O.; Modrowski, D.; Zerath, E.; Marie, P.J. . E-mail: pierre.marie@larib.inserm.fr

    2005-02-01

    The molecular mechanisms regulating the adipogenic differentiation of bone marrow stromal cells in vivo remain largely unknown. In this study, we investigated the regulatory effects of transforming growth factor beta-2 (TGF-{beta}2) on transcription factors involved in adipogenic differentiation induced by hind limb suspension in rat bone marrow stromal cells in vivo. Time course real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis of gene expression showed that skeletal unloading progressively increases the expression of CCAAT/enhancer-binding protein (C/EBP){alpha} and C/EBP{beta} {alpha} at 5 days in bone marrow stromal cells resulting in increased peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}2) transcripts at 7 days. TGF-{beta}2 administration in unloaded rats corrected the rise in C/EBP{alpha} and C/EBP{beta} transcripts induced by unloading in bone marrow stromal cells. This resulted in inhibition of PPAR{gamma}2 expression that was associated with increased Runx2 expression. Additionally, the inhibition of C/EBP{alpha} and C/EBP{beta} expression by TGF-{beta}2 was associated with increased PPAR{gamma} serine phosphorylation in bone marrow stromal cells, a mechanism that inhibits PPAR{gamma} transactivating activity. The sequential inhibitory effect of TGF-{beta}2 on C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma}2 resulted in reduced LPL expression and abolition of bone marrow stromal cell adipogenic differentiation, which contributed to prevent bone loss induced by skeletal unloading. We conclude that TGF-{beta}2 inhibits the excessive adipogenic differentiation of bone marrow stromal cells induced by skeletal unloading by inhibiting C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma} expression and activity, which provides a sequential mechanism by which TGF-{beta}2 regulates adipogenic differentiation of bone marrow stromal cells in vivo.

  8. The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis.

    PubMed

    Sime, Patricia J

    2008-02-01

    Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in controlling cell differentiation and that PPARgamma ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor gamma ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-beta-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARgamma ligands is under investigation but seems to involve both PPARgamma-dependent and PPARgamma-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARgamma ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARgamma ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.

  9. Inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.

    PubMed

    Andela, Valentine B; Altuwaijri, Saleh; Wood, James; Rosier, Randy N

    2005-03-14

    We demonstrate expression and coordinate induction of PPARgamma and lipogenic enzymes (HMG-CoA synthase, HMG-CoA reductase and fatty acid synthase) in a murine lung alveolar carcinoma cell line (Line 1) treated with the PPARgamma agonist troglitazone (TRO) [0-100 microM]. We postulate that TRO induces a shift in cellular energy metabolism towards fatty acid oxidation (beta-oxidative respiration). Accordingly, co-treatment with TRO [30 microM] and increasing concentrations of trimetazidine (TMZ) [0.1-3 mM], an inhibitor of beta-oxidation, results in a dose dependent decrease cellular ATP levels and a dose dependent induction of apoptosis. These findings, suggest that inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.

  10. PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells.

    PubMed

    Schaefer, Katherine L; Takahashi, Hirokazu; Morales, Victor M; Harris, Gianni; Barton, Susan; Osawa, Emi; Nakajima, Atsushi; Saubermann, Lawrence J

    2007-02-01

    The nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has been identified as an important therapeutic target in murine models of colorectal cancer (CRC). To examine whether PPARgamma inhibition has therapeutic effects in late-stage CRC, the effects of PPARgamma inhibitors on CRC cell survival were examined in CRC cell lines and a murine CRC model. Low doses (0.1-1 microM) of PPARgamma inhibitors (T0070907, GW9662 and BADGE) did not affect cell survival, while higher doses (10-100 microM) of all 3 PPARgamma inhibitors caused caspase-dependent apoptosis in HT-29, Caco-2 and LoVo CRC cell lines. Apoptosis was preceded by altered cell morphology, and this alteration was not prevented by caspase inhibition. PPARgamma inhibitors also caused dual G and M cell cycle arrest, which was not required for apoptosis or for morphologic alterations. Furthermore, PPARgamma inhibitors triggered loss of the microtubule network. Notably, unlike other standard antimicrotubule agents, PPARgamma inhibitors caused microtubule loss by regulating tubulin post-transcriptionally rather than by altering microtubule polymerization or dynamics. Proteasome inhibition by epoxomicin was unable to prevent tubulin loss. siRNA-mediated reduction of PPARgamma and PPARdelta proteins did not replicate the effects of PPARgamma inhibitors or interfere with the inhibitors' effects on apoptosis, cell cycle or tubulin. PPARgamma inhibitors also reduced CRC cell migration and invasion in assays in vitro and reduced both the number and size of metastases in a HT-29/SCID xenograft metastatic model of CRC. These results suggest that PPARgamma inhibitors are a novel potential antimicrotubule therapy for CRC that acts by directly reducing microtubule precursors.

  11. Activation of PPAR{gamma} negatively regulates O-GlcNAcylation of Sp1

    SciTech Connect

    Chung, Sung Soo; Kim, Ji Hyun; Park, Ho Seon; Choi, Hye Hun; Lee, Kyeong Won; Cho, Young Min; Lee, Hong Kyu; Park, Kyong Soo

    2008-08-08

    O-GlcNAcylation is a kind of post-translational modification and many nuclear and cytoplasmic proteins are O-GlcNAcylated. In this study, we demonstrated that thiazolidinediones (TZDs), which are used as insulin sensitizer, specifically inhibited the O-GlcNAcylation of Sp1 but did not affect the O-GlcNAcylation of the total proteins in cell culture systems and mouse models. This effect was mediated by peroxisome proliferator activated receptor {gamma} (PPAR{gamma}) activation and probably by synthesis of a specific protein induced by PPAR{gamma} activation. In addition, we demonstrated that the O-GlcNAcylation sites in the zinc-finger domain were involved in the transcriptional activation of Sp1 and that rosiglitazone, a member of TZDs, affected Sp1 transcriptional activity partially by regulating the O-GlcNAcylation level of these sites. Considering the role of hexosamine biosynthesis pathway in hyperglycemia-induced insulin resistance and Sp1 in the hyperglycemia-induced gene expression, the regulation of Sp1 O-GlcNAcylation by TZDs may help to explain the function of TZDs as a treatment for insulin resistance and diabetes.

  12. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease.

    PubMed

    Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta; Heneka, Michael

    2008-07-01

    Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARgamma agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARgamma agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARgamma represents an important new therapeutic target in treating AD.

  13. PPARgamma agonist pioglitazone does not enhance performance in mice.

    PubMed

    Sanchis-Gomar, Fabian; Pareja-Galeano, Helios; Martinez-Bello, Vladimir E

    2014-09-01

    Peroxisome-proliferator-activated receptor (PPAR) delta and adenosine monophosphate (AMP)-activated protein kinases (AMPKs) regulate the metabolic and contractile characteristics of myofibres. PPAR proteins are nuclear receptors that function as transcription factors and regulate the expression of multiple genes. AMPK has been described as a master metabolic regulator which also controls gene expression through the direct phosphorylation of some nuclear proteins. Since it was discovered that both PPARdelta agonists (GW1516) and AMPK activators (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, known as AICAR) are very effective performance-enhancing substances in sedentary mice, the World Anti-doping Agency (WADA) included AICAR and GW1516 in the prohibited list of substances as metabolic modulators in the class 'Hormone and metabolic modulators'. Thiazolidinediones are PPARgamma agonists that can induce similar biological effects to those of PPARdelta and PPARdelta-AMPK agonists. Thus in this study, the effects of pioglitazone on mitochondrial biogenesis and performance were evaluated. Blood glucose levels and the protein expression of the intermediates involved in the mitochondrial biogenesis pathway and the citrate synthase activity were determined in both gastrocnemius and soleus muscles. Maximal aerobic velocity (MAV), endurance capacity, and grip strength before and after the training period were also determined. The MAV endurance capacity and grip strength of trained animals significantly increased. We found that the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and the nuclear respiratory factor-1 (NRF-1) protein content and citrate synthase activity significantly increased in the soleus muscle of trained animals. No effect of treatment was found. Therefore in our study, pioglitazone administration did not affect mitochondrial biogenesis signaling pathway. Copyright © 2013 John Wiley & Sons, Ltd.

  14. PPARgamma: a novel molecular target in lung disease.

    PubMed

    Hart, C Michael; Roman, Jesse; Reddy, Raju; Sime, Patricia J

    2008-02-01

    Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled "PPARgamma: A Novel Molecular Target in Lung Disease" was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARgamma in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodulatory role of PPARgamma in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARgamma in pulmonary vascular disease. This brief introduction

  15. Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium difficile-Induced Colitis

    PubMed Central

    Buffie, Charlie G.; Jarchum, Irene; Equinda, Michele; Lipuma, Lauren; Gobourne, Asia; Viale, Agnes; Ubeda, Carles; Xavier, Joao

    2012-01-01

    Antibiotic-induced changes in the intestinal microbiota predispose mammalian hosts to infection with antibiotic-resistant pathogens. Clostridium difficile is a Gram-positive intestinal pathogen that causes colitis and diarrhea in patients following antibiotic treatment. Clindamycin predisposes patients to C. difficile colitis. Here, we have used Roche-454 16S rRNA gene pyrosequencing to longitudinally characterize the intestinal microbiota of mice following clindamycin treatment in the presence or absence of C. difficile infection. We show that a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota for at least 28 days, with an enduring loss of ca. 90% of normal microbial taxa from the cecum. Loss of microbial complexity results in dramatic sequential expansion and contraction of a subset of bacterial taxa that are minor contributors to the microbial consortium prior to antibiotic treatment. Inoculation of clindamycin-treated mice with C. difficile (VPI 10463) spores results in rapid development of diarrhea and colitis, with a 4- to 5-day period of profound weight loss and an associated 40 to 50% mortality rate. Recovering mice resolve diarrhea and regain weight but remain highly infected with toxin-producing vegetative C. difficile bacteria and, in comparison to the acute stage of infection, have persistent, albeit ameliorated cecal and colonic inflammation. The microbiota of “recovered” mice remains highly restricted, and mice remain susceptible to C. difficile infection at least 10 days following clindamycin, suggesting that resolution of diarrhea and weight gain may result from the activation of mucosal immune defenses. PMID:22006564

  16. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.

    PubMed

    Wayman, Nicole S; Hattori, Yoshiyuki; McDonald, Michelle C; Mota-Filipe, Helder; Cuzzocrea, Salvatore; Pisano, Babrbara; Chatterjee, Prabal K; Thiemermann, Christoph

    2002-07-01

    This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the

  17. Anti-diabetic action of Punica granatum flower extract: Activation of PPAR-{gamma} and identification of an active component

    SciTech Connect

    Huang, Tom H.W.; Peng Gang; Kota, Bhavani P.; Li, George Q.; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao . E-mail: yuhao@pharm.usyd.edu.au

    2005-09-01

    Peroxisome proliferator-activated receptor (PPAR)-{gamma} activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-{gamma} mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-{gamma} mRNA and protein expression and increased PPAR-{gamma}-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-{gamma} is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF.

  18. The anti-hepatic fibrosis activity of ergosterol depended on upregulation of PPARgamma in HSC-T6 cells.

    PubMed

    Tai, Chen-Jei; Choong, Chen-Yen; Lin, Yu-Chun; Shi, Yeu-Ching; Tai, Cheng-Jeng

    2016-04-01

    Advanced glycation endproducts (AGEs) were shown to play an important role in metabolic syndrome and were suggested to contribute to the development of hepatic fibrosis. Evidence indicates that AGEs resulted in hepatic fibrosis coupled to the activation of the receptor for AGEs (RAGE) in hepatic stellate cells (HSCs). NADPH oxidase is downstream of the RAGE signaling pathway, resulting in an increase in reactive oxygen species (ROS), alpha-smooth muscle actin (alpha-SMA), RAGE, and matrix metalloproteinase-9 (MMP-9). This study was designed to evaluate the effects of ergosterol on RAGE signaling in HSC-T6 cells. Ergosterol suppressed the activation of HSC-T6 cells induced by AGEs, and attenuated overexpressions of alpha-SMA, MMP-9, and epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin. We also found that these inhibitory effects of ergosterol on the activation of HSCs were dependent on peroxisome proliferator-activated receptor-gamma (PPARgamma) confirmed by PPARgamma reporter assay and PPARgamma knockdown. In addition, ergosterol also showed an inhibitory effect on the generation of AGEs, fructosamine, and α-dicarbonyl compounds in this study. Our results show that ergosterol can be used as a protective agent against hepatic fibrosis caused by induction of AGEs.

  19. Effect of heterodimer partner RXR{alpha} on PPAR{gamma} activation function-2 helix in solution

    SciTech Connect

    Lu Jianyun Chen Minghe; Stanley, Susan E.; Li, Ellen

    2008-01-04

    The structural mechanism of allosteric communication between retinoid X receptor (RXR) and its heterodimer partners remains controversial. As a first step towards addressing this question, we report a nuclear magnetic resonance (NMR) study on the GW1929-bound peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligand-binding domain (LBD) with and without the 9-cis-retinoic acid (9cRA)-bound RXR{alpha} LBD. Sequence-specific {sup 13}C{sup {alpha}}, {sup 13}C{sup {beta}}, and {sup 13}CO resonance assignments have been established for over 95% of the 275 residues in the PPAR{gamma} LBD monomer. The {sup 1}HN, {sup 15}N, and {sup 13}CO chemical shift perturbations induced by the RXR{alpha} LBD binding are located at not only the heterodimer interface that includes the C-terminal residue Y477 but also residues Y473 and K474 in the activation function-2 (AF-2) helix. This result suggests that 9cRA-bound RXR{alpha} can affect the PPAR{gamma} AF-2 helix in solution and demonstrates that NMR is a powerful new tool for studying the mechanism of allosteric ligand activation in RXR heterodimers.

  20. Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-{gamma}

    SciTech Connect

    Kanata, Sohya; Akagi, Masao . E-mail: makagi@med.kindai.ac.jp; Nishimura, Shunji; Hayakawa, Sumio; Yoshida, Kohji; Sawamura, Tatsuya; Munakata, Hiroshi; Hamanishi, Chiaki

    2006-09-29

    It has been reported that vascular endothelial growth factor (VEGF) and its receptors play an important role in the destruction of articular cartilage in osteoarthritis through increased production of matrix metalloproteinases. We investigated whether the oxidized low-density lipoprotein (ox-LDL) binding to lectin-like ox-LDL receptor-1 (LOX-1) upregulates VEGF expression in cultured bovine articular chondrocytes (BACs). Ox-LDL markedly increased VEGF mRNA expression and protein release in time- and dose-dependent manners, which was significantly suppressed by anti-LOX-1 antibody pretreatment. Activation of peroxisome proliferator-activated receptor (PPAR)-{gamma} was evident in BACs with ox-LDL addition and was attenuated by anti-LOX-1 antibody. The specific PPAR-{gamma} inhibitor GW9662 suppressed ox-LDL-induced VEGF expression. These results suggest that the ox-LDL/LOX-1 system upregulates VEGF expression in articular cartilage, at least in part, through activation of PPAR-{gamma} and supports the hypothesis that ox-LDL is involved in cartilage degradation via LOX-1.

  1. Co-crystal structure guided array synthesis of PPAR[gamma] inverse agonists

    SciTech Connect

    Trump, Ryan P.; Cobb, Jeffrey E.; Shearer, Barry G.; Lambert, Millard H.; Nolte, Robert T.; Willson, Timothy M.; Buckholz, Richard G.; Zhao, Sumin M.; Leesnitzer, Lisa M.; Iannone, Marie A.; Pearce, Kenneth H.; Billin, Andrew N.; Hoekstra, William J.

    2008-10-02

    PPAR{gamma}-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPAR{gamma} rich adipose. Both pro- and anti-adipogenic PPAR{gamma} ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPAR{gamma} in mature adipocytes.

  2. Development of Novel Nonagonist PPAR-Gamma Ligands for Lung Cancer Treatment

    DTIC Science & Technology

    2016-08-01

    AWARD NUMBER: W81XWH-15-1-0165 TITLE: Development of Novel Nonagonist PPAR-Gamma Ligands for Lung Cancer Treatment PRINCIPAL INVESTIGATOR...2016 4. TITLE AND SUBTITLE For 5a. CONTRACT NUMBER 0165 Development of Novel Nonagonist PPAR-Gamma Ligands for Lung Cancer Treatment 5b...establish the role of non-agonist PPAR-gamma ligands as potential therapeutic candidates for lung cancer . In this grant period, we have been able to

  3. Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells.

    PubMed

    Horiguchi, S; Petersson, M; Nakazawa, T; Kanda, M; Zea, A H; Ochoa, A C; Kiessling, R

    1999-06-15

    Whereas transplantable tumors can be readily cured with immunotherapeutic approaches, similar therapies in cancer patients have been less effective. This difference may be explained by an immunosuppression resulting from the presence of a slowly growing primary tumor in the patient, whereas the immune system in a mouse with a rapidly proliferating transplantable tumor would be less affected. As a more appropriate model to the immune dysfunction in patients, slowly progressing primary tumors were induced by the carcinogen methylcholanthrene (MC) in mice. Their ability to induce immunosuppression in T cells and natural killer (NK) cells was compared to that of rapidly growing transplanted MC-induced tumors. The results demonstrate that mice bearing primary MC tumors had significantly diminished T-cell and NK-cell functions, impaired capacity to produce Th1 cytokines, and markedly reduced levels of the signal-transducing zeta chain in T cells and NK cells, similar to that described in cancer patients. Moreover, a substantial number of CD8+ T cells in mice with large primary MC tumors were undergoing apoptosis, correlating with alterations in CD4/CD8 ratios. In contrast, T cells and NK cells from mice bearing rapidly growing transplanted tumors were only marginally affected. These findings could explain the apparent discrepancy between the consistent findings of a diminished immune response and alterations in signal transduction in cancer patients as compared to the less reproducible observations in murine transplantable tumors. In addition, they could explain the differences in the high efficacy of immunotherapy in mice with transplantable tumors and the low therapeutic results in cancer patients.

  4. Effects of Dan-shao-hua-xian on expression of PPAR-gamma and NF-kappa B in rat liver fibrosis.

    PubMed

    Wang, He-Yan; Cheng, Ming-Liang

    2008-04-01

    Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and nuclear factor kappa B (NF-kappaB) play important roles in liver fibrosis. This study aimed to investigate the effects of Dan-shao-hua-xian, a preparation of traditional Chinese medicine, on the expression of PPAR-gamma and NF-kappaB in the fibrotic livers of rats. Seventy Wistar rats were randomly divided into 4 groups: treatment (model, 8 weeks+treatment, 8 weeks; group A), natural recovery ( model, 8 weeks+saline, 8 weeks; group B), model (model only, 8 weeks; group C), and control (normal, untreated, 16 weeks; group D). Each group consisted of 20 rats (except for group D, which had 10). Fibrotic liver models were induced in rats by subcutaneous injection of CCl4, oral administration of alcohol and a high-lipid/low-protein diet for 8 weeks. After the models were established, the rats in group A were orally given Dan-shao-hua-xian capsules daily for another 8 weeks. Then, the liver indices serum hyaluronic acid (HA), tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) were measured. The degree of hepatic fibrosis was evaluated by optical microscopy. Hydroxyproline (Hyp) in the liver tissue was determined. The expression of PPAR-gamma was detected by immunohistochemical techniques. The protein levels of PPAR-gamma and NF-kappaB were determined by Western blotting. The concentrations of serum HA, TNF-alpha and Hyp in group C increased compared with group D (P<0.05), and they decreased in group A compared with group C (P<0.05). The expression of PPAR-gamma in group C decreased compared with group D (P<0.05), and it increased in group A compared with groups B and C (P<0.05). Similarly, Western blotting showed that the expression of PPAR-gamma in group C decreased compared with group D, and it increased in group A compared with group C. The expression of NF-kappaB increased in group C compared with group D (P<0.05), and it decreased in group A compared with group C (P<0.05). Dan

  5. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARgamma activation.

    PubMed

    Mastrofrancesco, Arianna; Ottaviani, Monica; Aspite, Nicaela; Cardinali, Giorgia; Izzo, Enzo; Graupe, Klaus; Zouboulis, Christos C; Camera, Emanuela; Picardo, Mauro

    2010-09-01

    Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 mM, a concentration achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced interleukins-1beta, -6 and tumor necrosis factor-alpha mRNA expression and protein secretion. Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor gamma, (PPARgamma) which has a crucial role in the control of inflammation, is activated by fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated receptor-gamma mRNA and its transcriptional activity. The PPARgamma antagonist GW9662 abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release and on the cell proliferation. Our study provides new insights into the molecular mechanisms of the activity of azelaic acid and lands additional evidences for its therapeutic effects on inflammatory skin diseases, such as rosacea.

  6. Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes.

    PubMed

    Jiang, Wen G; Douglas-Jones, Anthony; Mansel, Robert E

    2003-09-20

    Peroxisome-proliferator activated receptor-gamma (PPARgamma) belongs to a family of nuclear receptors and acts as receptor for peroxisome-proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. Our study examined the transcript levels of peroxisome-proliferator activated receptor-gamma (PPARgamma) and its co-activator (PGC-1) in a cohort of patients with breast cancer. An invasive breast cancer cell, MDA MB 231 exhibited lower level of expression of PPARgamma, compared to non-invasive MCF-7. Breast cancer tissues (n = 120) exhibited a lower level of PPARgamma mRNA compared to normal tissues (n = 25, p = 0.05). No difference, however, was seen with PGC-1. Although the levels of PPARgamma and PGC-1 did not correlate with nodal involvement and grade, significantly lower levels of PPARgamma were seen in TNM3 and TNM4 tumors and from patients with local recurrence and those who died of breast cancer. Lowest level of PGC-1 was also seen in TNM3 and TNM4 tumors and patients who died of breast cancer. We conclude that there is aberrant expression of PPARgamma and its co-activator, PGC-1, in human breast cancer and low levels of these molecules in cancer tissues are associated with poor clinical outcomes. Copyright 2003 Wiley-Liss, Inc.

  7. Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

    SciTech Connect

    Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong

    2012-06-28

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

  8. O-GlcNAc modification of PPAR{gamma} reduces its transcriptional activity

    SciTech Connect

    Ji, Suena; Park, Sang Yoon; Roth, Juergen; Kim, Hoe Suk; Cho, Jin Won

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer We found that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1 adipocytes. Black-Right-Pointing-Pointer The Thr54 of PPAR{gamma}1 is the major O-GlcNAc site. Black-Right-Pointing-Pointer Transcriptional activity of PPAR{gamma}1 was decreased on treatment with the OGA inhibitor. -- Abstract: The peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear receptor superfamily, is a key regulator of adipogenesis and is important for the homeostasis of the adipose tissue. The {beta}-O-linked N-acetylglucosamine (O-GlcNAc) modification, a posttranslational modification on various nuclear and cytoplasmic proteins, is involved in the regulation of protein function. Here, we report that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1 adipocytes. Mass spectrometric analysis and mutant studies revealed that the threonine 54 of the N-terminal AF-1 domain of PPAR{gamma} is the major O-GlcNAc site. Transcriptional activity of wild type PPAR{gamma} was decreased 30% by treatment with the specific O-GlcNAcase (OGA) inhibitor, but the T54A mutant of PPAR{gamma} did not respond to inhibitor treatment. In 3T3-L1 cells, an increase in O-GlcNAc modification by OGA inhibitor reduced PPAR{gamma} transcriptional activity and terminal adipocyte differentiation. Our results suggest that the O-GlcNAc state of PPAR{gamma} influences its transcriptional activity and is involved in adipocyte differentiation.

  9. Pioglitazone reverses down-regulation of cardiac PPAR{gamma} expression in Zucker diabetic fatty rats

    SciTech Connect

    Pelzer, Theo . E-mail: pelzer_t@klinik.uni-wuerzburg.de; Jazbutyte, Virginija; Arias-Loza, Paula Anahi; Segerer, Stephan; Lichtenwald, Margit; Law, Marilyn P.; Schaefers, Michael; Ertl, Georg; Neyses, Ludwig

    2005-04-08

    Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPAR{gamma} in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPAR{gamma} agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPAR{gamma}, glucose transporter-4 and {alpha}-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPAR{gamma}, glut-4, and {alpha}-MHC expression levels in diabetic ZDF rats. Cardiac [{sup 18}F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPAR{gamma} agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPAR{gamma} expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin.

  10. PPARgamma Pro12Ala polymorphism in HIV-1-infected patients with HAART-related lipodystrophy.

    PubMed

    Saumoy, Maria; Veloso, Sergi; Alonso-Villaverde, Carlos; Domingo, Pere; Chacón, Matilde R; Miranda, Merce; Aragonès, Gerard; Gutiérrez, Maria Mar; Viladés, Consuelo; Peraire, Joaquim; Sirvent, Joan-Josep; López-Dupla, Miguel; Aguilar, Carmen; Richart, Cristóbal; Vidal, Francesc

    2009-09-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in obesity and in some components of the metabolic syndrome in unselected population. To determine whether PPARgamma genetic variants are associated with the risk of developing lipodystrophy and its associated metabolic disturbances in HIV-1-infected patients treated with HAART and to assess PPARgamma mRNA expression in subcutaneous adipose tissue (SAT). The study group comprised 278 patients infected with HIV-1 and treated with antiretroviral drugs (139 with lipodystrophy and 139 without) and 105 uninfected controls (UC). The PPARgamma Pro12Ala (C%>G) single nucleotide polymorphism (SNP) was assessed using PCR-RFLPs on white cell DNA. PPARgamma mRNA expression in SAT was assessed in 38 patients (25 with lipodystrophy and 13 without) and in 21 UC by real-time PCR. Statistical analysis was based on Student's T tests, Chi(2) tests, Spearman's correlations tests and logistic regression tests. PPARgamma Pro12Ala genotype distribution and allele frequencies were non-significantly different between both HIV-1-infected categories, lipodystrophy vs non-lipodystrophy (p=0.9 and p=0.87, respectively). Lipodystrophic patients harbouring the rare X/Ala genotype (Ala/Ala plus Pro/Ala) had significantly greater plasma total and LDL cholesterol levels compared with carriers of the common Pro/Pro genotype (p=0.029 and p=0.016, respectively) at univariate analyses. At multivariate analyses these associations were no longer significant. There was a near-significant decreased SAT PPARgamma mRNA expression in patients with lipodystrophy compared to UC (p=0.054). PPARgamma Pro12Ala SNP has no effect on the risk of developing lipodystrophy in HIV-1-infected patients treated with HAART. PPARgamma mRNA SAT expression appears decreased in lipodystrophy.

  11. Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPAR{gamma} activation

    SciTech Connect

    Takahashi, Nobuyuki; Goto, Tsuyoshi; Taimatsu, Aki; Egawa, Kahori; Katoh, Sota; Kusudo, Tatsuya; Sakamoto, Tomoya; Ohyane, Chie; Lee, Joo-Young; Kim, Young-il; Uemura, Taku; Hirai, Shizuka; Kawada, Teruo

    2009-12-25

    Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. The uptake is dependent on adipocyte differentiation, which is controlled at mRNA transcription level. The peroxisome proliferator-activated receptor (PPAR), a ligand-regulated nuclear receptor, is involved in the differentiation. Many food-derived compounds serve as ligands to activate or inactivate PPAR. In this study, we demonstrated that bixin and norbixin (annatto extracts) activate PPAR{gamma} by luciferase reporter assay using GAL4-PPAR chimera proteins. To examine the effects of bixin on adipocytes, 3T3-L1 adipocytes were treated with bixin or norbixin. The treatment induced mRNA expression of PPAR{gamma} target genes such as adipocyte-specific fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and adiponectin in differentiated 3T3-L1 adipocytes and enhanced insulin-dependent glucose uptake. The observations indicate that bixin acts as an agonist of PPAR{gamma} and enhances insulin sensitivity in 3T3-L1 adipocytes, suggesting that bixin is a valuable food-derived compound as a PPAR ligand to regulate lipid metabolism and to ameliorate metabolic syndrome.

  12. Long-term pharmacological activation of PPARgamma does not prevent left ventricular remodeling in dogs with advanced heart failure.

    PubMed

    Suzuki, George; Khanal, Sanjaya; Rastogi, Sharad; Morita, Hideaki; Mishima, Takayuki; Anagnostopoulos, Petros V; Nass, Omar; Sharov, Victor G; Tanhehco, Elaine J; Goldstein, Sidney; Sabbah, Hani N

    2007-02-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.

  13. Identification of a truncated alternative splicing variant of human PPAR{gamma}1 that exhibits dominant negative activity

    SciTech Connect

    Kim, Hyo Jung; Woo, Im Sun; Kang, Eun Sil; Eun, So Young; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Kim, Jin-Hoi; Seo, Han Geuk . E-mail: hgseo@gnu.ac.kr

    2006-09-01

    We have identified a novel variant of human peroxisome proliferator-activated receptor gamma (hPPAR{gamma}), derived from insertion of a novel exon 3'. Insertion leads to the introduction of a premature stop codon, resulting in the formation of a truncated splice variant of PPAR{gamma}1 (PPAR{gamma}1{sub tr}). Western blot analysis confirmed the presence of PPAR{gamma}1{sub tr} in tumor-derived cell lines. Although PPAR{gamma}1{sub tr} interfered with transcriptional activity of wild-type PPAR{gamma}1 (PPAR{gamma}1{sub wt}), activity could be rescued by cotransfection with a vector expressing p300. Overexpression of PPAR{gamma}1{sub tr} protein in CHO cells greatly enhanced their proliferation and anchorage-independent colony growth on soft agar. These data demonstrate that PPAR{gamma}1{sub tr} is an important physiologic isoform of PPAR{gamma} that modulates cellular functions of PPAR{gamma}1{sub wt}.

  14. [The role of the expression of PPAR-gamma gene in the adipogenesis in hemangioma evolution].

    PubMed

    Yuan, Si-Ming; Chen, Rong-Liang; Chen, Hai-Ni; Shen, Wei-Min; Zhou, Xiao-Jun

    2013-01-01

    To investigate the role of the expression of PPAR-gamma gene in the adipogenesis in hemangioma evolution. Routine immunohistochemistry staining of Perilipin A, the marker antigen of adipocytes, was performed to observe the adipogenesis in hemangioma. Immunofluorescence staining of PPAR-gamma, the important transcription factor in promoting adipogenesis, was carried out to observe its location in hemangioma tissue, with the co-staining of alpha-SMA and CD31. And RT-PCR was used to examine the expression of PPAR-gamma gene in hemangioma in different stages. In the evolution of hemangioma, the number of adipocytes increased continuously. And the tumor was replaced by fibrofatty tissue finally. PPAR-gamma was located in the nuclei of perivascular cell in hemangioma tissue. The expression of PPAR-gamma gene in hemangioma increased in the evolution of hemangioma, but still was lower than that in normal fat tissue from children. The expression of PPAR-gamma in the perivascular cells suggests that they may contribute to the adipogenesis in hemangioma involution.

  15. The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPAR{gamma}

    SciTech Connect

    Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar; Park, Yun-Yong; Kim, Kyung Tae; Park, Sang Chul; Lee, Young Chul; Kim, Jae Bum Choi, Hueng-Sik

    2008-05-30

    DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) {gamma} is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPAR{gamma}. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPAR{gamma} in a dose-dependent manner. DAX-1 directly competed with the PPAR{gamma} coactivator (PGC)-1{alpha} for binding to PPAR{gamma}. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpression downregulates the expression of PPAR{gamma} target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPAR{gamma} and performs a potential function in the regulation of PPAR{gamma}-mediated cellular differentiation.

  16. IP receptor-dependent activation of PPAR{gamma} by stable prostacyclin analogues

    SciTech Connect

    Falcetti, Emilia; Flavell, David M.; Staels, Bart; Tinker, Andrew; Haworth, Sheila G.; Clapp, Lucie H. . E-mail: l.clapp@ucl.ac.uk

    2007-09-07

    Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPAR{alpha} and PPAR{delta} but not PPAR{gamma}. Given PPAR{gamma} agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPAR{gamma} activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPAR{gamma} in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPAR{gamma} antagonist, GW9662. We conclude that PPAR{gamma} is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues.

  17. PPARgamma-Dependent Control of Renin Expression: Molecular Mechanisms and Pathophysiological Relevance.

    PubMed

    Todorov, Vladimir T

    2013-01-01

    During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome.

  18. PPARgamma-Dependent Control of Renin Expression: Molecular Mechanisms and Pathophysiological Relevance

    PubMed Central

    Todorov, Vladimir T.

    2013-01-01

    During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome. PMID:24288524

  19. Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation.

    PubMed

    Kim, Ki Young; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2007-09-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPARgamma activation in human lung cancers by using a novel PPARgamma agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARgamma activation selectively inhibited cell viability of non-small-cell lung cancer with little effect on small-cell lung cancer and normal lung cells. The cell death induced by PPARgamma activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non-small-cell lung cancer cell line. Reactive oxygen species (ROS) production was accompanied by increased expression of proline oxidase (POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNA interference treatment blocked PPARgamma-induced ROS formation and cytotoxicity, suggesting that POX plays a functional role in apoptosis through ROS formation. The apoptotic effects by the agonists were antagonized by bisphenol A diglycidyl ether, a PPARgamma antagonist, and by knockdown of PPARgamma expression, indicating the involvement of PPARgamma in these actions. The results of the present study suggest that PPARgamma activation induces apoptotic cell death in non-small-cell lung carcinoma mainly through ROS formation via POX induction.

  20. When Lightning Strikes Twice: Profoundly Gifted, Profoundly Accomplished.

    PubMed

    Makel, Matthew C; Kell, Harrison J; Lubinski, David; Putallaz, Martha; Benbow, Camilla P

    2016-07-01

    The educational, occupational, and creative accomplishments of the profoundly gifted participants (IQs ⩾ 160) in the Study of Mathematically Precocious Youth (SMPY) are astounding, but are they representative of equally able 12-year-olds? Duke University's Talent Identification Program (TIP) identified 259 young adolescents who were equally gifted. By age 40, their life accomplishments also were extraordinary: Thirty-seven percent had earned doctorates, 7.5% had achieved academic tenure (4.3% at research-intensive universities), and 9% held patents; many were high-level leaders in major organizations. As was the case for the SMPY sample before them, differential ability strengths predicted their contrasting and eventual developmental trajectories-even though essentially all participants possessed both mathematical and verbal reasoning abilities far superior to those of typical Ph.D. recipients. Individuals, even profoundly gifted ones, primarily do what they are best at. Differences in ability patterns, like differences in interests, guide development along different paths, but ability level, coupled with commitment, determines whether and the extent to which noteworthy accomplishments are reached if opportunity presents itself. © The Author(s) 2016.

  1. Peroxisome proliferator-activated receptor (PPAR)gamma can inhibit chronic renal allograft damage.

    PubMed

    Kiss, Eva; Popovic, Zoran V; Bedke, Jens; Adams, Judith; Bonrouhi, Mahnaz; Babelova, Andrea; Schmidt, Claudia; Edenhofer, Frank; Zschiedrich, Inka; Domhan, Sophie; Abdollahi, Amir; Schäfer, Liliana; Gretz, Norbert; Porubsky, Stefan; Gröne, Hermann-Josef

    2010-05-01

    Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor known to have antidiabetogenic and immune effects, and PPARgamma forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPARgamma-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 +/- 5.8 (controls) vs. 8.1 +/- 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 +/- 1.8 (controls) vs. 2.6 +/- 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-beta1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPARgamma activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPARgamma-dependent manner. The combination of PPARgamma- and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPARgamma activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/RXR-agonist.

  2. Protective effects of a PPARgamma agonist pioglitazone on anti-oxidative system in testis of diabetic rabbits.

    PubMed

    Gumieniczek, A; Hopkała, H; Zabek, A

    2008-05-01

    In the present study, modulation of oxidative stress by pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, was examined in testis of alloxan-induced diabetic rabbits. In diabetic animals, an increase in the activity of anti-oxidative enzymes: superoxide dismutase (Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-R), and in the level of glutathione (GSH) but a decrease in the level of ascorbic acid (AA) were observed. These effects were accompanied by a significant increase in testicular lipid and protein oxidation. Pioglitazone affected the activity of Cu,Zn-SOD, normalized the activity of CAT, the level of AA as well as the levels of LPO and PCG without having any significant effect on blood glucose level.

  3. PPAR-gamma ligands and amino acid deprivation promote apoptosis of melanoma, prostate, and breast cancer cells.

    PubMed

    Núñez, Nomelí P; Liu, Huaitian; Meadows, Gary G

    2006-05-08

    The PPAR-gamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J(2) and ciglitazone, and the PPAR-alpha ligand, WY-14643, were examined for their effects on proliferation and apoptosis of A375 melanoma, DU145 and PC3 prostate cancer, and MB-MDA-231 breast cancer. While 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited proliferation of A375 melanoma, ciglitazone was inactive against this and the other cell lines. Restriction of specific amino acids known to inhibit proliferation and induce apoptosis sensitized all cell lines to ciglitazone, and the combined effects were greater than the individual effects of either treatment. WY-14643 alone or in combination with amino acid deprivation was inactive. Normal fibroblasts were resistant to the treatments.

  4. [Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) and their role in immunoregulation and inflammation control].

    PubMed

    Sokołowska, Milena; Kowalski, Marek L; Pawliczak, Rafał

    2005-01-01

    Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) are members of the nuclear receptor superfamily containing transcription factors regulating gene expression. PPAR-gamma have attracted attention so far as key factors in adipogenesis, lipid metabolism, insulin sensitivity, and apoptosis. Recently, growing evidence points to their implication in the regulation of the immune response, particularly in inflammation control. Not only are PPAR-gamma found in various structures of the immune system, but many inflammatory mediators, such as arachidonic acid and its metabolites, also act as potent and specific ligands of them. Inflammation is the basis of the pathogeneses of such chronic diseases as bronchial asthma, atherosclerosis, rheumatoid arthritis, and chronic inflammatory bowel diseases. The causative relationship between PPAR-gamma activity and the pathogeneses of these inflammatory disorders has been found in specific animal models. Moreover, PPAR-gamma agonists have been shown to act as potent anti-inflammatory agents. Thus, PPAR-gamma can serve as potential therapeutic targets in the treatment of inflammation. The aim of this paper is to present the characteristics of PPAR-gamma regarding their gene and protein structures, ligand selectivity, mechanisms of action, and target genes. The review highlights the roles that PPAR-gamma play in inflammation and immune responses. Particular emphasis is focused on their roles in asthma, atheroclerosis, rheumatoid arthritis and chronic inflammatory bowel diseases.

  5. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in inflammatory bowel disease.

    PubMed

    Atug, Ozlen; Tahan, Veysel; Eren, Fatih; Tiftikci, Arzu; Imeryuz, Nese; Hamzaoglu, Hulya Over; Tozun, Nurdan

    2008-12-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has recently been implicated as an endogenous regulator of cellular proliferation and inflammation. Impaired expression of PPAR-gamma in colonic epithelial cells in ulcerative colitis (UC) and increased expression in hypertrophic mesenteric adipose tissue in Crohn's disease (CD) have been reported. Furthermore, PPAR-gamma ligands have been shown to inhibit tissue injury associated with immune activation in UC. Any mutation in PPAR-gamma gene may be responsible for the increase in inflammatory mediators and hence the perpetuation of inflammation in inflammatory bowel disease (IBD) patients. One common polymorphism in PPAR-gamma gene is proline to alanine substitution (Pro12Ala) which results from a CCA to GCA missense substitution in codon 12 of exon 2 of the PPAR-gamma gene. In this study, we aimed to explore Pro12Ala polymorphism in PPAR-gamma gene in IBD in Turkish patients. 69 patients with CD, 45 with UC and 100 controls of similar age and sex were studied. Genomic DNA was isolated from peripheral blood leucocytes and mutagenically separated-polymerase chain reaction (PCR) analyses were performed to determine the Pro12Ala polymorphism of the PPAR-gamma gene. We observed no significant differences in the frequency of the Pro12Ala polymorphism in the PPAR-gamma gene among subjects with CD, UC and controls (15.9%, 15.5% and 13%, respectively, p>0.05). These results suggest that Pro12Ala polymorphism in the PPAR-gamma gene relates neither to the risk of the development of inflammatory bowel disease nor to the clinical subtypes of CD in the Turkish population.

  6. Inhibition of PPARgamma prevents type I diabetic bone marrow adiposity but not bone loss.

    PubMed

    Botolin, Sergiu; McCabe, Laura R

    2006-12-01

    Diabetes type I is associated with bone loss and increased bone adiposity. Osteoblasts and adipocytes are both derived from mesenchymal stem cells located in the bone marrow, therefore we hypothesized that if we could block adipocyte differentiation we might prevent bone loss in diabetic mice. Control and insulin-deficient diabetic BALB/c mice were chronically treated with a peroxisomal proliferator-activated receptor gamma (PPARgamma) antagonist, bisphenol-A-diglycidyl ether (BADGE), to block adipocyte differentiation. Effects on bone density, adiposity, and gene expression were measured. BADGE treatment did not prevent diabetes-associated hyperglycemia or weight loss, but did prevent diabetes-induced hyperlipidemia and effectively blocked diabetes type I-induced bone adiposity. Despite this, BADGE treatment did not prevent diabetes type I suppression of osteoblast markers (runx2 and osteocalcin) and bone loss (as determined by micro-computed tomography). BADGE did not suppress osteoblast gene expression or bone mineral density in control mice, however, chronic (but not acute) BADGE treatment did suppress osteocalcin expression in osteoblasts in vitro. Taken together, our findings suggest that BADGE treatment is an effective approach to reduce serum triglyceride and free fatty acid levels as well as bone adiposity associated with type I diabetes. The inability of BADGE treatment to prevent bone loss in diabetic mice suggests that marrow adiposity is not linked to bone density status in type I diabetes, but we cannot exclude the possibility of additional BADGE effects on osteoblasts or other bone cells, which could contribute to preventing the rescue of the bone phenotype.

  7. Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)alpha agonist fenofibrate and the PPARgamma agonist pioglitazone.

    PubMed

    Syversen, Unni; Stunes, Astrid K; Gustafsson, Björn I; Obrant, Karl J; Nordsletten, Lars; Berge, Rolf; Thommesen, Liv; Reseland, Janne E

    2009-03-30

    All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARgamma agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARalpha agonist fenofibrate (FENO) and the PPARgamma agonist pioglitazone (PIO) on bone in intact female rats. Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. We show opposite skeletal effects of PPARalpha and gamma agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARalpha activation.

  8. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha.

    PubMed

    Goldwasser, Jonathan; Cohen, Pazit Y; Yang, Eric; Balaguer, Patrick; Yarmush, Martin L; Nahmias, Yaakov

    2010-08-25

    Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARalpha, PPARgamma, and LXRalpha. We show it activates the ligand-binding domain of both PPARalpha and PPARgamma, while inhibiting LXRalpha in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRalpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARalpha co-activator, PGC1alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXRalpha response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRalpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRalpha inhibitor.

  9. The Membrane-Active Tri-Block Copolymer Pluronic F-68 Profoundly Rescues Rat Hippocampal Neurons from Oxygen–Glucose Deprivation-Induced Death through Early Inhibition of Apoptosis

    PubMed Central

    Shelat, Phullara B.; Plant, Leigh D.; Wang, Janice C.; Lee, Elizabeth

    2013-01-01

    Pluronic F-68, an 80% hydrophilic member of the Pluronic family of polyethylene-polypropylene-polyethylene tri-block copolymers, protects non-neuronal cells from traumatic injuries and rescues hippocampal neurons from excitotoxic and oxidative insults. F-68 interacts directly with lipid membranes and restores membrane function after direct membrane damage. Here, we demonstrate the efficacy of Pluronic F-68 in rescuing rat hippocampal neurons from apoptosis after oxygen–glucose deprivation (OGD). OGD progressively decreased neuronal survival over 48 h in a severity-dependent manner, the majority of cell death occurring after 12 h after OGD. Administration of F-68 for 48 h after OGD rescued neurons from death in a dose-dependent manner. At its optimal concentration (30 μm), F-68 rescued all neurons that would have died after the first hour after OGD. This level of rescue persisted when F-68 administration was delayed 12 h after OGD. F-68 did not alter electrophysiological parameters controlling excitability, NMDA receptor-activated currents, or NMDA-induced increases in cytosolic calcium concentrations. However, F-68 treatment prevented phosphatidylserine externalization, caspase activation, loss of mitochondrial membrane potential, and BAX translocation to mitochondria, indicating that F-68 alters apoptotic mechanisms early in the intrinsic pathway of apoptosis. The profound neuronal rescue provided by F-68 after OGD and the high level of efficacy with delayed administration indicate that Pluronic copolymers may provide a novel, membrane-targeted approach to rescuing neurons after brain ischemia. The ability of membrane-active agents to block apoptosis suggests that membranes or their lipid components play prominent roles in injury-induced apoptosis. PMID:23884935

  10. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways

    SciTech Connect

    Yamamoto, Yasuhiro; Fujita, Megumi; Koma, Hiromi; Yamamori, Motohiro; Nakamura, Tsutomu; Okamura, Noboru; Yagami, Tatsurou

    2011-07-08

    Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.

  11. Regulation of PPARgamma and obesity by agouti/melanocortin signaling in adipocytes.

    PubMed

    Mynatt, Randall L; Stephens, Jacquelins M

    2003-06-01

    To study the potential biological role of agouti/melanocortin signaling in human adipose tissue, we engineered transgenic mice to overexpress agouti in adipose tissue. The aP2-agouti transgenic mice become significantly heavier than littermates. The increased body weight is maintained at approximately 15% above nontransgenic mice through 20 weeks and is caused by increased fat mass. The obesity is increased by a high-fat diet. There is no change in food intake in the aP2-agouti mice suggesting changes in energy utilization. A possible mechanism is that the agouti/melanocortin signaling regulates levels of PPARgamma. PPARgamma functions as a major regulator of adipocyte differentiation and as a receptor for the antidiabetic thiazolidinediones. Agouti increases PPARgamma protein levels in differentiated 3T3-L1 adipocytes, and PPARgamma expression is elevated in the fat pads of the aP2-agouti transgenic mice. The modest weight gain observed in the transgenic mice suggests that hypothalamic pathways regulating food intake are intact and the observed adiposity is within ranges that can be achieved by a paracrine mechanism at the adipocyte level.

  12. PPARgamma and Wnt/beta-Catenin pathway in human breast cancer: expression pattern, molecular interaction and clinical/prognostic correlations.

    PubMed

    Jiang, Ying; Zou, Lin; Zhang, Chunhui; He, Song; Cheng, Chun; Xu, Junfei; Lu, Weiqi; Zhang, Yong; Zhang, Hua; Wang, Donglin; Shen, Aiguo

    2009-11-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor expressed in a large number of human cancers and plays important roles in breast cancer cell proliferation. Its association with clinicopathologic features and Wnt/beta-Catenin signaling pathway, a crucial factor in embryonic and malignant development, in breast cancer has not been reported systematically. In the present study, expression patterns, interaction and the correlations with clinical/prognostic factors of PPARgamma and beta-Catenin were investigated among patients with breast cancer. Using immunohistochemistry, we performed a study on 70 patient-derived human breast tumors and compared the protein expression levels of PPARgamma, beta-Catenin and Ki-67. Correlations were then analyzed between IHC-assessed level of these molecules and major clinicopathologic variables and survival. Furthermore, western blot (WB) analysis before and after immunoprecipitation with PPARgamma and beta-Catenin were performed on breast cancer tissues and cell lines to evaluate their protein level and molecular interaction. We showed that PPARgamma expression was of significant prognostic value in the outcome of breast carcinomas, which positively correlated with ER status (P = 0.012) and inversely associated with histologic grade (P = 0.012), tumor size (P = 0.007), axillary lymph node status (P = 0.044), TNM stage (P = 0.026), Ki-67 (P = 0.006) and abnormal beta-Catenin expression (P = 0.023), whereas no correlation was seen between PPARgamma and age (P = 0.513), histology (P = 0.764), PR (P = 0.099) or HER-2 status (P = 0.175). Kaplan-Meier survival curves of the study population showed that high expression level of PPARgamma significantly correlated with long-term survival. Molecular interaction could also be demonstrated between PPARgamma and beta-Catenin both in breast cancer cell lines and tissue samples. On the basis of these results, we suggested that PPARgamma might serve as a future

  13. Peroxisome proliferator-activated receptor (PPAR)-gamma positively controls and PPARalpha negatively controls cyclooxygenase-2 expression in rat brain astrocytes through a convergence on PPARbeta/delta via mutual control of PPAR expression levels.

    PubMed

    Aleshin, Stepan; Grabeklis, Sevil; Hanck, Theodor; Sergeeva, Marina; Reiser, Georg

    2009-08-01

    Peroxisome proliferator-activated receptor (PPAR) transcription factors are pharmaceutical drug targets for treating diabetes, atherosclerosis, and inflammatory degenerative diseases. The possible mechanism of interaction between the three PPAR isotypes (alpha, beta/delta, and gamma) is not yet clear. However, this is important both for understanding transcription factor regulation and for the development of new drugs. The present study was designed to compare the effects of combinations of synthetic agonists of PPARalpha [2-[4-[2-[4-cyclohexylbutyl (cyclohexylcarbamoyl)amino]ethyl]phenyl] sulfanyl-2-methylpropanoic acid (GW7647)], PPARbeta/delta [4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid, (L-165041)], and PPARgamma (rosiglitazone, ciglitazone) on inflammatory gene regulation in rat primary astrocytes. We measured cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) synthesis in lipopolysaccharide (LPS)-stimulated cells. PPARalpha, PPARbeta/delta, and PPARgamma knockdown models served to delineate the contribution of each PPAR isotype. Thiazolidinediones enhanced the LPS-induced COX-2 expression via PPARgamma-dependent pathway, whereas L-165041 and GW7647 had no influence. However, the addition of L-165041 potentiated the effect of PPARgamma activation through PPARbeta/delta-dependent mechanism. On the contrary, PPARalpha activation (GW7647) suppressed the effect of the combined L-165041/rosiglitazone application. The mechanism of the interplay arising from combined applications of PPAR agonists involves changes in PPAR expression levels. A PPARbeta/delta overexpression model confirmed that PPARbeta/delta expression level is the point at which PPARgamma and PPARalpha pathways converge in control of COX-2 gene expression. Thus, we discovered that in primary astrocytes, PPARgamma has a positive influence and PPARalpha has a negative influence on PPARbeta/delta expression and activity. A positive/negative-feedback loop is formed by

  14. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} down-regulates CXCR4 on carcinoma cells through PPAR{gamma}- and NF{kappa}B-mediated pathways

    SciTech Connect

    Richard, Cynthia Lee; Lowthers, Erica Lauren; Blay, Jonathan

    2007-10-01

    The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE{sub 2}, PGA{sub 2}, PGD{sub 2}, PGJ{sub 2} and 15dPGJ{sub 2} each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD{sub 2} and its metabolites PGJ{sub 2} and 15dPGJ{sub 2}. Down-regulation was most rapid with the end-product 15dPGJ{sub 2} and was accompanied by a marked reduction in CXCR4 mRNA. 15dPGJ{sub 2} is known to be a ligand for the nuclear receptor PPAR{gamma}. Down-regulation of CXCR4 was also observed with the PPAR{gamma} agonist rosiglitazone, while 15dPGJ{sub 2}-induced CXCR4 down-regulation was substantially diminished by the PPAR{gamma} antagonists GW9662 and T0070907. These data support the involvement of PPAR{gamma}. However, the 15dPGJ{sub 2} analogue CAY10410, which can act on PPAR{gamma} but which lacks the intrinsic cyclopentenone structure found in 15dPGJ{sub 2}, down-regulated CXCR4 substantially less potently than 15dPGJ{sub 2}. The cyclopentenone grouping is known to inhibit the activity of NF{kappa}B. Consistent with an additional role for NF{kappa}B, we found that the cyclopentenone prostaglandin PGA{sub 2} and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NF{kappa}B p50 and that 15dPGJ{sub 2} interfered with this p50 nuclear localization. These data suggest that 15dPGJ{sub 2} can down-regulate CXCR4 on cancer cells through both PPAR{gamma} and NF{kappa}B. 15dPGJ{sub 2}, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.

  15. Highly Pathogenic H5N1 and Novel H7N9 Influenza A Viruses Induce More Profound Proteomic Host Responses than Seasonal and Pandemic H1N1 Strains.

    PubMed

    Simon, Philippe François; McCorrister, Stuart; Hu, Pingzhao; Chong, Patrick; Silaghi, Alex; Westmacott, Garrett; Coombs, Kevin M; Kobasa, Darwyn

    2015-11-06

    Influenza A viruses (IAV) are important human and animal pathogens with potential for causing pandemics. IAVs exhibit a wide spectrum of clinical illness in humans, from relatively mild infections by seasonal strains to acute respiratory distress syndrome during infections with some highly pathogenic avian influenza (HPAI) viruses. In the present study, we infected A549 human cells with seasonal H1N1 (sH1N1), 2009 pandemic H1N1 (pdmH1N1), or novel H7N9 and HPAI H5N1 strains. We used multiplexed isobaric tags for relative and absolute quantification to measure proteomic host responses to these different strains at 1, 3, and 6 h post-infection. Our analyses revealed that both H7N9 and H5N1 strains induced more profound changes to the A549 global proteome compared to those with low-pathogenicity H1N1 virus infection, which correlates with the higher pathogenicity these strains exhibit at the organismal level. Bioinformatics analysis revealed important modulation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response in infection. Cellular fractionation and Western blotting suggested that the phosphorylated form of NRF2 is not imported to the nucleus in H5N1 and H7N9 virus infections. Fibronectin was also strongly inhibited in infection with H5N1 and H7N9 strains. This is the first known comparative proteomic study of the host response to H7N9, H5N1, and H1N1 viruses and the first time NRF2 is shown to be implicated in infection with highly pathogenic strains of influenza.

  16. An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor gamma (PPARgamma) binding and activation on some PPAR response elements.

    PubMed

    Temple, Karla A; Cohen, Ronald N; Wondisford, Sarah R; Yu, Christine; Deplewski, Dianne; Wondisford, Fredric E

    2005-02-04

    Peroxisome proliferator-activated receptor gamma (PPARgamma) interacts with retinoid X receptor (RXR) on PPAR response elements (PPREs) to regulate transcription of PPAR-responsive genes. To investigate the binding of PPARgamma and RXR to PPREs, three mutations were constructed in the DNA-binding domains of PPARgamma; two of the mutants maintained the structure of zinc finger I (PPARgamma-GS and PPARgamma-AA), and a third mutation disrupted the protein structure of zinc finger I (PPARgamma-CS). Results indicated that the mutations of PPARgamma that maintained intact zinc fingers were capable of binding to a variety of PPREs in the presence of RXR and could activate transcription on several PPREs. In parallel, a mutation was created in the DNA-binding domain of RXRalpha that maintained the structure of the zinc fingers (RXR-GS) but did not bind DNA and was transcriptionally inactive. Examination of the 3' half-site of several PPREs revealed that variations from the consensus sequence reduced or abolished transcriptional activity, but conversion to consensus improved transcriptional activity with PPARgamma-GS and PPARgamma-AA. Examination of the 5' half-site indicated that the upstream three nucleotides were more important for transcriptional activity than the downstream three nucleotides. Our data demonstrated that stringent binding of RXR to the 3' half-site of a PPRE is more influential on the binding of the PPARgamma/RXR heterodimer than the ability of PPARgamma to bind DNA. Thus, unlike RXR, PPARgamma exhibits promiscuity in binding on a PPRE, suggesting that the definition of a PPRE for PPARgamma may need to be expanded.

  17. Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome.

    PubMed

    Mrówka, Piotr; Głodkowska, Eliza; Młynarczuk-Biały, Izabela; Biały, Lukasz; Kuckelkorn, Ulrike; Nowis, Dominika; Makowski, Marcin; Legat, Magdalena; Gołab, Jakub

    2008-01-01

    Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-gamma agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.

  18. Phenolics from Glycyrrhiza glabra roots and their PPAR-gamma ligand-binding activity.

    PubMed

    Kuroda, Minpei; Mimaki, Yoshihiro; Honda, Shinichi; Tanaka, Hozumi; Yokota, Shinichi; Mae, Tatsumasa

    2010-01-15

    Bioassay-guided fractionation of the EtOH extract of licorice (Glycyrrhiza glabra roots), using a GAL-4-PPAR-gamma chimera assay method, resulted in the isolation of 39 phenolics, including 10 new compounds (1-10). The structures of the new compounds were determined by analysis of their spectroscopic data. Among the isolated compounds, 5'-formylglabridin (5), (2R,3R)-3,4',7-trihydroxy-3'-prenylflavane (7), echinatin, (3R)-2',3',7-trihydroxy-4'-methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, and glabrone all exhibited significant PPAR-gamma ligand-binding activity. The activity of these compounds at a sample concentration of 10microg/mL was three times more potent than that of 0.5microM troglitazone. Copyright 2009 Elsevier Ltd. All rights reserved.

  19. Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein.

    PubMed

    Looze, Christopher; Yui, David; Leung, Lester; Ingham, Matthew; Kaler, Maryann; Yao, Xianglan; Wu, Wells W; Shen, Rong-Fong; Daniels, Mathew P; Levine, Stewart J

    2009-01-16

    Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-gamma (PPARgamma), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatory cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPARgamma as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors.

  20. [Association of PPARgamma2 Pro12Ala polymorphism and cognitive dysfunction in hypertension patients].

    PubMed

    Peng, Yong; Luo, Xiao-jia; Chen, Xiao-ping; Li, Long-xin; Wan, Li-yan; He, Sen; Chen, Xiao-ni; Wu, Kai

    2010-11-01

    To study the relationship between PPARgamma2 Pro12Ala polymorphism and cognitive function in patients with primary hypertension. This study enrolled 502 hypertensive patients of Chinese Han population from Jan 2008 to Feb 2009 in West China Hospital of Sichuan University. We collected the general data and applied the mini mental state examination (MMSE) to test the cognitive function and computed score. Total cholesterol (TC), triglyeride (TG), fasting plasma glucose (FPG) and postprandial blood sugar (PPBS), fasting insulin (FINS) and postprandial plasma insulin (PINS) were measured. PCR-RELP method was used to analysis the PPARgamma2 Pro12Ala gene polymorphism. Pro12Pro genotype was present in 88.6% of the patients and Prol2Ala genotype was present in 11.4% of the population. Allele frequencies were 94.3% for Pro allele and 5.7% for Ala allele. In cognitive normal group, the frequencies of PP and PA genotype were 328 (87.2%) and 48 (12.8%), while the frequencies of PP and PA genotypes in the cognitive dysfunction group were 126 (92.9%), 9 (7.1%) respectively. Analyzed by chi2 test, both the genotype frequency and the allele frequency of PPARy2 Pro12Ala polymorphism did not display statistical variability between the cognitive normal group and the cognitive dysfunction group, even eliminating the influence of age and sexuality. Pro12Ala polymorphism in PPARgamma2 with primary hypertension may not associate with cognitive impairment.

  1. Regulation of hepatic PPAR{gamma}2 and lipogenic gene expression by melanocortin

    SciTech Connect

    Poritsanos, Nicole J.; Wong, Davie; Vrontakis, Maria E.; Mizuno, Tooru M.

    2008-11-14

    The central melanocortin system regulates hepatic lipid metabolism. Hepatic lipogenic gene expression is regulated by transcription factors including sterol regulatory element-binding protein 1c (SREBP-1c), carbohydrate responsive element-binding protein (ChREBP), and peroxisome proliferator-activated receptor {gamma}2 (PPAR{gamma}2). However, it is unclear if central melanocortin signaling regulates hepatic lipogenic gene expression through the activation of these transcription factors. To delineate the molecular mechanisms by which the melanocortin system regulates hepatic lipid metabolism, we examined the effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on hepatic expression levels of genes involved in lipid metabolism in mice. SHU9119 treatment increased hepatic triglyceride content and mRNA levels of lipogenic genes, SREBP-1c, and PPAR{gamma}2, whereas it did not cause any changes in hepatic ChREBP mRNA levels. These findings suggest that reduced central melanocortin signaling increases hepatic lipid deposition by stimulating hepatic lipogenic gene expression at least partly through the activation of SREBP-1c and PPAR{gamma}2.

  2. Characterization of new PPARgamma agonists: benzimidazole derivatives - the importance of position 2.

    PubMed

    Goebel, Matthias; Staels, Bart; Unger, Thomas; Kintscher, Ulrich; Gust, Ronald

    2009-07-01

    Probing SAR: The 1-(biphenyl-4-ylmethyl)-1H-benzo[d]imidazole moiety is known to be an essential structural component of telmisartan for PPARgamma activation. This study focused on the substituents at position 2 of the benzimidazole in an attempt to optimize PPARgamma activation. In particular, the elongation of the alkyl chain and the introduction of an aromatic ring system were studied (shown).The relevance of substituents at C-2 of the central benzimidazole of telmisartan for PPARgamma activation has recently been demonstrated, and the most active compound identified in our previous work, 4'-[(2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (4 a), is used as lead structure in the present study. Modifications at C-2 included butyl (4 b), iso-butyl (4 c), tert-butyl (4 d), phenyl (4 e), benzyl (4 f), phenethyl (4 g), 4-chlorobenzyl (4 h), 4-methoxyphenyl (4 i), and 4-hydroxyphenyl (4 j) moieties. The compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells, transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARgamma activation. The activity in the luciferase assay increased in the alkyl series: propyl (4 a)

  3. Profound thrombocytopenia after primary exposure to eptifibatide.

    PubMed

    Norgard, Nicholas B; Badgley, Brian T

    2010-01-01

    Eptifibatide is a glycoprotein IIb/IIIa receptor antagonist used to reduce the incidence of ischemic events in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention. A minority of patients given eptifibatide develop acute, profound thrombocytopenia (<20,000 cells/mm(3)) within a few hours of receiving the drug. This case report discusses a patient who developed profound thrombocytopenia within hours of receiving eptifibatide for the first time. The Naranjo algorithm classified the likelihood that this patient's thrombocytopenia was related to eptifibatide as probable. Profound thrombocytopenia is an uncommon but clinically important complication of eptifibatide. This case report emphasizes the importance of monitoring platelet counts routinely at baseline and within 2-6 hours of eptifibatide administration.

  4. Effects of the PPAR{gamma} agonist troglitazone on endothelial cells in vivo and in vitro: Differences between human and mouse

    SciTech Connect

    Kakiuchi-Kiyota, Satoko; Vetro, Joseph A.; Suzuki, Shugo; Varney, Michelle L.; Han, Huai-Yun; Nascimento, Merielen; Pennington, Karen L.; Arnold, Lora L.; Singh, Rakesh K.; Cohen, Samuel M.

    2009-05-15

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists and PPAR{gamma}/{alpha} dual agonists have been or are being developed for clinical use in the treatment of type 2 diabetes mellitus and hyperlipidemias. A common tumor finding in rodent carcinogenicity studies for these agonists is hemangioma/hemangiosarcoma in mice but not in rats. We hypothesized that increased endothelial cell proliferation may be involved in the mechanism of PPAR agonist-induced vascular tumors in mice, and we investigated the effects on endothelial cells utilizing troglitazone, the first clinically used PPAR{gamma} agonist, in vivo and in vitro. Troglitazone (400 and 800 mg/kg/day) induced hemangiosarcomas in mice in a 2-year bioassay. We showed that troglitazone increased endothelial cell proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses after 4 weeks of treatment. Troglitazone was cytotoxic both to human dermal microvascular endothelial cells (HMEC1) and mouse mammary fat pad microvascular endothelial cells (MFP MVEC) at high concentrations. However, MFP MVEC were more resistant to the cytotoxic effects of troglitazone based on the much lower LC{sub 50} in HMEC1 (17.4 {mu}M) compared to MFP MVEC (92.2 {mu}M). Troglitazone increased the proliferation and survival of MFP MVEC but not HMEC1 in growth factor reduced conditions. Our data demonstrate that troglitazone may induce hemangiosarcomas in mice, at least in part, through enhancement of survival and proliferation of microvascular endothelial cells. Such an effect does not occur with human cells, suggesting that human may react differently to exposure to PPAR agonists compared with mice.

  5. In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{gamma} and quantitative analysis of in vivo induction pathway

    SciTech Connect

    Takeuchi, Shinji; Matsuda, Tadashi; Kobayashi, Satoshi; Takahashi, Tetsuo; Kojima, Hiroyuki . E-mail: kojima@iph.pref.hokkaido.jp

    2006-12-15

    Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and key regulators of lipid metabolism and cell differentiation. However, there have been few studies reporting on a variety of environmental chemicals, which may interact with these receptors. In the present study, we characterized mouse PPAR{alpha} and PPAR{gamma} agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 11 acid amides, 7 triazines, 8 ureas and 44 others) by in vitro reporter gene assays using CV-1 monkey kidney cells. Three of the 200 pesticides, diclofop-methyl, pyrethrins and imazalil, which have different chemical structures, showed PPAR{alpha}-mediated transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPAR{gamma} agonistic activity at concentrations {<=} 10{sup -5} M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPAR{alpha}-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds ({<=} 300 mg/kg). RT-PCR revealed significantly high induction levels of CYP4A10 and CYP4A14 mRNAs in diclofop-methyl- and pyrethrins-treated mice, whereas imazalil induced almost no gene expressions of CYP4As. In particular, diclofop-methyl induced as high levels of CYP4A mRNAs as WY-14643, a potent PPAR{alpha} agonist. Thus, most of the 200 pesticides tested do not activate PPAR{alpha} or PPAR{gamma} in in vitro assays, but only diclofop-methyl and pyrethrins induce PPAR{alpha} agonistic activity in vivo as well as in vitro.

  6. Meeting the Needs of Profoundly Handicapped Students.

    ERIC Educational Resources Information Center

    McGovern, Matthew A.

    1996-01-01

    The Southern Westchester, New York, Board of Educational Services reviewed its facilities and made major changes at Rye Lake Campus. Built in the 1970s, the facility now serves students who are profoundly handicapped. A few unique features include nursing tables with automatic controls and special toilet equipment. New lighting and a bright color…

  7. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.

    PubMed

    Henke, B R; Blanchard, S G; Brackeen, M F; Brown, K K; Cobb, J E; Collins, J L; Harrington, W W; Hashim, M A; Hull-Ryde, E A; Kaldor, I; Kliewer, S A; Lake, D H; Leesnitzer, L M; Lehmann, J M; Lenhard, J M; Orband-Miller, L A; Miller, J F; Mook, R A; Noble, S A; Oliver, W; Parks, D J; Plunket, K D; Szewczyk, J R; Willson, T M

    1998-12-03

    We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

  8. PPARgamma and GLUT-4 expression as developmental regulators/markers for preadipocyte differentiation into an adipocyte.

    PubMed

    Fernyhough, M E; Okine, E; Hausman, G; Vierck, J L; Dodson, M V

    2007-11-01

    In this document, we have integrated knowledge about two major cellular markers found in cells of the adipocyte lineage (an adipogenic marker and a metabolic marker). This review provides information as to how differentiation of a cell (such as an adipofibroblast, fibroblast or preadipocyte) to become a viable (and new) adipocyte is under different regulation than that experienced by an immature adipocyte that is just beginning to accumulate lipid. The differentiation, prior to lipid-filling, involves PPARgamma. Subsequently, lipid-filling of the adipocyte relies on a late subset of genes and, depending on depot specificity, involves GLUT-4 or any number of other metabolic markers.

  9. Profound biotinidase deficiency in two asymptomatic adults.

    PubMed

    Wolf, B; Norrgard, K; Pomponio, R J; Mock, D M; McVoy, J R; Fleischhauer, K; Shapiro, S; Blitzer, M G; Hymes, J

    1997-11-28

    Biotinidase deficiency is an autosomal-recessive disorder of biotin recycling. Children with profound biotinidase deficiency usually have neurological and cutaneous symptoms in early childhood, but they may not develop symptoms until adolescence. We now report on a man and a woman with profound biotinidase deficiency who are asymptomatic and who were diagnosed only because their biotinidase-deficient children were identified by newborn screening. These adults have never exhibited symptoms of the disorder and are homozygous for two different mutations resulting in different aberrant enzymes. There is no evidence of an increased dietary intake of biotin to explain why they have remained asymptomatic. Although these adults may still be at risk for developing symptoms, they could represent a small group of individuals with profound biotinidase deficiency who will never develop clinical problems. Their lack of symptoms suggests that there are probably epigenetic factors that protect some enzyme-deficient individuals from developing symptoms. These individuals broaden the spectrum of expression of biotinidase deficiency.

  10. Lemierre's Syndrome Associated with Mechanical Ventilation and Profound Deafness

    PubMed Central

    2017-01-01

    Lemierre's syndrome is a rare disorder that is characterized by anaerobic organisms inducing a thrombophlebitis of the internal jugular vein (IJV) following a course of oropharyngeal infection. It often occurs in young and healthy patients. Clinicians continuously misinterpret early symptoms until infection disseminates systematically and life-threatening sepsis transpires. We report the case of a 58-year-old female developing Lemierre's syndrome accompanied by invasive ventilation support and a profound deafness requiring the implementation of a cochlear implant. This is one of two reported cases of Lemierre's syndrome associated with mechanical ventilation support and the only case associated with a cochlear implant. PMID:28331642

  11. Proteomic profiling of human plasma exosomes identifies PPAR{gamma} as an exosome-associated protein

    SciTech Connect

    Looze, Christopher; Yui, David; Leung, Lester; Ingham, Matthew; Kaler, Maryann; Yao, Xianglan; Wu, Wells W.; Shen Rongfong; Daniels, Mathew P.; Levine, Stewart J.

    2009-01-16

    Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatory cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPAR{gamma} as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors.

  12. Ginsenoside 20S-protopanaxatriol (PPT) activates peroxisome proliferator-activated receptor gamma (PPARgamma) in 3T3-L1 adipocytes.

    PubMed

    Han, Kyu Lee; Jung, Myeong Ho; Sohn, Jong Hee; Hwang, Jae-Kwan

    2006-01-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor of ligand-activated transcription factors, regulates the expression of key genes involved in lipid and glucose metabolism or adipocyte differentiation. Ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of Type2 diabetes. Ginseng saponins or ginsenosides are reported to provide anti-diabetic activity as well as to modulate glucose metabolism, although the mechanism remains unclear. In this study, we examined the effect of ginsenosides on activation of PPARgamma and adipogenes in 3T3-L1. Using a GAL-4/PPARgamma transactivation assay, 20(S)-protopanaxatriol (PPT), one of the ginsenoside metabolites, was found to increase PPARgamma-transactivation activity dose-dependently with similar activity as troglitazone, a well-known PPARgamma agonist. PPT enhanced adipogenesis by increasing the expression of PPARgamma target genes such as aP2, LPL and PEPCK. Furthermore, PPT significantly increased expression of glucose transporter 4 (GLUT4). These results indicate that PPT can be developed as a PPARgamma agonist for the improvement of insulin resistance associated with diabetes.

  13. The Pro12Ala polymorphism of the PPAR-gamma gene is not associated with the polycystic ovary syndrome.

    PubMed

    Xita, Nectaria; Lazaros, Leandros; Georgiou, Ioannis; Tsatsoulis, Agathocles

    2009-01-01

    Insulin resistance is a key factor in the pathogenesis of polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated- receptor-gamma (PPAR-gamma) has been implicated in insulin resistance and adiposity. The aim of the study was to investigate the possible involvement of the Pro12Ala polymorphism of the PPAR-gamma gene in the pathogenesis of PCOS. We studied 180 women with PCOS and 140 healthy controls. Body mass index (BMI) was recorded. Blood samples were drawn after overnight fasting and serum glucose, insulin, lipid and hormonal profiles were determined. The fasting glucose/insulin ratio and HOMA index were calculated. Moreover, 100 women with PCOS underwent a 75g oral glucose tolerance test and the area under the curve for insulin and glucose was estimated. DNA was extracted from peripheral blood leucocytes and the Pro12Ala polymorphism was genotyped. The PPAR-gamma genotypes were found to be in the Hardy-Weinberg equilibrium in both study groups. No difference was found in the distribution of the Pro12Ala polymorphism between PCOS and controls. Insulin resistance indices and lipid and hormonal profile were not different among the various genotypes of the Pro12Ala polymorphism. The Pro12Ala polymorphism of the PPAR-gamma gene is not involved in the pathogenesis or the phenotypic expression of PCOS.

  14. Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice.

    PubMed

    Harmon, Gregory S; Dumlao, Darren S; Ng, Damian T; Barrett, Kim E; Dennis, Edward A; Dong, Hui; Glass, Christopher K

    2010-03-01

    Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

  15. Factitious hypobicarbonatemia associated with profound hyperlipidemia.

    PubMed

    Rifkin, Stephen I; Shaub, Beth

    2014-08-01

    We describe a patient who presented on two occasions with severe hypobicarbonatemia and an associated high anion gap on enzymatic analysis. She also had profound hyperlipidemia. Her low bicarbonate was shown to be factitious by analysis of her blood using a direct ion-selective electrode method. Reanalysis of blood samples after treatment with a lipid clearing agent resulted in marked improvement in the bicarbonate level. We suggest that the light scattering effect of the hyperlipidemia interfered with the photometric analysis causing this factitious phenomenon.

  16. Profound hypernatremia due to central diabetes insipidus.

    PubMed

    Vaqar, Abeer; Rafiq, Asim; Javaid, Khalid Hussain; Parveen, Rashida; Sadaf, Rabia

    2012-06-01

    Diabetes insipidus is a rare endocrine disorder in paediatric patients. Polyuria is a cardinal manifestation that is extremely difficult to recognize in diapered infants. Careful urine quantification is the key to diagnosis in appropriate clinical setting. We report a case of a 4 months old infant presenting with an acute life threatening event following an episode of vomiting and decreased oral intake. She had profound hypernatremia which persisted after stabilization. Polyuria unrecognized by the mother was revealed by 24-hour urine output measurement. A diagnosis of diabetes insipidus was made after appropriate laboratory investigations including serum and urine osmolality. The central nature of the disease was confirmed by neuroimaging which showed holoprosencephaly.

  17. Crosstalk between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR{gamma} binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} mediated transactivation

    SciTech Connect

    Alimirah, Fatouma; Peng, Xinjian; Yuan, Liang; Mehta, Rajeshwari R.; Knethen, Andreas von; Choubey, Divaker; Mehta, Rajendra G.

    2012-11-15

    Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ER{alpha}) physically binds to peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and inhibits its transcriptional activity. The interaction between PPAR{gamma} and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPAR{gamma} and VDR signaling, and for the first time we show that PPAR{gamma} physically associates with VDR in human breast cancer cells. We found that overexpression of PPAR{gamma} decreased 1{alpha},25-dihydroxyvitamin D{sub 3} (1,25D{sub 3}) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPAR{gamma}'s hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPAR{gamma}'s AF2 domain attenuated its repressive action on 1,25D{sub 3} transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPAR{gamma} was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXR{alpha}). Overexpression of RXR{alpha} blocked PPAR{gamma}'s suppressive effect on 1,25D{sub 3} action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPAR{gamma} and VDR pathways. -- Highlights: PPAR{gamma}'s role on 1{alpha},25-dihydroxyvitamin D{sub 3} transcriptional activity is examined. Black-Right-Pointing-Pointer PPAR{gamma} physically binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} action. Black-Right-Pointing-Pointer PPAR{gamma}'s hinge and ligand binding domains are important for this inhibitory effect. Black-Right-Pointing-Pointer PPAR{gamma} competes with VDR for the availability of their binding partner, RXR{alpha}.

  18. Profound hypokalemia associated with severe diabetic ketoacidosis.

    PubMed

    Davis, Shanlee M; Maddux, Aline B; Alonso, Guy T; Okada, Carol R; Mourani, Peter M; Maahs, David M

    2016-02-01

    Hypokalemia is common during the treatment of diabetic ketoacidosis (DKA); however, severe hypokalemia at presentation prior to insulin treatment is exceedingly uncommon. A previously healthy 8-yr-old female presented with new onset type 1 diabetes mellitus, severe DKA (pH = 6.98), and profound hypokalemia (serum K = 1.3 mmol/L) accompanied by cardiac dysrhythmia. Insulin therapy was delayed for 9 h to allow replenishment of potassium to safe serum levels. Meticulous intensive care management resulted in complete recovery. This case highlights the importance of measuring serum potassium levels prior to initiating insulin therapy in DKA, judicious fluid and electrolyte management, as well as delaying and/or reducing insulin infusion rates in the setting of severe hypokalemia.

  19. Pro12Ala polymorphism in PPARgamma2 associated with depression in Chinese nonagenarians/centenarians.

    PubMed

    Ji-Rong, Yue; Bi-Rong, Dong; Chang-Quan, Huang; Zhen-Chan, Lu; Hong-Mei, Wu; Yan-Ling, Zhang; Mattis, Tod A

    2009-07-01

    The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPARgamma) has been associated with decreased obesity, insulin resistance, type 2 diabetes and other age-associated diseases such as cognitive impairment, hypertension, cancer, osteoarthritis. Each one of these diseases had been linked to depression. Moreover, there is also an association between Pro12 Ala polymorphism in PPAR gamma2 and longevity. The aim of the study was to evaluate the association between Pro12 Ala polymorphism and depression in Chinese nonagenarians and centenarians. The sample included 697 unrelated Chinese nonagenarians/centenarians (aged between 90-108 years, mean age: 93.5+/-3.35 years; 67.2% women). The Pro12Ala variant was examined using polymerase chain reaction-restriction fragment length polymorphism. Depression was measured with brief 23-item Geriatrics Depression Scale Chinese-edition (GDS-CD). In this sample, the genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.2% Pro12Ala, 90.8% Pro12Pro and the prevalence of depression was 25.3%. Subjects who were 12Ala carriers had significantly lower prevalence of depression than those who were not 12Ala carriers (14.06 vs. 26.38%, p=0.034). Subjects without depression also had a higher frequency of 12Ala gene than those with depression (5.28 vs. 2.56%, p=0.031). Adjusting for certain clinical factors that may be associated with depression or with 12Ala carriers, multiple logistic regressions showed the 12Ala gene was associated with decreased incidence of depression. In summary, we found that among Chinese nonagenarians and centenarians, the Pro12Ala polymorphism in PPARgamma2 was associated with depression and that the 12Ala gene may be a factor for decreased depression.

  20. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta.

    PubMed

    Kawai, Toru; Masaki, Takao; Doi, Shigehiro; Arakawa, Tetsuji; Yokoyama, Yukio; Doi, Toshiki; Kohno, Nobuoki; Yorioka, Noriaki

    2009-01-01

    Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have a central role in insulin sensitization and adipogenesis. It has been reported that TZDs exert protective effects in both diabetic and nondiabetic models of renal disease, although the exact mechanism is not well understood. In particular, only a few studies have reported the renoprotective effects of TZDs in nondiabetic models of tubulointerstitial fibrosis and inflammation. Therefore, we investigated the anti-fibrotic and anti-inflammatory effects of the TZD troglitazone in the mouse model of unilateral ureteral obstruction (UUO). C57BL/6J mice underwent UUO and were studied after 3 and 7 days. Animals were divided into three groups and received control vehicle, troglitazone (150 mg/kg per day) or troglitazone (300 mg/kg per day) by gavage. Kidneys were harvested for morphological, mRNA and protein analysis. Reverse-transcriptase-PCR was used to assess the expression of transforming growth factor-beta1 (TGF-beta1) and the TGF-beta1 type I receptor (TGF beta R-I). Protein expression was assessed by western blotting (TGF beta R-I) and immunostaining (TGF beta R-I, alpha-smooth muscle actin (alpha-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of alpha-SMA, collagen I, and F4/80 was decreased in mice treated with troglitazone compared with the control group. The numbers of PCNA-positive interstitial cells were decreased in mice treated with troglitazone. TGF-beta1 mRNA and TGF beta R-I mRNA and protein expression were decreased in the group treated with troglitazone compared with the control group. The beneficial effects of troglitazone treatment were also dose dependent. PPAR-gamma agonist significantly reduced TGF-beta and attenuated renal interstitial fibrosis and inflammation in the model of UUO.

  1. Antagonist of peroxisome proliferator-activated receptor {gamma} induces cerebellar amyloid-{beta} levels and motor dysfunction in APP/PS1 transgenic mice

    SciTech Connect

    Du, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, Zhao

    2009-07-03

    Recent evidences show that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is involved in the modulation of the amyloid-{beta} (A{beta}) cascade causing Alzheimer's disease (AD) and treatment with PPAR{gamma} agonists protects against AD pathology. However, the function of PPAR{gamma} steady-state activity in A{beta} cascade and AD pathology remains unclear. In this study, an antagonist of PPAR{gamma}, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR{gamma} activity in cerebellum. The results show that inhibition of PPAR{gamma} significantly induced A{beta} levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of A{beta}. Since cerebellum is spared from significant A{beta} accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR{gamma} steady-state activity in protection of cerebellum against AD pathology.

  2. Identification of novel PPAR{gamma} target genes by integrated analysis of ChIP-on-chip and microarray expression data during adipocyte differentiation

    SciTech Connect

    Nakachi, Yutaka; Yagi, Ken; Nikaido, Itoshi; Bono, Hidemasa; Tonouchi, Mio; Schoenbach, Christian; Okazaki, Yasushi

    2008-07-25

    PPAR{gamma} (peroxisome proliferator-activated receptor gamma) acts as a key molecule of adipocyte differentiation, and transactivates multiple target genes involved in lipid metabolic pathways. Identification of PPAR{gamma} target genes will facilitate to predict the extent to which the drugs can affect and also to understand the molecular basis of lipid metabolism. Here, we have identified five target genes regulated directly by PPAR{gamma} during adipocyte differentiation in 3T3-L1 cells using integrated analyses of ChIP-on-chip and expression microarray. We have confirmed the direct PPAR{gamma} regulation of five genes by luciferase reporter assay in NIH-3T3 cells. Of these five genes Hp, Tmem143 and 1100001G20Rik are novel PPAR{gamma} targets. We have also detected PPREs (PPAR response elements) sequences in the promoter region of the five genes computationally. Unexpectedly, most of the PPREs detected proved to be atypical, suggesting the existence of more atypical PPREs than previously thought in the promoter region of PPAR{gamma} regulated genes.

  3. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-{gamma} activation

    SciTech Connect

    Moriuchi, Akie ||. E-mail: f1195@cc.nagasaki-u-ac.jp; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Satoh, Tsuyoshi; Satoh, Tsuyoshi; Fujishima, Keiichiro; Fukushima, Keiko |; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Kawasaki, Eiji

    2007-05-18

    Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-{gamma}, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-{gamma}.

  4. Sp1 mediates repression of the resistin gene by PPAR{gamma} agonists in 3T3-L1 adipocytes

    SciTech Connect

    Chung, S.S.; Choi, H.H.; Cho, Y.M.; Lee, H.K.; Park, K.S. . E-mail: kspark@snu.ac.kr

    2006-09-15

    Resistin is an adipokine related to obesity and insulin resistance. Expression of the resistin gene is repressed by the treatment of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists, thiazolidinediones (TZDs). In this study, we investigated the mechanism by which TZDs inhibit the resistin gene expression. Resistin gene expression was decreased by TZD in fully differentiated 3T3-L1 adipocytes, which was abolished after treatment of cycloheximide (a protein synthesis inhibitor). TZD could not repress the expression of the resistin gene in the presence of mithramycin A (an Sp1 binding inhibitor). Sp1 binding site of the resistin promoter (-122/-114 bp) was necessary for the repression. Further investigation of the effect of TZDs on the modification of Sp1 showed that the level of O-glycosylation of Sp1 was decreased in this process. These results suggest that PPAR{gamma} activation represses the expression of the resistin gene by modulating Sp1 activity.

  5. PPARgamma agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control.

    PubMed

    Festuccia, W T; Laplante, M; Berthiaume, M; Gélinas, Y; Deshaies, Y

    2006-10-01

    The aim of this study was to investigate the effect and mechanisms of action of in vivo peroxisome proliferator-activated receptor gamma (PPARgamma) activation on white adipose tissue (WAT) lipolysis and NEFA metabolism. Study rats were treated for 7 days with 15 mg/kg of rosiglitazone per day; control rats were not treated. After a 6-h fast, lipolysis and levels of mRNA for lipases were assessed in explants from various adipose depots. Rosiglitazone markedly increased basal and noradrenaline (norepinephrine)-stimulated glycerol and NEFA release from WAT explants, and amplified their inhibition by insulin. Primary adipocytes isolated from PPARgamma agonist-treated rats were also more responsive to noradrenaline stimulation expressed per cell, ruling out a contribution of an altered number of mature adipocytes in explants. Rosiglitazone concomitantly increased levels of mRNA transcripts for adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) in subcutaneous and visceral WAT, and mRNA for hormone-sensitive lipase (HSL) in subcutaneous WAT. Lipase expression increased within 12 h of in vitro exposure of naïve explants to rosiglitazone, suggesting direct transcriptional activation. In parallel, chronic in vivo treatment with rosiglitazone lowered plasma NEFAs and in WAT its expected stimulatory action on glycerol and NEFA recycling, and on the expression of genes involved in NEFA uptake and retention by WAT, such processes counteracting net NEFA export. These findings demonstrate that, in the face of its plasma NEFA-lowering action, PPARgamma agonism stimulates WAT lipolysis, an effect that is compensated by lipid-retaining pathways. The results further suggest that PPARgamma agonism stimulates lipolysis by increasing the lipolytic potential, including the expression levels of the genes encoding adipose triglyceride lipase and monoglyceride lipase.

  6. Profound 62 Myr Cycle in Fossil Diversity

    NASA Astrophysics Data System (ADS)

    Muller, R. A.; Rohde, R. A.

    2004-12-01

    By combining the Sepkoski Compendium of Marine Fossil Genera with the new ICS 2004 geologic time scale, we have shown that the fossil record contains a 62 +/- 3 Myr cycle in the diversity of genera. This cycle has a very high statistical significance and while the associated changes in diversity are frequently gradual, all of the sharp drops known as major mass extinctions have occurred during declining phases of this cycle. This suggests that the timing or magnitude of these extinctions has been influenced by this periodic process; however, it remains unclear whether extinction events actually cause the cycle. While, we cannot explain the origin of the 62 Myr cycle, we believe it indicates a profound influence of some periodic physical process on Earth's environment throughout at least the last 540 Myr. In addition, the diversity data contain a statistically ambiguous 140 +/- 15 Myr cycle which could be due to changes of the same frequency reported in climate and cosmic rays. While all major mass extinctions seem to bear some relation to this cycle, we also find that the Permian-Triassic extinction was qualitatively unique. This extinction, the most severe in Earth's history, had substantial impact on classes of organisms that were historically resistant to the 62 Myr changes. This suggests that the processes leading to the P-T extinction may have included factors that were unique to that point in the Phanerozoic. It should be noted that the 62 Myr hypothesis is originally due to Thomson (Thomson KS, Nature 261, 578-580 (1976); Devs. in Palaeo. and Strat. 5, 377-404 (1977)) and Ager (Ager DV, Proc. Geologists' Assoc. 87, 131-159 (1977)), though their work has largely been forgotten. At the time of this submission, our revival of the 62 Myr hypothesis and related analysis is currently undergoing peer review at Nature.

  7. Profound Olfactory Dysfunction in Myasthenia Gravis

    PubMed Central

    Leon-Sarmiento, Fidias E.; Bayona, Edgardo A.; Bayona-Prieto, Jaime; Osman, Allen; Doty, Richard L.

    2012-01-01

    In this study we demonstrate that myasthenia gravis, an autoimmune disease strongly identified with deficient acetylcholine receptor transmission at the post-synaptic neuromuscular junction, is accompanied by a profound loss of olfactory function. Twenty-seven MG patients, 27 matched healthy controls, and 11 patients with polymiositis, a disease with peripheral neuromuscular symptoms analogous to myasthenia gravis with no known central nervous system involvement, were tested. All were administered the University of Pennsylvania Smell Identification Test (UPSIT) and the Picture Identification Test (PIT), a test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds. The UPSIT scores of the myasthenia gravis patients were markedly lower than those of the age- and sex-matched normal controls [respective means (SDs) = 20.15 (6.40) & 35.67 (4.95); p<0.0001], as well as those of the polymiositis patients who scored slightly below the normal range [33.30 (1.42); p<0.0001]. The latter finding, along with direct monitoring of the inhalation of the patients during testing, implies that the MG-related olfactory deficit is unlikely due to difficulties sniffing, per se. All PIT scores were within or near the normal range, although subtle deficits were apparent in both the MG and PM patients, conceivably reflecting influences of mild cognitive impairment. No relationships between performance on the UPSIT and thymectomy, time since diagnosis, type of treatment regimen, or the presence or absence of serum anti-nicotinic or muscarinic antibodies were apparent. Our findings suggest that MG influences olfactory function to the same degree as observed in a number of neurodegenerative diseases in which central nervous system cholinergic dysfunction has been documented. PMID:23082113

  8. Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages.

    PubMed

    Caito, Samuel; Yang, Se-Ran; Kode, Aruna; Edirisinghe, Indika; Rajendrasozhan, Saravanan; Phipps, Richard P; Rahman, Irfan

    2008-02-01

    Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls. Furthermore, it was shown that PPARgamma interacts with the RelA/p65 subunit of NF-kappaB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARgamma. Thus, these new data show that activation of PPARgamma with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis.

  9. Troglitazone enhances tamoxifen-induced growth inhibitory activity of MCF-7 cells

    SciTech Connect

    Yu, Hong-Nu; Noh, Eun-Mi; Lee, Young-Rae; Roh, Si-Gyun; Song, Eun-Kyung; Han, Myung-Kwan; Lee, Yong-Chul; Shim, In Kyong; Lee, Seung Jin; Jung, Sung Hoo; Kim, Jong-Suk Youn, Hyun Jo

    2008-12-05

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands have been identified as a potential source of therapy for human cancers. However, PPAR{gamma} ligands have a limitation for breast cancer therapy, since estrogen receptor {alpha} (ER{sub {alpha}}) negatively interferes with PPAR{gamma} signaling in breast cancer cells. Here we show that ER{sub {alpha}} inhihits PPAR{gamma} transactivity and ER{sub {alpha}}-mediated inhibition of PPAR{gamma} transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ER{sub {alpha}} with 17-{beta}-estradiol blocked PPRE transactivity induced by troglitazone, a PPAR{gamma} ligand, indicating the resistance of ER{sub {alpha}}-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ER{sub {alpha}}-negative MDA-MB-231 cells more than that of ER{sub {alpha}}-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ER{sub {alpha}}-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ER{sub {alpha}}-positive MCF-7 cells.

  10. Persistent Thalamic Sound Processing Despite Profound Cochlear Denervation

    PubMed Central

    Chambers, Anna R.; Salazar, Juan J.; Polley, Daniel B.

    2016-01-01

    Neurons at higher stages of sensory processing can partially compensate for a sudden drop in peripheral input through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where >95% of afferent synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, auditory cortex (ACtx) processing and perception recover despite the absence of an auditory brainstem response (ABR) or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC), an auditory midbrain nucleus. In this study, we induced a profound cochlear neuropathy with ouabain and asked whether central gain enabled a compensatory plasticity in the auditory thalamus comparable to the full recovery of function previously observed in the ACtx, the partial recovery observed in the IC, or something different entirely. Unilateral ouabain treatment in adult mice effectively eliminated the ABR, yet robust sound-evoked activity persisted in a minority of units recorded from the contralateral medial geniculate body (MGB) of awake mice. Sound driven MGB units could decode moderate and high-intensity sounds with accuracies comparable to sham-treated control mice, but low-intensity classification was near chance. Pure tone receptive fields and synchronization to broadband pulse trains also persisted, albeit with significantly reduced quality and precision, respectively. MGB decoding of temporally modulated pulse trains and speech tokens were both greatly impaired in ouabain-treated mice. Taken together, the absence of an ABR belied a persistent auditory processing at the level of the MGB that was likely enabled through increased central gain. Compensatory plasticity at the level of the

  11. Persistent Thalamic Sound Processing Despite Profound Cochlear Denervation.

    PubMed

    Chambers, Anna R; Salazar, Juan J; Polley, Daniel B

    2016-01-01

    Neurons at higher stages of sensory processing can partially compensate for a sudden drop in peripheral input through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where >95% of afferent synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, auditory cortex (ACtx) processing and perception recover despite the absence of an auditory brainstem response (ABR) or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC), an auditory midbrain nucleus. In this study, we induced a profound cochlear neuropathy with ouabain and asked whether central gain enabled a compensatory plasticity in the auditory thalamus comparable to the full recovery of function previously observed in the ACtx, the partial recovery observed in the IC, or something different entirely. Unilateral ouabain treatment in adult mice effectively eliminated the ABR, yet robust sound-evoked activity persisted in a minority of units recorded from the contralateral medial geniculate body (MGB) of awake mice. Sound driven MGB units could decode moderate and high-intensity sounds with accuracies comparable to sham-treated control mice, but low-intensity classification was near chance. Pure tone receptive fields and synchronization to broadband pulse trains also persisted, albeit with significantly reduced quality and precision, respectively. MGB decoding of temporally modulated pulse trains and speech tokens were both greatly impaired in ouabain-treated mice. Taken together, the absence of an ABR belied a persistent auditory processing at the level of the MGB that was likely enabled through increased central gain. Compensatory plasticity at the level of the

  12. Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP.

    PubMed

    Wang, Li Hua; Yang, Xiao Yi; Zhang, Xiaohu; Farrar, William L

    2007-12-15

    Binding of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) triggers expression of adhesive molecules and secretion of interleukin-6 (IL-6), promoting MM cell growth, survival, drug resistance, and migration, which highlights the possibility of developing and validating novel anti-MM therapeutic strategies targeting MM cells-host BMSC interactions and their sequelae. Recently, we have found that expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands can potently inhibit IL-6-regulated MM cell growth. Here we demonstrate that PPARgamma agonists 15-d-PGJ2 and troglitazone significantly suppress cell-cell adhesive events, including expression of adhesion molecules and IL-6 secretion from BMSCs triggered by adhesion of MM cells, as well as overcome drug resistance by a PPARgamma-dependent mechanism. The synthetic and natural PPARgamma agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-kappaB and 5'-CCAAT/enhancer-binding protein beta (C/EBPbeta). Both 15-d-PGJ2 and troglitazone blocked C/EBPbeta transcriptional activity by forming PPARgamma complexes with C/EBPbeta. 15-d-PGJ2 and troglitazone also blocked NF-kappaB activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non-PPARgamma-dependent effect by inactivation of phosphorylation of IKK and IkappaB. These studies provide the framework for PPARgamma-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.

  13. Influence of the Pro12Ala polymorphism of PPAR-gamma on age at onset and sRAGE levels in Alzheimer's disease.

    PubMed

    Yao, Lifen; Li, Keshen; Zhang, Liming; Yao, Songpo; Piao, Zhongyuan; Song, Lin

    2009-09-29

    Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been described to have a role in the modulation of various genes involved in Abeta homeostasis, inflammation, and energy metabolism, making it a candidate gene for risk of Alzheimer's disease (AD). A functional polymorphism in exon 2 of the PPAR-gamma gene has been related to AD, but the effects are inconsistent across studies. To determine the role of PPAR-gamma in genetic susceptibility to AD in a representative Chinese sample, we genotyped 362 AD patients and 370 healthy controls for PPAR-gamma Pro12Ala polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. We also examined the potential impact of this polymorphism on plasma level of soluble receptor for advanced glycation end products (sRAGE), a decoy receptor whose reduction has been associated with a higher risk of AD. Our results suggest that PPAR-gamma Pro12Ala polymorphism was not associated with an increased risk of AD in the overall sample. Stratification analysis revealed that the PPAR-gamma Pro/Ala genotype may be associated with the development of early-onset AD in the individuals without APOE epsilon4 allele (OR=3.76, 95% CI=1.10-12.84; p=0.03), but this association became insignificant after Bonferroni correction (p (corr)=0.10). Moreover, in the subgroup of APOE epsilon4 noncarriers, Kaplan-Meier survival analyses indicated that AD patients with the Pro/Ala genotype presented with disease onset 4.6 years earlier than carriers of Pro/Pro genotype. Further investigation revealed that AD patients carrying Pro/Ala genotype had significantly lower plasma sRAGE levels than patients with Pro/Pro genotype. These findings suggest that the functional PPAR-gamma Pro12Ala polymorphism may modify the age at onset of AD.

  14. Pro12Ala polymorphism in PPAR-gamma2 and dementia in Chinese nonagenarians/centenarians.

    PubMed

    Yue, Ji-Rong; Dong, Bi-Rong; Huang, Chang-Quan; Lu, Zhen-Chan; Wu, Hong-Mei; Zhang, Yan-Ling

    2010-09-01

    We examined the existence of a relationship between polymorphism and dementia in subjects aged 90 years and above. The sample included 732 unrelated Chinese nonagenarians/centenarians (aged 90-108 years, mean age 93.68 years; 67.5% women). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism. Cognitive function was measured with 30-item mini-mental state examination. The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.1% Pro12Ala, and 90.9% Pro12Pro. The prevalence rates of dementia were 64.9% in the whole sample (45.0% for men and 74.5% for women). In both men and women, between subjects with and without 12Ala carriers, there was no significant difference in cognitive function scores and also no significant difference in prevalence of dementia; there was no significant difference in frequency of 12Ala carriers between subjects with and without dementia. Multiple logistic regression was performed by adjusting clinical factors that are thought to be associated with cognitive function or with 12Ala carriers. We found that 12Ala is not a risk factor for dementia. We found that Pro12Ala polymorphism in PPAR-gamma2 was not directly correlated with dementia among Chinese nonagenarians and centenarians.

  15. Profound Impacts of AN Arctic Face Lift

    NASA Astrophysics Data System (ADS)

    Nghiem, Son

    Son Nghiem, son.v.nghiem@jpl.nasa.gov Jet Propulsion Laboratory, California Institute of Technology, Pasadena, California, United States The ice cover on the Arctic Ocean has undergone a face lift that removes much of the older and thicker perennial ice and replaces it with the younger and thinner seasonal ice. Although the sea ice cover is a thin skin compared to the depth of the Arctic Ocean, this face lift exerts profound change in the Arctic environment. Here, we present scatterometer remote sensing of Arctic sea ice change and its implication on chemical processes from the ice surface to the troposphere extending into the internal continental land. In the context of a half century change, the extent of perennial ice declines at rate of 0.5 million km2 per decade in the 1970s-1990s while there is no discernable trend in the 1950s-1960s. Abruptly, the rate of decrease has tripled to 1.5 million km2 per decade in the 2000s. A record was set in the reduction of Arctic perennial ice extent in winter 2008. By 1 March 2008, perennial ice extent was reduced by one million km2 compared to that at the same time in 2007. On 1 May 2009, perennial ice extent was reduced to 2.1 million km2 , which is a virtual tie to 2.2 million km2 of perennial ice extent on 1 May 2008 given the uncertainty of ±0.2 million km2 . Although the extent of perennial ice extent is similar, its distribution is quite different, with a significant perennial ice pack in the Beaufort Sea in 2008, and in contrast a large expanse of perennial ice along the Transpolar Drift Stream in 2009. The continuing drastic reduction of perennial ice significantly decreases the overall surface albedo, resulting in enhanced solar heat absorption in spring and summer, which further decreases the Arctic ice pack through the ice-albedo feedback mechanism and ice melt from the underside due to oceanic thermodynamic interactions. Satellite maps of sea ice class distribution show the closely conformation with patterns of

  16. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by nitroalkene fatty acids: importance of nitration position and degree of unsaturation.

    PubMed

    Gorczynski, Michael J; Smitherman, Pamela K; Akiyama, Taro E; Wood, Harold B; Berger, Joel P; King, S Bruce; Morrow, Charles S

    2009-08-13

    Nitroalkene fatty acids are potent endogenous ligand activators of PPARgamma-dependent transcription. Previous studies with the naturally occurring regioisomers of nitrolinoleic acid revealed that the isomers are not equivalent with respect to PPARgamma activation. To gain further insight into the structure-activity relationships between nitroalkenes and PPARgamma, we examined additional naturally occurring nitroalkenes derived from oleic acid, 9-nitrooleic acid (E-9-NO2-18:1 [1]) and 10-nitrooleic acid (E-10-NO2-18:1 [2]), and several synthetic nitrated enoic fatty acids of variable carbon chain length, double bonds, and nitration site. At submicromolar concentrations, E-12-NO2 derivatives were considerably more potent than isomers nitrated at carbons 5, 6, 9, 10, and 13, and chain length (16 versus 18) or number of double bonds (1 versus 2) was of little consequence for PPARgamma activation. Interestingly, at higher concentrations (>2 microM) the nitrated enoic fatty acids (E-9-NO2-18:1 [1], E-9-NO2-16:1 [3], E-10-NO2-18:1 [2], and E-12-NO2-18:1 [7]) deviated significantly from the saturable pattern of PPARgamma activation observed for nitrated 1,4-dienoic fatty acids (E-9-NO2-18:2, E-10-NO2-18:2, E-12-NO2-18:2, and E-13-NO2-18:2).

  17. Individuals with Profound Disabilities: Instructional and Assistive Strategies. Third Edition.

    ERIC Educational Resources Information Center

    Sternberg, Les, Ed.

    This collection of 14 essays focuses on the education of individuals with profound disabilities. The essays include: (1) "Individuals with Profound Disabilities: Definitions, Characteristics, and Conceptual Framework" (Les Sternberg); (2) "Creating Environments That Support and Enhance the Lives of All Individuals" (Lucille Zeph); (3) "Biomedical…

  18. Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia.

    PubMed

    Liu, Weiguo; Liu, Kun; Wood, Harold B; McCann, Margaret E; Doebber, Thomas W; Chang, Ching H; Akiyama, Taro E; Einstein, Monica; Berger, Joel P; Meinke, Peter T

    2009-07-23

    A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARgamma modulator with additional moderate intrinsic PPARalpha agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARgamma full agonists. The moderate PPARalpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARgamma efficacy in lowering glucose levels in preclinical diabetic animal models.

  19. Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARgamma-coactivator 1 (PGC-1).

    PubMed

    Feilchenfeldt, Jonas; Bründler, Marie Anne; Soravia, Claudio; Tötsch, Martin; Meier, Christoph A

    2004-01-08

    Peroxisome proliferator-activated receptors (PPARs) alpha,beta/delta and gamma are fatty acid sensitive transcription factors that have been implicated in colorectal cancer. To better understand their role, we studied the expression levels of all PPAR-isoforms and transcriptional partners such as the retinoid X receptor alpha (RXRalpha) and PPARgamma-coactivator-1 (PGC-1) by means of real-time PCR in 17 patients with colon cancer. While a heterogeneous pattern was observed for the expression level of the PPAR-isoforms alpha,beta/delta and gamma, the coactivator PGC-1 was significantly decreased in 15 of 17 tumors. Taken together our data suggest that the transcriptional activity of PPARgamma may not only be decreased by mutation but also by downregulation of the coactivator PGC-1 of PPARgamma.

  20. No association of Pro12Ala polymorphism of PPAR-gamma gene with coronary artery disease in Korean subjects.

    PubMed

    Rhee, Eun Jung; Kwon, Chang Hee; Lee, Won Young; Kim, Se Yeon; Jung, Chan Hee; Kim, Byung Jin; Sung, Ki Chul; Kim, Bum Soo; Oh, Ki Won; Kang, Jin Ho; Park, Sung Woo; Kim, Sun Woo; Lee, Man Ho; Park, Jung Roe

    2007-03-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-gamma was investigated in Korean adults. The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD. There was no significant association between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future.

  1. Energy balance and food intake: the role of PPARgamma gene polymorphisms.

    PubMed

    Cecil, Joanne E; Watt, Peter; Palmer, Colin N; Hetherington, Marion

    2006-06-30

    Mechanisms regulating energy balance involve complex interactions between genetic, environmental and behavioural (learnt and intrinsic) factors. Genotype may drive the partitioning of energy metabolism and predispose to site-specific adiposity, culminating in a state of energy imbalance. One candidate gene with a direct link to adiposity is the peroxisome proliferator-activated receptor gamma (PPARG) gene. PPARG is a cell nuclear receptor expressed almost exclusively in adipose tissue that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity. PPARgamma appears to be a key regulator of energy balance, with polymorphisms on the PPARG gene linked to obesity and effects on body composition. Our research has confirmed an association between the pro12ala allele and reduced incidence of obesity in pre-pubertal children and there are strong associations between genetic variation at the PPARG locus and percentage body fat. Moreover, our evidence suggests that PPARG C-681G and pro12ala polymorphisms display opposing effects in terms of growth phenotype, with pro12Ala associated with deficient energy utilisation, leading to reduced growth and the G-681 variant associated with accelerated growth compared with wildtypes. Common differences in this gene have also been associated with variations in body weight in response to dietary macronutrients. Preliminary evidence suggests that PPARG variants may even be involved in the control of short term energy compensation. Taken together these data suggest that the role of PPARG is varied and complex, influencing fat deposition and growth velocity early in life, with potential impact in the control of energy intake and appetite regulation, and could provide a key target for future research and anti-obesity agents.

  2. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

    PubMed

    Cobb, J E; Blanchard, S G; Boswell, E G; Brown, K K; Charifson, P S; Cooper, J P; Collins, J L; Dezube, M; Henke, B R; Hull-Ryde, E A; Lake, D H; Lenhard, J M; Oliver, W; Oplinger, J; Pentti, M; Parks, D J; Plunket, K D; Tong, W Q

    1998-12-03

    3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

  3. Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.

    PubMed

    Lee, Kyung Sun; Park, Seoung Ju; Kim, So Ri; Min, Kyung Hoon; Jin, Sun Mi; Lee, Hern Ku; Lee, Yong Chul

    2006-10-15

    Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARgamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARgamma agonist, rosiglitazone, or pioglitazone, and PPARgamma on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-beta1, and NF-kappaB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARgamma agonists or adenovirus carrying PPARgamma2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta1, and NF-kappaB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappaB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta1 after TDI inhalation. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the TDI-induced asthma phenotype.

  4. Auditory Reinforcement in Profoundly Retarded Multiply Handicapped Children

    ERIC Educational Resources Information Center

    Remington, R. E.; And Others

    1977-01-01

    Four profoundly retarded multiply handicapped children (with a mean age of 12 years) were placed in a situation where auditory stimulation was made contingent on a visually directed lever-pulling response. (Author/MH)

  5. Auditory Reinforcement in Profoundly Retarded Multiply Handicapped Children

    ERIC Educational Resources Information Center

    Remington, R. E.; And Others

    1977-01-01

    Four profoundly retarded multiply handicapped children (with a mean age of 12 years) were placed in a situation where auditory stimulation was made contingent on a visually directed lever-pulling response. (Author/MH)

  6. PPARalpha, but not PPARgamma, activators decrease macrophage-laden atherosclerotic lesions in a nondiabetic mouse model of mixed dyslipidemia.

    PubMed

    Hennuyer, Nathalie; Tailleux, Anne; Torpier, Gérard; Mezdour, Hafid; Fruchart, Jean-Charles; Staels, Bart; Fiévet, Catherine

    2005-09-01

    Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are nuclear receptors that may modulate atherogenesis, not only by correcting metabolic disorders predisposing to atherosclerosis but also by directly acting at the level of the vascular wall. The accumulation of lipid-laden macrophages in the arterial wall is an early pivotal event participating in the initiation and promotion of atherosclerotic lesion formation. Because PPARalpha and gamma modulate macrophage gene expression and cellular function, it has been suggested that their ligands may modulate atherosclerosis development via direct effects on macrophages. In this report, we investigated the effect of a PPARalpha ligand (fenofibrate) and 2 PPARgamma ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden lesions. Mice were fed a Western diet supplemented or not with fenofibrate (100 mpk), rosiglitazone (10 mpk), or pioglitazone (40 mpk) for 10 weeks. Atherosclerotic lesions together with metabolic parameters were measured after treatment. Fenofibrate treatment significantly improved lipoprotein metabolism toward a less atherogenic phenotype but did not affect insulin sensitivity. Contrarily, rosiglitazone and pioglitazone improved glucose homeostasis, whereas they did not improve lipoprotein metabolism. Fenofibrate treatment significantly decreased the accumulation of lipids and macrophages in the aortic sinus. However, surprisingly, neither rosiglitazone nor pioglitazone had an effect on lesion lipid accumulation or macrophage content. These results indicate that in a dyslipidemic nondiabetic murine model, PPARalpha, but not PPARgamma, activators protect against macrophage foam cell formation.

  7. Flavanone exhibits PPAR{gamma} ligand activity and enhances differentiation of 3T3-L1 adipocytes

    SciTech Connect

    Saito, Takeshi; Abe, Daigo; Sekiya, Keizo

    2009-03-06

    Flavanones are class of polyphenolic compounds, some of which are found in foods and provide health benefits. In this study, we show that flavanone significantly enhances differentiation of 3T3-L1 preadipocytes. During adipogenesis, flavanone enhanced expression of genes and accumulation of proteins that are involved in adipocyte function. Some reports have indicated that flavanone inhibits proliferation of mammalian cells, and down-regulates expression of growth-related proteins. Such proteins include phosphorylated ERK1/2, cyclins, and Cdks that are important for an early event in adipogenesis, mitotic clonal expansion (MCE). We demonstrated that flavanone did not inhibit MCE or expression of MCE-related proteins, except for a modest inhibition of cyclin D1 expression. Using luciferase reporter assays, we found that flavanone acted as a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligand in a dose-dependent manner. Together, our results suggest that flavanone enhances adipogenesis, at least in part, through its PPAR{gamma} ligand activity.

  8. Pathway of PPAR-gamma coactivators in thermogenesis: a pivotal traditional Chinese medicine-associated target for individualized treatment of rheumatoid arthritis

    PubMed Central

    Bai, Ming; Zhang, Bo; Liu, Chunfang; Sun, Yanqun; Li, Shao; Lin, Na

    2016-01-01

    Traditional Chinese medicine (TCM) syndromes have been regarded as the crucial clinical manifestations for individualized diagnosis and treatment of complex diseases, including rheumatoid arthritis (RA) and cancer. Especially, RA patients are classified into cold and hot syndromes with different clinical manifestations, interventions and molecular mechanisms. Better effectiveness of a classic cold syndrome-specific herbal formula Wu-tou decoction (WTD) has been achieved. To explore molecular mechanisms of syndrome-specific formulae is of great clinical significance to improve the effectiveness and pertinence of treatment for the complex diseases with personalized conditions. However, the scientific basis of WTD treatment on RA with the cold syndrome remains unclear. Here, we predicted the putative targets for composite compounds contained in WTD using drugCIPHER-CS and constructed a WTD herbs-putative targets-RA related genes network. Next, a list of major WTD targets was identified based on their topological features, including the degree, node betweenness, closeness and k-coreness in the above pharmacological network. Importantly, pathway enrichment analysis revealed that these major WTD targets were significantly associated with the pathway of peroxisome proliferator-activated receptor (PPAR)-gamma (PPAR-γ) coactivators in thermogenesis. These computational findings were subsequently verified by experiments on a rat model of collagen-induced arthritis (CIA) with cold or hot syndromes, and on human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) cell line. In conclusion, the pathway of PPAR-γ coactivators in thermogenesis might be one of the potential pharmacological targets of WTD to alleviate RA with the TCM cold syndrome. These findings may open new avenues for designing individualized treatment regimens for RA patients. PMID:26895106

  9. M2/M1 Ratio of Tumor Associated Macrophages and PPAR-gamma Expression in Uveal Melanomas with Class 1 and Class 2 Molecular Profiles

    PubMed Central

    Herwig, Martina C.; Bergstrom, Chris; Wells, Jill R.; Höller, Tobias; Grossniklaus, Hans E.

    2012-01-01

    Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point towards a disease-progressing role of proangiogenic M2 macrophages in melanomas with monosomy 3. Although most studies implicate a protective effect of PPAR-gamma activation in tumors, PPAR-gamma has also been shown to promote the polarization of M1 macrophages towards the M2 phenotype. The purpose of this investigation was first, to characterize the phenotype of tumor infiltrating macrophages and second, to study PPAR-gamma expression in uveal melanomas with molecular gene expression profile as prognostic predictors for patients’ outcome. Twenty specimens from patients with uveal melanoma were analyzed for clinical and histologic tumor characteristics. The molecular RNA profile (class 1 or class 2) was commercially determined. Using immunohistochemical techniques, the specimens were dual labeled for CD68 and CD163. CD68+CD163− M1 macrophages and CD68+CD163+ M2 macrophages were analyzed in ten high power fields sparing macrophage-poor areas and a mean value was calculated for each tumor. The tumors were immunostained for von Willebrand factor and the mean vascular density (MVD) was analyzed according to Foss. To assess the proliferative rate of each tumor, Ki67 expression was evaluated in ten high power fields followed by calculation of a mean value. Expression of PPAR-gamma was evaluated using a score from 0 (no staining) to 3 (tumor entirely stained). Statistical analysis and a respective correlation was made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 versus M2), MVD, proliferative rate, and PPAR-gamma expression. Our results showed a correlation between the ratio of M2/M1 macrophages and the molecular profile with a ratio of approximately 1 corresponding to molecular class 1 and a ratio of approximately 2 corresponding to molecular class 2 (p=0.01). The ratio of M2/M1

  10. Effects of the PPARgamma activator pioglitazone on p38 MAP kinase and IkappaBalpha in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis.

    PubMed

    Shibata, Noriyuki; Kawaguchi-Niida, Motoko; Yamamoto, Tomoko; Toi, Sono; Hirano, Asao; Kobayashi, Makio

    2008-08-01

    Emerging evidence suggests the involvement of programmed cell death and inflammation in amyotrophic lateral sclerosis (ALS). To assess molecular pathological effects of the anti-inflammatory peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone in ALS, we verified changes in the population of neurons, astrocytes, and microglia in the ventral horns of spinal cord lumbar segments from the pioglitazone-treated and non-treated groups of mice carrying a transgene for G93A mutant human superoxide dismutase-1 (SOD1) (ALS mice) and non-transgenic littermates (control mice), performed immunohistochemical and immunoblot analyses of PPARgamma, active form of phosphorylated p38 mitogen-activated protein kinase (p-p38) and inhibitor of nuclear factor-kappaB (NF-kappaB)-alpha (IkappaBalpha) in the spinal cords, and compared the results between the different groups. Image analysis revealed that optical density of NeuN-immunoreactive neurons was significantly lower in the non-treated groups of presymptomatic and advanced ALS mice than in the non-treated groups of age-matched control mice and was recovered with pioglitazone treatment, and that optical densities of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia were significantly higher in the non-treated group of advanced ALS mice than in the non-treated group of control mice and were recovered with pioglitazone treatment. Immunohistochemical analysis demonstrated that immunoreactivities for PPARgamma and p-p38 were mainly localized in neurons, and that IkappaBalpha immunoreactivity was mainly localized in astrocytes and microglia. Immunoblot analysis showed that pioglitazone treatment resulted in no significant change in nuclear PPARgamma-immunoreactive density, a significant decrease in cytosolic p-p38-immunoreactive density, and a significant increase in cytosolic IkappaBalpha-immunoreactive density. Our results suggest that pioglitazone protects motor neurons against p38-mediated

  11. The developmental changes and effect on IMF content of H-FABP and PPARgamma mRNA expression in sheep muscle.

    PubMed

    Huang, Zhi-Guo; Xiong, Li; Liu, Zhen-Shan; Qiao, Yong; Liu, Shou-Ren; Ren, Hang-Xing; Xie, Zhuang; Liu, Guo-Qing; Li, Xue-Bin

    2006-06-01

    Male Kazak sheep and Xinjiang fine wool sheep of different ages were selected to investigate the developmental changes and effect on intramuscular fat (IMF) content of heart fatty acid-binding protein (H-FABP) and peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in muscle. Longissimus dorsal muscle was sampled to measure IMF content; and total RNA was extracted to determine H-FABP and PPARgamma mRNA expression levels by real-time PCR. The results showed that: (1) The IMF content increased continuously with growing and showed significant differences (P<0.05) between ages in male Kazak sheep, but no such differences (P>0.05) existed in Xinjiang fine wool sheep. Furthermore, the IMF content in Kazak sheep was very much higher (P<0.01) than that of the other breed from day 30 to 90; (2) H-FABP mRNA expression level was the highest on day 2 and showed significant differences (P<0.05) between ages in male Kazak sheep as well as in Xinjiang fine wool sheep. In the former breed, the expression reached the lowest point at day 30, and then rose continuously. But in the latter breed, it declined continuously from day 2 to 90, and then increased; (3) Significant differences (P<0.05) of PPARgamma mRNA expression between ages occurred in both breeds. In male Kazak sheep, PPARgamma mRNA expression declined from day 2 to 90, while in the other breed it increased continuously from day 2 to 60, but reached the lowest level at day 90, then increased; (4) In male Kazak sheep, the mRNA expression level of H-FABP was highly positively correlated (r=0.737, P<0.01) with IMF content from day 30 to 90, but that of PPARgamma was highly negatively correlated (r=-0.835, P<0.01) with IMF content from day 2 to 90.

  12. Human dignity and the profoundly disabled: a theological perspective.

    PubMed

    Matthews, Pia

    2011-01-01

    One challenge to the concept of human dignity is that it is a rootless notion invoked simply to mask inequalities that inevitably exist between human beings. This privileging of humans is speciesist and its weak point is the profoundly disabled human being. This article argues that far from being a weak point, the profoundly disabled person is a source of strength and witness to the intrinsic dignity that all human beings have by virtue of being human. The disabled represent the reality of human existence that is both strong and fragile. Although human dignity can be understood philosophically its depth is rooted in Christian theological insights. The profoundly disabled occupy a privileged position and share in a theology of mission since they testify to the interdependence of every human being and human dependence on God to a myopic world that only values strength, autonomy and independence.

  13. Treating profound hyponatremia: a strategy for controlled correction.

    PubMed

    Sterns, Richard H; Hix, John Kevin; Silver, Stephen

    2010-10-01

    An alcoholic patient presented with profound hyponatremia (serum sodium concentration, 96 mEq/L) caused by the combined effects of a thiazide diuretic, serotonin reuptake inhibitor, beer potomania, and hypovolemia. A computed tomographic scan of the brain was indistinguishable from one obtained 3 weeks earlier when he was normonatremic. Concurrent administration of 3% saline solution and desmopressin controlled the rate of correction to an average of 6 mEq/L daily and resulted in full neurologic recovery without evidence of osmotic demyelination. This case illustrates the value of controlled correction of profound hyponatremia.

  14. Rosiglitazone inhibits cell proliferation by inducing G1 cell cycle arrest and apoptosis in ADPKD cyst-lining epithelia cells.

    PubMed

    Liu, Yawei; Dai, Bing; Fu, Lili; Jia, Jieshuang; Mei, Changlin

    2010-06-01

    Abnormal proliferation is an important pathological feature of autosomal dominant polycystic kidney disease (ADPKD). Many drugs inhibiting cell proliferation have been proved to be effective in slowing the disease progression in ADPKD. Recent evidence has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have anti-neoplasm effects through inhibiting cell growth and inducing cell apoptosis in various cancer cells. In the present study, we examined the expression of PPARgamma in human ADPKD kidney tissues and cyst-lining epithelial cell line, and found that the expression of PPARgamma was greater in ADPKD kidney tissues and cyst-lining epithelial cell line than in normal kidney tissues and human kidney cortex (HKC) cell line. Rosiglitazone inhibited significantly proliferation of cyst-lining epithelial cells in a concentration- and time-dependent manner. These effects were diminished by GW9662, a specific PPARgamma antagonist. Cell cycle analysis showed a G0/G1 arrest in human ADPKD cyst-lining epithelial cells with rosiglitazone treatment. Analysis of cell cycle regulatory proteins revealed that rosiglitazone decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, cyclin D2 and Cdk4 but increased the levels of p21 and p27 in a dose-dependent manner. Rosiglitazone also induced apoptosis in cyst-lining epithelial cells, which was correlated with increased bax expression and decreased bcl-2 expression. These results suggest PPARgamma agonist might serve as a promising drug for the treatment of ADPKD.

  15. Genome wide analysis of inbred mouse lines identifies a locus containing Ppar-gamma as contributing to enhanced malaria survival.

    PubMed

    Bopp, Selina E R; Ramachandran, Vandana; Henson, Kerstin; Luzader, Angelina; Lindstrom, Merle; Spooner, Muriel; Steffy, Brian M; Suzuki, Oscar; Janse, Chris; Waters, Andrew P; Zhou, Yingyao; Wiltshire, Tim; Winzeler, Elizabeth A

    2010-05-28

    The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-gamma in malaria infection.

  16. Perioperative Concerns for Profound Metabolic Alkalosis During Kidney Transplantation: A Case Report

    PubMed Central

    Choi, Jung Ju; Kim, Yong Beom; Kim, Hong Soon; Lee, Kyung Cheon; Jo, Youn Yi

    2016-01-01

    Introduction Profound metabolic alkalosis is an uncommon consideration for the anesthetic management of kidney transplantation. Serum total carbon dioxide content and complex electrolyte abnormalities might be important diagnostic clues for the presence of metabolic alkalosis in the absence of arterial blood gas analysis. Case Presentation A 34-year-old female visited Gachon University Gil Medical Center, Incheon, South Korea during year 2015. She experienced aggravated renal function due to chronic hypokalemia and severe hypochloremic metabolic alkalosis, induced by laxative abuse, and underwent ABO incompatible kidney transplantation. Serum total carbon dioxide content remained high (about 60 mEq/L) over eight months of monthly follow-up prior to kidney transplantation. Conclusions The authors described their anesthetic experience of profound metabolic alkalosis with complex electrolyte abnormalities and provided a review of relevant literature. PMID:28210501

  17. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma.

    PubMed

    Zhang, Ming; Deng, Changsheng; Zheng, Jiaju; Xia, Jian; Sheng, Dan

    2006-08-01

    Curcumin is a widely used spice with anti-inflammatory and anti-cancer properties. It has been reported that curcumin held therapeutic effects on experimental colitis by inhibition of nuclear factor kappa B (NF-kappaB). The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with anti-tumor and anti-inflammatory effects and its activation may inhibit the nuclear translocation of NF-kappaB. Several studies have shown that PPARgamma ligands had an important therapeutic effect in colitis. However there is no report about the alteration of PPARgamma in trinitrobenzene sulphonic acid (TNBS)-induced colitis treated with curcumin. In this study, we administered curcumin (30 mg/kg/day) by intraperitoneal injection immediately after colitis was induced and the injection lasted for two weeks. have evaluated the effects of curcumin on the colitis induced by trinitrobenzene sulphonic acid (TNBS). Curcumin (30 mg/kg d) was administered by intraperitoneal just after colitis was induced and lasted for two weeks. Therapeutic effects of dexamethasone (Dex, 2 mg/kg d) alone and the combined effects of curcumin+Dex were also examined. We found that curcumin improved long-term survival rate of disease-bearing rats, promoted rat body weight recovery, and decreased macroscopic scores of the colitis. The expression levels of PPARgamma, 15-deoxy-D12,14-prostaglandin J(2) (15d-PGJ(2)) and prostaglandin E(2) (PGE(2)) were all increased, but the expression level of cyclooxygenase-2 (COX-2) was decreased in rats after administration of curcumin. Treatment with Dex improved PPARgamma expression and inhibited the expression of COX-2, 15d-PGJ(2) and PGE(2). Combined effects of curcumin+Dex were similar to that of Dex. In summary, curcumin showed therapeutic effects on TNBS-induced colitis and the mechanisms by which curcumin exerts its effects may involve activation of PPARgamma and its ligands.

  18. Guide to Resources for Severely/Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Northeast Regional Resource Center, Hightstown, NJ.

    Intended for educators, parents, and other interested individuals, the guide provides information on finding resources for severely/profoundly handicapped children. Listed are the names and addresses of eight national and 52 state organizations in Connecticut, Maine, New Hampshire, New Jersey, Rhode Island, Massachusetts, and Vermont which serve…

  19. Reduction of Disruptive Behaviors of a Hyperactive Profoundly Retarded Person.

    ERIC Educational Resources Information Center

    Lockhart, Diana Brookover; Jablonski, Eugene

    Reinforcing contact with toys by providing chocolate milk odors, and tactile reinforcement helped to reduce the self injurious behaviors, feces smearing, and destructive behavior of a profoundly retarded deaf/blind hyperactive female. The underlying assumption of the approach was that increasing toy contact would result in improved alternative…

  20. An Informal Paper: Teaching the Profoundly Handicapped Child.

    ERIC Educational Resources Information Center

    Silverrain, Ann

    The paper outlines the operative principles for understanding learning and discusses how these principles can help in planning a functional program for a severely or profoundly brain-damaged child. Discussed are: (1) the role of memory in learning; (2) simple associative learning (Pavlovian Conditioning and Operant Conditioning); (3) Piaget's…

  1. An Annotated Bibliography on the Severely and Profoundly Mentally Retarded.

    ERIC Educational Resources Information Center

    Cass, Michael, Comp.; Schilit, Jeffrey, Comp.

    Presented is an annotated bibliography with approximately 250 entries relating to the severely and profoundly retarded. Citations are listed alphabetically by author under the following categories: assessments, measurements, evaluations; associations; attending behavior; behavior modification; books; classical conditioning; cognitive development;…

  2. Physical Education for the Severely and Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Jansma, Paul

    1982-01-01

    The article offers ideas for providing appropriate physical, motor, fitness, and play training experiences for children with severe to profound developmental disabilities. Following a section with testing recommendations are general and specific teaching guidelines covering such areas as programing, adaptive equipment, multisensory stimulation,…

  3. Comprehension of English Syntax by Profoundly Deaf Children.

    ERIC Educational Resources Information Center

    Bishop, D. V. M.

    1983-01-01

    A total of 79 profoundly deaf 8- to 12-year-old children were tested for comprehension of spoken, written, and signed (Paget-Gorman Sign System, PGSS) English grammatical contrasts. It is concluded that the PGSS provides a communication channel that does not hinder language acquisition, but does not overcome the grammatical problems of deaf…

  4. Do Profoundly Prelingually Deaf Patients with Psychosis Really Hear Voices?

    ERIC Educational Resources Information Center

    Paijmans, R.; Cromwell, J.; Austen, S.

    2006-01-01

    The psychiatric literature has described profoundly prelingually deaf people with psychosis who report hearing voices. The present study proposes that such reports in fact reflect the beliefs of professionals in mental health and deafness and not the hallucinatory experience of psychotic deaf people. The study demonstrates that it is functionally…

  5. Prognostic factors of profound idiopathic sudden sensorineural hearing loss.

    PubMed

    Wen, Yu-Hsuan; Chen, Peir-Rong; Wu, Hung-Pin

    2014-06-01

    Profound idiopathic sudden sensorineural hearing loss is thought to have a poor prognosis, but few studies have focused on this condition. We aimed to assess the impact of patient factors, audiologic parameters, and salvage intratympanic steroid injection therapy on the prognosis of profound idiopathic sudden sensorineural hearing loss. The demographic, clinical, and audiologic data, degree of hearing recovery, and efficacy of intratympanic steroid injection therapy in 576 patients with profound idiopathic sudden sensorineural hearing loss (mean age 56.2 ± 14.9 years) who had been admitted at four tertiary referral centers between 2000 and 2011 were retrospectively reviewed. The mean hearing level at the initial presentation was 108.1 ± 9.5 dB. Many patients experienced vertigo (52.1%) and tinnitus (77.4%). At the 2-month follow-up, 172 (29.8%) patients showed some degree of hearing recovery, but only 21 (3.6%) patients recovered normal hearing. Further, the 116 patients who had received salvage intratympanic steroid injections showed a better audiologic outcome (improvement, 26.1 ± 24.3 vs. 15.7 ± 22.1 dB; P = 0.000) than those who had not (n = 429). In conclusion, a higher degree of hearing loss at the initial presentation indicates a poorer prognosis. Salvage intratympanic steroid injection therapy may improve the hearing of patients with profound idiopathic sudden sensorineural hearing loss after the failure of systemic steroid therapy.

  6. Teaching Profoundly Retarded Adults to Ascend Stairs Safely.

    ERIC Educational Resources Information Center

    Cipani, Ennio; And Others

    1982-01-01

    The study was designed to modify the stair climbing behavior of two profoundly retarded residents through backward shaping with graduated guidance, edible rewards, a correction procedure, and a 30 second timeout. Both residents showed an increase in the number of correct steps used while ascending the stairs.

  7. Aerobic Fitness for the Severely and Profoundly Mentally Retarded.

    ERIC Educational Resources Information Center

    Bauer, Dan

    1981-01-01

    The booklet discusses the aerobic fitness capacities of severely/profoundly retarded students and discusses approaches for improving their fitness. An initial section describes a method for determining the student's present fitness level on the basis of computations of height, weight, blood pressure, resting pulse, and Barach Index and Crampton…

  8. Sixteen Trends...Their Profound Impact on Our Future

    ERIC Educational Resources Information Center

    Marx, Gary

    2011-01-01

    Seismic Shifts. Future Forces. Call them whatever you'd like. The Sixteen Trends revealed in this benchmark book will have a profound impact on our future. Noted futurist, educator, communicator, executive and leadership counsel, author, and international speaker Gary Marx makes the case for those trends and speculates on their implications for…

  9. Mindful Caregiving Increases Happiness among Individuals with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Singh, Nirbhay N.; Lancioni, Giulio E.; Winton, Alan S. W.; Wahler, Robert G.; Singh, Judy; Sage, Monica

    2004-01-01

    Happiness is a critical indicator of quality of life in humans. A few studies have measured levels of happiness displayed under different conditions by individuals with profound multiple disabilities. We were interested in determining whether increasing the mindfulness of caregivers would result in increased levels of happiness in adults with…

  10. Sixteen Trends...Their Profound Impact on Our Future

    ERIC Educational Resources Information Center

    Marx, Gary

    2011-01-01

    Seismic Shifts. Future Forces. Call them whatever you'd like. The Sixteen Trends revealed in this benchmark book will have a profound impact on our future. Noted futurist, educator, communicator, executive and leadership counsel, author, and international speaker Gary Marx makes the case for those trends and speculates on their implications for…

  11. Tips on Teaching Severely and Profoundly Handicapped Children.

    ERIC Educational Resources Information Center

    Gay, Sylvia

    1981-01-01

    A teacher of severely and profoundly handicapped students shares tips for encouraging communication skills and appropriate behavior. Among tips are to encourage and set up home exercise programs, ask other students if a student's reply is correct, and use a time to signal when an activity is to begin or end. (CL)

  12. Acceleration of Object Permanence with Severely and Profoundly Retarded Children.

    ERIC Educational Resources Information Center

    Kahn, James V.

    Examined was the effectiveness of training four severely and profoundly retarded children (3-6 years old) to improve their level of functioning on a measure of object permanence and to demonstrate generalization to other areas of sensorimotor intelligence. Ss were given a pretest and posttest on the I. Uzgiris and J. Hunt instrument which consists…

  13. Music Training for Severely and Profoundly Retarded Individuals.

    ERIC Educational Resources Information Center

    Kesler, Buford; Richmond, Bert O.

    Investigated were the effects of sex, ability and training method on the musical instrument playing ability of 16 institutionalized severely and profoundly retarded persons ages 7 to 20 years. Ss were randomly assigned to one of four treatment groups, and the time required to reach criterion playing a familiar tune was recorded. Data indicated…

  14. Foveal Processing under Concurrent Peripheral Load in Profoundly Deaf Adults

    ERIC Educational Resources Information Center

    Dye, Matthew W. G.

    2016-01-01

    Development of the visual system typically proceeds in concert with the development of audition. One result is that the visual system of profoundly deaf individuals differs from that of those with typical auditory systems. While past research has suggested deaf people have enhanced attention in the visual periphery, it is still unclear whether or…

  15. Foveal Processing under Concurrent Peripheral Load in Profoundly Deaf Adults

    ERIC Educational Resources Information Center

    Dye, Matthew W. G.

    2016-01-01

    Development of the visual system typically proceeds in concert with the development of audition. One result is that the visual system of profoundly deaf individuals differs from that of those with typical auditory systems. While past research has suggested deaf people have enhanced attention in the visual periphery, it is still unclear whether or…

  16. Developing Skills in Severely and Profoundly Handicapped Children.

    ERIC Educational Resources Information Center

    Thomas, M. Angele, Ed.

    Included in the publication are 10 articles on developing basic skills in severely and profoundly handicapped children. The first paper focuses on the development of object permanence, a basic cognitive skill, while the second and third review procedures for developing self care skills (toileting and eating). A fourth paper discusses an…

  17. Developing a Holistic Approach for Educating Persons with Profound Disabilities.

    ERIC Educational Resources Information Center

    Williams, Karen

    This paper reports on three studies within a 6-year longitudinal study which explored the use of Piagetian sensori-motor substages as a curriculum base for individuals with profound mental retardation (MR). In the first study, a simple observational inventory, the Cognitive Marker Natural Observational Tool (CM-NOT), was developed and evaluated…

  18. Preliminary Study of Imipramine in Profoundly Retarded Residents.

    ERIC Educational Resources Information Center

    Aman, Michael G.; And Others

    1986-01-01

    The effects of imipramine were assessed in 10 profoundly retarded subjects (aged 8-25 years) who exhibited either depressionlike symptoms or acting out behaviors. Results of observation, interval sampling, and the Aberrant Behavior Checklist indicated behavioral deterioration on irritability, lethargy/social withdrawal, and hyperactivity…

  19. Do Profoundly Prelingually Deaf Patients with Psychosis Really Hear Voices?

    ERIC Educational Resources Information Center

    Paijmans, R.; Cromwell, J.; Austen, S.

    2006-01-01

    The psychiatric literature has described profoundly prelingually deaf people with psychosis who report hearing voices. The present study proposes that such reports in fact reflect the beliefs of professionals in mental health and deafness and not the hallucinatory experience of psychotic deaf people. The study demonstrates that it is functionally…

  20. Preparation of Personnel to Serve the Severely and Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Maurer, Steven, Comp.

    The inservice training package for teachers of severely and profoundly handicapped children consists of six field tested modules. Each module consists of the following components: objectives (general and specific), instructional methodology, instructor materials (lecture notes and transparencies), participant materials (worksheets and handouts),…

  1. Teaching Vowels to Profoundly Hearing-Impaired Speakers Using Glossometry.

    ERIC Educational Resources Information Center

    Fletcher, Samuel G.; And Others

    1991-01-01

    Glossometry, a method of providing visual feedback of tongue positions, was used to teach four vowel sounds to six profoundly hearing-impaired children. After 15 to 20 50-minute training sessions, all subjects showed greater diversification of tongue postures for the vowels. Listener identifications were also generally better after therapy.…

  2. Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue of massively obese subjects.

    PubMed

    Kolehmainen, M; Uusitupa, M I J; Alhava, E; Laakso, M; Vidal, H

    2003-04-01

    The aim was to study the effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue. Adipose tissue samples were collected from 30 massively obese subjects (10 men and 20 women) from omental, sc abdominal, and femoral depots. The mRNA expression of PPARgamma1, PPARgamma2, lipoprotein lipase, p85alpha phosphatidylinositol 3-kinase, and uncoupling protein 2 were quantified by reverse transcription-competitive PCR. The genotypes of Pro12Ala polymorphism were determined by single-strand conformation polymorphism analysis. The frequency of the Ala12 allele was 13.3% (8 Pro12Ala and 22 Pro12Pro). There were no differences in body weight, fat mass, and fasting serum leptin between the genotypes. The mRNA expression of p85alpha phosphatidylinositol 3-kinase was significantly lower in the omental fat of the Pro12Ala carriers than the Pro12Pro carriers (P < 0.01). It also appeared that PPARgamma2 expression was higher in men with Ala12 allele (P < 0.01). Interestingly, particularly in women, the expression of both PPARgamma splice variants was lower in omental than sc fat independently of the genotype (P < 0.05-0.01). The common Pro12Ala polymorphism of the PPARgamma2 gene has minor influence on mRNA expression of PPARgamma target genes in adipose tissue of obese subjects. Expression of both PPARgamma splice variants is dependent on fat depot: omental fat shows lower mRNA levels, compared with sc fat depots.

  3. Proteasome inhibitors induce peroxisome proliferator-activated receptor transactivation through RXR accumulation and a protein kinase C-dependent pathway

    SciTech Connect

    Tsao, W.-C.; Wu, H.-M.; Chi, K.-H.; Chang, Y.-H.; Lin, W.-W. . E-mail: wwl@ha.mc.ntu.edu.tw

    2005-03-10

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a member of nuclear hormone receptors, forms a heterodimeric DNA binding complex with retinoid X receptor (RXR) and serves as a transcriptional regulator of gene expression. In this study, using luciferase assay of a reporter gene containing PPAR response element (PPRE), we found PPRE transactivity was additively induced by PPAR{gamma} activator (15dPGJ{sub 2}) and RXR activator (9-cis retinoic acid, 9-cis RA). Proteasome inhibitors MG132 and MG262 also stimulate PPRE transactivity in a concentration-dependent manner, and this effect is synergistic to 15dPGJ{sub 2} and 9-cis RA. PKC activation by 12-myristate 13-acetate (PMA) and ingenol 3,20-dibenzoate (IDB) also led to an increased PPRE activation, and this action was additive to PPAR{gamma} activators and 9-cis RA, but not to proteasome inhibitors. Results indicate that the PPAR{gamma} enhancing effect of proteasome inhibitors was attributed to redox-sensitive PKC activation. Western blot analysis showed that the protein level of RXR{alpha}, but not PPAR{gamma}, RXR{beta}, or PKC isoforms, was accumulated in the presence of proteasome inhibitors. Taken together, we conclude that proteasome inhibitors can upregulate PPRE activity through RXR{alpha} accumulation and a PKC-dependent pathway. The former is due to inhibition of RXR{alpha} degradation through ubiquitin-dependent proteasome system, while the latter is mediated by reactive oxygen species (ROS) production.

  4. Inhibition of cyclooxygenase-2 and activation of peroxisome proliferator-activated receptor-gamma synergistically induces apoptosis and inhibits growth of human breast cancer cells.

    PubMed

    Michael, Michael S; Badr, Mostafa Z; Badawi, Alaa F

    2003-06-01

    Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-gamma (PPARgamma) inactivation are linked to increased risk of human breast cancer. This study examines the effect of simultaneous targeting of COX-2 and PPARgamma on the proliferation of human breast cancer cells and on the expression of Bcl-2, BAX, and caspases-3 and -9, modulators of apoptotic cell death. Treatment of MDA-MB-231 breast cancer cells with NS-398 (a COX-2 inhibitor) or ciglitazone (CGZ, a PPARgamma-ligand) significantly inhibited cell proliferation and markedly increased apoptotic rates. These effects were accompanied by upregulation of BAX and caspases-3 and -9 mRNA expression and downregulation of Bcl-2. Compared to the influence of separate treatments, simultaneous treatment with NS-398 and CGZ synergistically inhibited cell proliferation and induced apoptotic cell death. In conclusion, combinational targeting of COX-2 and PPARgamma can inhibit the growth of human breast cancer cells and induce apoptosis to an extent more suprior to that produced by targeting each molecule alone. COX-2 and PPARgamma can be promising molecular targets for combinational chemoprevention or treatment of breast cancer.

  5. Profound childhood deafness in Nigeria: a three year survey.

    PubMed

    Obiako, M N

    1987-04-01

    A 3 year survey at the University of Nigeria Teaching Hospital was conducted to determine causes of childhood deafness in children seen for that condition. Of the many factors causing this handicap, measles, seizures, and meningitis were identified most frequently. Due to poor medical facilities and widespread malnutrition, communicable diseases in children produce high rates of morbidity and mortality. As a result, a high percentage of infants acquire disabilities, including profound deafness. Improvement of the health care delivery system, breastfeeding, and compulsory immunization of all babies against infectious diseases, as well as making specialist centers accessible to all are suggested as the most efficacious ways to arrest the high incidence of profound deafness in childhood in Nigeria and other developing countries.

  6. Seventeen novel mutations that cause profound biotinidase deficiency.

    PubMed

    Wolf, B; Jensen, K; Hüner, G; Demirkol, M; Baykal, T; Divry, P; Rolland, M-O; Perez-Cerdá, C; Ugarte, M; Straussberg, R; Basel-Vanagaite, L; Baumgartner, E R; Suormala, T; Scholl, S; Das, A M; Schweitzer, S; Pronicka, E; Sykut-Cegielska, J

    2002-01-01

    We report 17 novel mutations that cause profound biotinidase deficiency. Six of the mutations are due to deletions, whereas the remaining 11 mutations are missense mutations located throughout the gene and encode amino acids that are conserved in mammals. Our results increase the total number of different mutations that cause biotinidase deficiency to 79. These additional mutations will undoubtedly be helpful in identifying structure/function relationships once the three-dimensional structure of biotinidase is determined.

  7. Observations on Working Psychoanalytically with a Profoundly Amnesic Patient

    PubMed Central

    Moore, Paul A.; Salas, Christian E.; Dockree, Suvi; Turnbull, Oliver H.

    2017-01-01

    Individuals with profound amnesia are markedly impaired in explicitly recalling new episodic events, but appear to preserve the capacity to use information from other sources. Amongst these preserved capacities is the ability to form new memories of an emotional nature – a skill at the heart of developing and sustaining interpersonal relationships. The psychoanalytic study of individuals with profound amnesia might contribute to the understanding the importance of each memory system, including effects on key analytic processes such as transference and countertransference. However, psychoanalytic work in the presence of profound amnesia might also require important technical modifications. In the first report of its kind, we describe observations from a long term psychoanalytic process (72 sessions) with an individual (JL) who has profound amnesia after an anoxic episode. The nature of therapy was shaped by JL’s impairment in connecting elements that belong to distant (and even relatively close) moments in the therapeutic process. However, we were also able to document areas of preservation, in what appears to be a functioning therapeutic alliance. As regards transference, the relationship between JL and his analyst can be viewed as the evolution of a narcissistic transference, and case material is provided that maps this into three phases: (i) rejecting; (ii) starting to take in; and (iii) full use of the analytic space – where each phase exhibits differing degrees of permeability between JL and the analyst. This investigation appears to have important theoretical implications for psychoanalytic practice, and for psychotherapy in general – and not only with regard to brain injured populations. We especially note that it raises questions concerning the mechanism of therapeutic action in psychoanalysis and psychotherapy, and the apparent unimportance of episodic memory for many elements of therapeutic change. PMID:28890703

  8. Observations on Working Psychoanalytically with a Profoundly Amnesic Patient.

    PubMed

    Moore, Paul A; Salas, Christian E; Dockree, Suvi; Turnbull, Oliver H

    2017-01-01

    Individuals with profound amnesia are markedly impaired in explicitly recalling new episodic events, but appear to preserve the capacity to use information from other sources. Amongst these preserved capacities is the ability to form new memories of an emotional nature - a skill at the heart of developing and sustaining interpersonal relationships. The psychoanalytic study of individuals with profound amnesia might contribute to the understanding the importance of each memory system, including effects on key analytic processes such as transference and countertransference. However, psychoanalytic work in the presence of profound amnesia might also require important technical modifications. In the first report of its kind, we describe observations from a long term psychoanalytic process (72 sessions) with an individual (JL) who has profound amnesia after an anoxic episode. The nature of therapy was shaped by JL's impairment in connecting elements that belong to distant (and even relatively close) moments in the therapeutic process. However, we were also able to document areas of preservation, in what appears to be a functioning therapeutic alliance. As regards transference, the relationship between JL and his analyst can be viewed as the evolution of a narcissistic transference, and case material is provided that maps this into three phases: (i) rejecting; (ii) starting to take in; and (iii) full use of the analytic space - where each phase exhibits differing degrees of permeability between JL and the analyst. This investigation appears to have important theoretical implications for psychoanalytic practice, and for psychotherapy in general - and not only with regard to brain injured populations. We especially note that it raises questions concerning the mechanism of therapeutic action in psychoanalysis and psychotherapy, and the apparent unimportance of episodic memory for many elements of therapeutic change.

  9. Profound deafness and the acquisition of spoken language in children.

    PubMed

    Vlastarakos, Petros V

    2012-12-08

    Profound congenital sensorineural hearing loss (SNHL) is not so infrequent, affecting 1 to 2 of every 1000 newborns in western countries. Nevertheless, universal hearing screening programs have not been widely applied, although such programs are already established for metabolic diseases. The acquisition of spoken language is a time-dependent process, and some form linguistic input should be present before the first 6 mo of life for a child to become linguistically competent. Therefore, profoundly deaf children should be detected early, and referred timely for the process of auditory rehabilitation to be initiated. Hearing assessment methods should reflect the behavioural audiogram in an accurate manner. Additional disabilities also need to be taken into account. Profound congenital SNHL is managed by a multidisciplinary team. Affected infants should be bilaterally fitted with hearing aids, no later than 3 mo after birth. They should be monitored until the first year of age. If they are not progressing linguistically, cochlear implantation can be considered after thorough preoperative assessment. Prelingually deaf children develop significant speech perception and production abilities, and speech intelligibility over time, following cochlear implantation. Age at intervention and oral communication, are the most important determinants of outcomes. Realistic parental expectations are also essential. Cochlear implant programs deserve the strong support of community members, professional bodies, and political authorities in order to be successful, and maximize the future earnings of pediatric cochlear implantation for human societies.

  10. Mindful caregiving increases happiness among individuals with profound multiple disabilities.

    PubMed

    Singh, Nirbhay N; Lancioni, Giulio E; Winton, Alan S W; Wahler, Robert G; Singh, Judy; Sage, Monica

    2004-01-01

    Happiness is a critical indicator of quality of life in humans. A few studies have measured levels of happiness displayed under different conditions by individuals with profound multiple disabilities. We were interested in determining whether increasing the mindfulness of caregivers would result in increased levels of happiness in adults with these conditions. Using alternating treatments embedded within a multiple baseline across caregivers design, we measured baseline levels of happiness displayed by three adults with profound multiple disabilities when they engaged in leisure activities, each by a different pair of caregivers. Then, we taught mindfulness methods to one of each pair and measured the levels of happiness displayed by the individuals during the 8-weeks training for the caregivers. Finally, we measured the levels of happiness displayed by the three individuals for 16 weeks following the termination of mindfulness training. We found that, regardless of whether the level of happiness was initially observed to be high or low in the presence of a caregiver, it increased markedly when an individual interacted with a caregiver who received training in mindfulness when compared to the control caregiver, who did not receive such training. Our study provides evidence that increasing the mindfulness of a caregiver can produce a substantial increase in the levels of happiness displayed by individuals with profound multiple disabilities.

  11. Foveal Processing Under Concurrent Peripheral Load in Profoundly Deaf Adults

    PubMed Central

    2016-01-01

    Development of the visual system typically proceeds in concert with the development of audition. One result is that the visual system of profoundly deaf individuals differs from that of those with typical auditory systems. While past research has suggested deaf people have enhanced attention in the visual periphery, it is still unclear whether or not this enhancement entails deficits in central vision. Profoundly deaf and typically hearing adults were administered a variant of the useful field of view task that independently assessed performance on concurrent central and peripheral tasks. Identification of a foveated target was impaired by a concurrent selective peripheral attention task, more so in profoundly deaf adults than in the typically hearing. Previous findings of enhanced performance on the peripheral task were not replicated. These data are discussed in terms of flexible allocation of spatial attention targeted towards perceived task demands, and support a modified “division of labor” hypothesis whereby attentional resources co-opted to process peripheral space result in reduced resources in the central visual field. PMID:26657078

  12. Influence of the type of transducer in profound hearing loss.

    PubMed

    Marangoni, Andréa Tortosa; Gil, Daniela

    2009-01-01

    individuals with profound hearing loss may present vibrotactile responses when tested with supra-aural earphones due to the large skull area exposed to vibration in these transducers. to verify the influence of the type of transducer when assessing air conducted pure tone thresholds in individuals with profound sensorineural hearing loss. 50 individuals, ranging in age from 16 to 55 years, were submitted to a clinical history questionnaire, meatoscopy, and pure tone and speech audiometry, using both TDH-39 supra-aural earphones and ER-3A insert earphones. in both pure tone and speech testing, thresholds were higher when obtained using insert earphones, with statistical significant differences for 250Hz and 1000Hz. Considering right and left ear testing with the different transducers, this difference was greater for the right ear, with statistical significant differences only for 250 Hz. Regarding gender, it was observed that the difference between the transducers was greater in males, with statistical significant differences for 250 Hz. However, in the SDT (Speech Detection Threshold), the greatest difference was found in females. people with bilateral sensorineural profound hearing loss presented higher (worse) thresholds with insert earphones (ER-3A) than with supra aural earphones (TDH-39) for low frequencies (250Hz and 1000Hz), confirming the existence of vibrotactile responses with supra aural earphones.

  13. Foveal Processing Under Concurrent Peripheral Load in Profoundly Deaf Adults.

    PubMed

    Dye, Matthew W G

    2016-04-01

    Development of the visual system typically proceeds in concert with the development of audition. One result is that the visual system of profoundly deaf individuals differs from that of those with typical auditory systems. While past research has suggested deaf people have enhanced attention in the visual periphery, it is still unclear whether or not this enhancement entails deficits in central vision. Profoundly deaf and typically hearing adults were administered a variant of the useful field of view task that independently assessed performance on concurrent central and peripheral tasks. Identification of a foveated target was impaired by a concurrent selective peripheral attention task, more so in profoundly deaf adults than in the typically hearing. Previous findings of enhanced performance on the peripheral task were not replicated. These data are discussed in terms of flexible allocation of spatial attention targeted towards perceived task demands, and support a modified "division of labor" hypothesis whereby attentional resources co-opted to process peripheral space result in reduced resources in the central visual field.

  14. Breast-feeding modifies the association of PPARgamma2 polymorphism Pro12Ala with growth in early life: the Generation R Study.

    PubMed

    Mook-Kanamori, Dennis O; Steegers, Eric A P; Uitterlinden, Andre G; Moll, Henriëtte A; van Duijn, Cornelia M; Hofman, Albert; Jaddoe, Vincent W V

    2009-04-01

    We examined whether the PPARgamma2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARgamma2 was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction <0.0001). In infants who were breast-fed for > or =4 months, PPARgamma2 Pro12Ala was not associated with growth rate. When breast-feeding duration was <2 months or 2-4 months, growth rate was higher in Ala12Ala than Pro12Pro carriers (differences 9.80 g/week [3.97-15.63] and 6.32 g/week [-1.04 to 13.68], respectively). The PPARgamma2 Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life.

  15. Manipulation of reciprocal salt bridges at the heterodimerization interface alters the dimerization properties of mouse RXR{alpha} and PPAR{gamma}1

    SciTech Connect

    Chan, Lap Shu; Wells, Richard A. . E-mail: rwells@sri.utoronto.ca

    2007-07-13

    Heterodimerization with RXR is essential for the high-affinity specific binding of multiple nuclear receptors to their cognate DNA sequences. NR dimerization is a two-step process, initiated in solution by interaction between amino acid residues with helices 9 and 10 of the ligand binding domains of RXR and its NR partners. Studies of the orphan nuclear receptor HNF4{alpha}, which forms homodimers exclusively, have indicated that two charged residues in this region, HNF4{alpha}{sub K300} and HNF4{alpha}{sub E327}, are key mediators of dimerization. We have analyzed the contribution of the homologous residues in RXR{alpha} (RXR{alpha}{sub E395}, RXR{alpha}{sub K422}) and PPAR{gamma} (PPAR{gamma}{sub E405}, PPAR{gamma}{sub K432}) to the formation of the RXR{alpha}-PPAR{gamma} heterodimer. Charge reversal mutants of RXR{alpha} (RXR{alpha}{sub E395K}, RXR{alpha}{sub K422E}) and PPAR{gamma} (PPAR{gamma}{sub E405K}, PPAR{gamma}{sub K432E}) show impaired ability to form heterodimers with wild-type PPAR{gamma} and RXR{alpha}, respectively. However, pairs of mutants with balanced charge changes, i.e., RXR{alpha}{sub E395K} with PPAR{gamma}{sub K432E} and RXR{alpha}{sub K422E} with PPAR{gamma}{sub E405K}, are able to form dimers. Ligand response is preserved in the PPAR{gamma} mutants, indicating the mutation does not result in major structural derangement of the protein. These results establish the importance of salt bridges between these residues in the heterodimerization of nuclear receptors, and offer a technical approach to generating functional NR mutants with directed heterodimerization specificity. Such mutants will be valuable tools in the genetic analysis of NR function.

  16. Intubation of Profoundly Agitated Patients Treated with Prehospital Ketamine.

    PubMed

    Olives, Travis D; Nystrom, Paul C; Cole, Jon B; Dodd, Kenneth W; Ho, Jeffrey D

    2016-12-01

    Profound agitation in the prehospital setting confers substantial risk to patients and providers. Optimal chemical sedation in this setting remains unclear. The goal of this study was to describe intubation rates among profoundly agitated patients treated with prehospital ketamine and to characterize clinically significant outcomes of a prehospital ketamine protocol. This was a retrospective cohort study of all patients who received prehospital ketamine, per a predefined protocol, for control of profound agitation and who subsequently were transported to an urban Level 1 trauma center from May 1, 2010 through August 31, 2013. Identified records were reviewed for basic ambulance run information, subject characteristics, ketamine dosing, and rate of intubation. Emergency Medical Services (EMS) ambulance run data were matched to hospital-based electronic medical records. Clinically significant outcomes are characterized, including unadjusted and adjusted rates of intubation. Overall, ketamine was administered 227 times in the prehospital setting with 135 cases meeting study criteria of use of ketamine for treatment of agitation. Endotracheal intubation was undertaken for 63% (85/135) of patients, including attempted prehospital intubation in four cases. Male gender and late night arrival were associated with intubation in univariate analyses (χ2=12.02; P=.001 and χ2=5.34; P=.021, respectively). Neither ketamine dose, co-administration of additional sedating medications, nor evidence of ethanol (ETOH) or sympathomimetic ingestion was associated with intubation. The association between intubation and both male gender and late night emergency department (ED) arrival persisted in multivariate analysis. Neither higher dose (>5mg/kg) ketamine nor co-administration of midazolam or haloperidol was associated with intubation in logistic regression modeling of the 120 subjects with weights recorded. Two deaths were observed. Post-hoc analysis of intubation rates suggested a

  17. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

    SciTech Connect

    Nitz, Inke . E-mail: initz@molnut.uni-kiel.de; Ewert, Agnes; Klapper, Maja; Doering, Frank

    2007-02-09

    Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha} and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.

  18. Unlike PPAR{gamma}, PPAR{alpha} or PPAR{beta}/{delta} activation does not promote human monocyte differentiation toward alternative macrophages

    SciTech Connect

    Bouhlel, Mohamed Amine; Brozek, John; Derudas, Bruno; Zawadzki, Christophe; Jude, Brigitte; Staels, Bart; Chinetti-Gbaguidi, Giulia

    2009-08-28

    Macrophages adapt their response to micro-environmental signals. While Th1 cytokines promote pro-inflammatory M1 macrophages, Th2 cytokines promote an 'alternative' anti-inflammatory M2 macrophage phenotype. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in macrophages where they control the inflammatory response. It has been shown that PPAR{gamma} promotes the differentiation of monocytes into anti-inflammatory M2 macrophages in humans and mice, while a role for PPAR{beta}/{delta} in this process has been reported only in mice and no data are available for PPAR{alpha}. Here, we show that in contrast to PPAR{gamma}, expression of PPAR{alpha} and PPAR{beta}/{delta} overall does not correlate with the expression of M2 markers in human atherosclerotic lesions, whereas a positive correlation with genes of lipid metabolism exists. Moreover, unlike PPAR{gamma}, PPAR{alpha} or PPAR{beta}/{delta} activation does not influence human monocyte differentiation into M2 macrophages in vitro. Thus, PPAR{alpha} and PPAR{beta}/{delta} do not appear to modulate the alternative differentiation of human macrophages.

  19. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats.

    PubMed

    Wakino, Shu; Hayashi, Koichi; Tatematsu, Satoru; Hasegawa, Kazuhiro; Takamatsu, Ichiro; Kanda, Takeshi; Homma, Koichiro; Yoshioka, Kyoko; Sugano, Naoki; Saruta, Takao

    2005-03-01

    Peroxisome proliferator activated receptor-gamma (PPARgamma) ligands increase nitric oxide (NO) production and reduce systemic blood pressure. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which has two isoforms, DDAH-I and -II. In order to elucidate the mechanism whereby PPARgamma ligands affect NO metabolism, their effects on the DDAH-ADMA pathway were investigated. Six-week-old male Wister-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were maintained with or without pioglitazone (PIO), a PPARgamma ligand. After 4 weeks, serum ADMA levels and urinary daily NO excretion were analyzed. Tissue DDAH expression was examined by real-time polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry. The results showed that PIO decreased serum ADMA and increased urinary NO excretion in both WKY and SHR. Also in both strains, the expression level of DDAH-II in the kidney was increased at transcriptional levels, although the DDAH-I level was unaffected. PIO lowered blood pressure in SHR, but not in WKY. We also demonstrated that PIO induced DDAH-II protein expression in Marbin-Dubin Canine Kidney (MDCK) cells, a renal tubular cell line. In conclusion, a PPARgamma ligand was here found to increase NO production partly by upregulating tissue DDAH-II expression and decreasing systemic ADMA levels. This mechanism constitutes a direct action on renal tubular cells, but is less likely to be responsible for the blood pressure-lowering effects of PPARgamma ligands. Since ADMA is one of the risk factors for cardiovascular events, this study provides compelling evidence that PPARgamma ligands have the potential for reducing cardiovascular risks.

  20. [Pharmacogenetic features of the effect of metformin in patients with coronary heart disease in the presence of metabolic syndrome and type 2 diabetes mellitus in terms of PPAR-gamma2 gene polymorphism].

    PubMed

    Lavrenko, A V; Shlykova, O A; Kutsenko, L A; Mamontova, T V; Kaĭdashev, I P

    2012-01-01

    To define the pharmacogenetic features of the effect of metformin in coronary heart disease (CHD) patients with metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM), by taking into consideration PPAR-gamma2 Pro1 2Ala polymorphism. Twenty-four men with CHD and MS and 28 men with CHD and T2DM were examined. The effect of metformin as a short course in combination therapy was evaluated. A population control group consisted of 46 apparently healthy men. The genetic PPRA-gamma2 Pro12Ala polymorphism was studied. A number of indicators (total cholesterol (TC), high-density lipoprotein cholesterol, total lipids, triglycerides, beta-lipoproteins, glycated hemoglobin, C-peptide) and proinflammatory markers, such as interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were determined in the blood. Analysis of the frequencies of Pro and Ala alleles indicated a decrease in the latter in CHD patients with T2DM. The CHD and MS patients who carried the Pro allele showed a significant metformin-induced reduction in weight, waist circumference, body mass index, and concentrations of TC, C-peptide, and cytokines, such IL-1beta, IL-6, IL-8, and TNF-alpha. Metformin exhibits a high therapeutic efficacy in patients with CHD in the presence of T2DM or MS who have the Pro/Pro genotype, which is of interest in terms of pharmacogenetics and calls for further investigation.

  1. Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity.

    PubMed

    Barbieri, Michelangela; Bonafè, Massimiliano; Rizzo, Maria Rosaria; Ragno, Emilia; Olivieri, Fabiola; Marchegiani, Francesca; Franceschi, Claudio; Paolisso, Giuseppe

    2004-07-01

    Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.

  2. Model-based development of a PPARgamma agonist, rivoglitazone, to aid dose selection and optimize clinical trial designs.

    PubMed

    Rohatagi, Shashank; Carrothers, Timothy J; Jin, Jinyan; Jusko, William J; Khariton, Tatiana; Walker, Joseph; Truitt, Kenneth; Salazar, Daniel E

    2008-12-01

    A model-based approach was implemented for the development of the proliferator-activated receptor gamma (PPARgamma) agonist rivoglitazone. Population pharmacokinetic and pharmacodynamic models were developed using data collected from 2 phase I and 2 phase II studies in healthy volunteers and participants with type 2 diabetes mellitus. A 2-compartment model with first-order absorption and elimination and an absorption time lag best described rivoglitazone pharmacokinetics. Modified indirect-response models were used to characterize changes in fasting plasma glucose, HbA(1c), and hemodilution as a function of rivoglitazone plasma concentrations. In addition, differences in hemodilution among participants correlated with the incidence of edema. Current use of oral antidiabetic medication was a significant covariate for the fasting plasma glucose-HbA(1c) exposure-response model. Using a learn-and-confirm process, models developed prior to the second phase II study were able to make valid predictions for exposures and response variables in that study. In future studies, seamless designs can be supported by models such as those developed here.

  3. Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone.

    PubMed

    Jové, Mireia; Salla, Joel; Planavila, Anna; Cabrero, Agatha; Michalik, Liliane; Wahli, Walter; Laguna, Juan C; Vázquez-Carrera, Manuel

    2004-01-01

    Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvate dehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPARgamma Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle. These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.

  4. Profound Retroactive Interference in Anterograde Amnesia: What interferes?

    PubMed Central

    Dewar, Michaela; Della Sala, Sergio; Beschin, Nicoletta; Cowan, Nelson

    2009-01-01

    Anterograde amnesia is characterised by a profound inability to retain new information. Recent research suggests that at least some of this severe memory impairment may be the product of retroactive interference. What specifically interferes with memory in amnesic patients however remains unknown. Here we reveal a substantial non-specific retroactive interference effect in densely amnesic patients: Whereas 7 out of 10 amnesic patients were able to recall some prose material following an unfilled delay period, only 1 of them was able to recall any material after a delay period in which they were required to listen for piano notes. The data reveal that some amnesic patients have the capacity to retain new material for much longer than usual but that any new post-learning information profoundly interferes with such retention. This non-specific retroactive interference effect deviates from the item-specific interference effect that is typically assessed in clinical practice, and which is frequently observed in patients with executive impairment. We hypothesise that these interference effects are qualitatively different, occurring during distinct memory processes, namely retrieval (item-specific interference) and consolidation (non-specific interference). PMID:20438213

  5. Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners.

    PubMed Central

    Fehlberg, Sebastian; Trautwein, Stefan; Göke, Alexandra; Göke, Rüdiger

    2002-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors which are involved in many biological processes, such as regulation of cell differentiation, lipid metabolism, inflammation and cell death. PPARs consist of three families, PPAR-alpha, PPAR-delta and PPAR-gamma. Bisphenol A diglycidyl ether (BADGE) has been described as a pure antagonist of PPAR-gamma. However, recent data also revealed PPAR-gamma-agonistic activities of BADGE. Here we show that BADGE kills transformed cells by apoptosis and promotes the cytotoxic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and indomethacin. The cytotoxic effect of BADGE does not require PPAR-gamma expression and is mediated in caspase-dependent and caspase-independent manners. PMID:11879183

  6. Pioglitazone and dexamethasone induce adipogenesis in D1 bone marrow stromal cell line, but not through the peroxisome proliferator-activated receptor-gamma pathway.

    PubMed

    Hung, Shao-Hung; Yeh, Ching-Hua; Huang, Hsuan-Ti; Wu, Peihua; Ho, Mei-Ling; Chen, Chung-Hwan; Wang, Chihuei; Chao, David; Wang, Gwo-Jaw

    2008-03-12

    Osteoblasts and adipocytes share a common progenitor in bone marrow. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in adipogenesis. Using a mouse pluripotent mesenchymal cell, D1, as a model, several reports have demonstrated that dexamethasone, a glucocorticoid, can induce adipogenesis. We first examined whether adipogenesis induction in D1 cells is initiated by activation of PPAR-gamma. The results revealed that pioglitazone induces adipogenesis in D1 cells in a dose-dependent manner and decreases alkaline phosphatase activity in D1 cells. Interestingly, this adipogenesis was not blocked by bisphenol A diglycidyl ether, a PPAR-gamma antagonist. A PPAR-gamma-mediated reporter gene assay showed no response to pioglitazone. We then asked whether dexamethasone-induced adipogenesis can be repressed by mifepristone (RU486), an antagonist of glucocorticoid receptor. The results disclosed that mifepristone cannot counteract dexamethasone-induced adipogenesis, and mifepristone itself induced adipogenesis in D1 cells. Moreover, glucocorticoid receptor-mediated reporter gene assay was not responsive to dexamethasone or mifepristone. We concluded that the adipogenesis induced by pioglitazone and dexamethasone in D1 cells may not occur via a PPAR-gamma and glucocorticoid receptor pathway. Finally, we analyzed the gene expression profile of D1 by cDNA microarray after treatment with dexamethasone. We found that the expression of several adipogenesis-related genes is highly provoked by this agent.

  7. Acute profound thrombocytopenia associated with readministration of eptifibatide: case report and review of the literature.

    PubMed

    Russell, Kimberly N; Schnabel, Joseph G; Rochetto, Richard P; Tanner, Matthew C

    2009-07-01

    The glycoprotein IIb-IIIa inhibitor eptifibatide has been shown to be beneficial in the treatment of acute coronary syndromes and during percutaneous coronary intervention (PCI). Case reports of acute profound thrombocytopenia have been reported with eptifibatide, yet the true incidence of this reaction is unknown. We describe a 50-year-old woman with severe coronary artery disease who developed acute profound thrombocytopenia after readministration of eptifibatide. Eptifibatide was administered through hospital day 3, when it was discontinued in preparation for coronary angiography and PCI; the drug was restarted on day 5. On hospital day 6, she was noted to have a platelet count below 5 x 10(3)/mm,(3) indicating a profound decrease from a baseline of 456 x 10(3)/mm(3) on admission. Eptifibatide, heparin, vancomycin, and clopidogrel were potential causative agents. Anticoagulation and vancomycin were stopped, and her platelet count increased to 30 x 10(3)/mm(3) on day 7. Subsequent reexposure to heparin and vancomycin yielded no adverse effects. The patient's platelet count increased over the remainder of her hospitalization, and she was discharged home on day 19. Based on clinical presentation and negative heparin platelet factor 4 antibody test, eptifibatide was the most likely cause of thrombocytopenia. Use of the Naranjo adverse drug reaction probability scale indicated that eptifibatide was the probable cause of thrombocytopenia (score of 5); scores of 1 (possible) or 0 (doubtful) were derived with heparin, vancomycin, and clopidogrel. We conducted a literature search and compiled information from published case reports to describe the pattern of onset and recovery of eptifibatide-induced thrombocytopenia. In all patients receiving eptifibatide, routine platelet counts should be monitored at baseline and within 2-6 hours after starting the drug.

  8. Reducing severe diurnal bruxism in two profoundly retarded females.

    PubMed Central

    Blount, R L; Drabman, R S; Wilson, N; Stewart, D

    1982-01-01

    Several diurnal audible teeth grinding (bruxism) was found to affect 21.5% of a profoundly retarded population. However, no previous research has treated bruxism in retarded individuals. In the current study a multiple baseline across subjects design was used to assess the effectiveness of contingent "icing," brief contingent tactile applications of ice, as a treatment for bruxism. Three 15-minute treatment periods and two 5-minute generalization periods were conducted 5 days per week. One resident displayed a 95% reduction in the percentage of intervals during which bruxism occurred during treatment periods and a 67% reduction during generalization periods. The other resident displayed a 94% reduction in the percentage of intervals during which bruxism occurred during treatment periods and a 53% reduction during generalization periods. PMID:6891381

  9. Vibrotactile Discrimination Training Affects Brain Connectivity in Profoundly Deaf Individuals

    PubMed Central

    González-Garrido, Andrés A.; Ruiz-Stovel, Vanessa D.; Gómez-Velázquez, Fabiola R.; Vélez-Pérez, Hugo; Romo-Vázquez, Rebeca; Salido-Ruiz, Ricardo A.; Espinoza-Valdez, Aurora; Campos, Luis R.

    2017-01-01

    Early auditory deprivation has serious neurodevelopmental and cognitive repercussions largely derived from impoverished and delayed language acquisition. These conditions may be associated with early changes in brain connectivity. Vibrotactile stimulation is a sensory substitution method that allows perception and discrimination of sound, and even speech. To clarify the efficacy of this approach, a vibrotactile oddball task with 700 and 900 Hz pure-tones as stimuli [counterbalanced as target (T: 20% of the total) and non-target (NT: 80%)] with simultaneous EEG recording was performed by 14 profoundly deaf and 14 normal-hearing (NH) subjects, before and after a short training period (five 1-h sessions; in 2.5–3 weeks). A small device worn on the right index finger delivered sound-wave stimuli. The training included discrimination of pure tone frequency and duration, and more complex natural sounds. A significant P300 amplitude increase and behavioral improvement was observed in both deaf and normal subjects, with no between group differences. However, a P3 with larger scalp distribution over parietal cortical areas and lateralized to the right was observed in the profoundly deaf. A graph theory analysis showed that brief training significantly increased fronto-central brain connectivity in deaf subjects, but not in NH subjects. Together, ERP tools and graph methods depicted the different functional brain dynamic in deaf and NH individuals, underlying the temporary engagement of the cognitive resources demanded by the task. Our findings showed that the index-fingertip somatosensory mechanoreceptors can discriminate sounds. Further studies are necessary to clarify brain connectivity dynamics associated with the performance of vibrotactile language-related discrimination tasks and the effect of lengthier training programs. PMID:28220063

  10. Vibrotactile Discrimination Training Affects Brain Connectivity in Profoundly Deaf Individuals.

    PubMed

    González-Garrido, Andrés A; Ruiz-Stovel, Vanessa D; Gómez-Velázquez, Fabiola R; Vélez-Pérez, Hugo; Romo-Vázquez, Rebeca; Salido-Ruiz, Ricardo A; Espinoza-Valdez, Aurora; Campos, Luis R

    2017-01-01

    Early auditory deprivation has serious neurodevelopmental and cognitive repercussions largely derived from impoverished and delayed language acquisition. These conditions may be associated with early changes in brain connectivity. Vibrotactile stimulation is a sensory substitution method that allows perception and discrimination of sound, and even speech. To clarify the efficacy of this approach, a vibrotactile oddball task with 700 and 900 Hz pure-tones as stimuli [counterbalanced as target (T: 20% of the total) and non-target (NT: 80%)] with simultaneous EEG recording was performed by 14 profoundly deaf and 14 normal-hearing (NH) subjects, before and after a short training period (five 1-h sessions; in 2.5-3 weeks). A small device worn on the right index finger delivered sound-wave stimuli. The training included discrimination of pure tone frequency and duration, and more complex natural sounds. A significant P300 amplitude increase and behavioral improvement was observed in both deaf and normal subjects, with no between group differences. However, a P3 with larger scalp distribution over parietal cortical areas and lateralized to the right was observed in the profoundly deaf. A graph theory analysis showed that brief training significantly increased fronto-central brain connectivity in deaf subjects, but not in NH subjects. Together, ERP tools and graph methods depicted the different functional brain dynamic in deaf and NH individuals, underlying the temporary engagement of the cognitive resources demanded by the task. Our findings showed that the index-fingertip somatosensory mechanoreceptors can discriminate sounds. Further studies are necessary to clarify brain connectivity dynamics associated with the performance of vibrotactile language-related discrimination tasks and the effect of lengthier training programs.

  11. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population

    PubMed Central

    Ghoussaini, Maya; Meyre, David; Lobbens, Stéphane; Charpentier, Guillaume; Clément, Karine; Charles, Marie-Aline; Tauber, Maïté; Weill, Jacques; Froguel, Philippe

    2005-01-01

    Background The Pro12Ala Single Nucleotide Polymorphism (SNP) of the Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-gamma 2) has been associated with insulin resistance and type 2 diabetes (T2D) and also inconsistently with obesity. The aim of this study was to evaluate the impact of this SNP with regards to T2D and childhood and adult obesity in the French Caucasian population. Methods We conducted three independent case/control studies encompassing 2126 cases and 1124 controls. Results We found a significant association between PPAR-gamma 2 Pro12Ala SNP and T2D (p = 0.04, OR = 1.37), which was stronger when the T2D cohort was stratified according to the obesity status (p = 0.03, OR = 1.81 in obese T2D subjects). In contrast, there was no association between the Pro12Ala SNP and childhood and adulthood obesity. In normal glucose tolerant obese adults (but not in lean subjects), the Pro12 allele was associated with a significant increase in fasting insulin levels (p = 0.01), and in insulin resistance estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (p = 0.003), after adjustment for age, gender and BMI. We didn't detect evidence for an interaction effect between the Pro12Ala SNP and the obesity status with respect to the HOMA-IR index in normal glucose tolerant children, but we found a borderline interaction (p = 0.06) in normal glucose tolerant adults. Conclusion Our results showed that the Pro12Ala polymorphism is not associated with childhood or adult obesity in the French Caucasian population. In contrast, we confirm a contribution of the PPAR-gamma 2 Pro12 allele in the genetic risk forT2D, especially in obese subjects, where this allele worsens insulin resistanceand increases fasting insulin levels. PMID:15784141

  12. Reversal of profound neuromuscular blockade with sugammadex in an infant after bronchial foreign body removal.

    PubMed

    Azizoglu, Mustafa; Birbicer, Handan; Memis, Suleyman; Taşkınlar, Hakan

    2016-09-01

    Sugammadex is a selective chemical agent that can reverse neuromuscular blockade induced by vecuronium and rocuronium. The aim of this report is to discuss the effectiveness of sugammadex in the reversal of neuromuscular blockade in children younger than 2 years. A 16-month-old boy, weighing 10 kg, was admitted to the pediatric emergency department due to choking, cyanosis, and severe respiratory distress that occurred while he was eating peanuts. In the emergency department, the patient's condition deteriorated, and he went into respiratory arrest. He was immediately intubated and taken to the operating room. A rigid bronchoscopy was performed under general anesthesia, with administration of intravenous pentothal (5 mg/kg), rocuronium (0.6 mg/kg), and fentanyl (0.5 μg/kg) in the operating room. The foreign body was removed within 6 minutes, and the profound neuromuscular blockade was reversed with a dose of 2 mg/kg sugammadex. He was extubated successfully after obtaining the spontaneous respiratory activity, and adequate breathing was restored. Clinical use of sugammadex in children younger than 2 years is not recommended because of the lack of clinical studies. In this case report, the profound neuromuscular blockade was successfully reversed with a dose of 2 mg/kg sugammadex in a 16-month-old boy. However, more prospective clinical studies are required for the safe use of this agent in children.

  13. The Final 2%: What It Takes to Create Profound Change in Leaders

    ERIC Educational Resources Information Center

    Sparks, Dennis

    2005-01-01

    Profound change in school begins with profound change in leaders that radiates to others and into the system. Profound change requires more than structural change--it requires changing the brains of teachers and administrators. Creating such change requires that leaders think, speak, and act differently on a daily basis, clarifying their ideas and…

  14. PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity.

    PubMed

    Jermendy, Agnes; Körner, Anna; Kovács, Margit; Madácsy, László; Cseh, Károly

    2011-01-01

    The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF-alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism.

  15. Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis.

    PubMed

    Aoki, Yasuhiro; Maeno, Toshitaka; Aoyagi, Kana; Ueno, Manabu; Aoki, Fumiaki; Aoki, Nozomi; Nakagawa, Junichi; Sando, Yoshichika; Shimizu, Yuji; Suga, Tatsuo; Arai, Masashi; Kurabayashi, Masahiko

    2009-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. To investigate whether the PPARgamma ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- beta (TGF-beta) for 6 h. PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day -7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases. Copyright 2008 S. Karger AG, Basel.

  16. Inhibitory effect of leptin on rosiglitazone-induced differentiation of primary adipocytes prepared from TallyHO/Jng mice

    SciTech Connect

    Kim, Ki Young; Kim, Joo Young; Sung, Yoon-Young; Jung, Won Hoon; Kim, Hee-Youn; Park, Ji Seon; Cheon, Hyae Gyeong; Rhee, Sang Dal

    2011-03-25

    Research highlights: {yields} In this study, we investigated the effects of leptin on adipocyte differentiation prepared from subcutaneous fat of TallyHo mice. {yields} Leptin inhibited the adipocytes differentiation at physiological concentration via inhibition of PPAR{gamma} expression. {yields} Inhibitors of ERK and STAT1 restored the leptin's inhibitory activity both in vitro and in vivo. -- Abstract: The effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary adipocytes prepared from subcutaneous fat of TallyHO/Jng (TallyHO) mouse, a recently developed model animal for type 2 diabetes mellitus (T2DM). The treatment of leptin inhibited the rosiglitazone-induced adipocyte differentiation with a decreased expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) a key adipogenic transcription factor, both in mRNA and protein levels. Leptin (10 nM) was sufficient to inhibit the adipocyte differentiation, which seemed to come from increased expression of leptin receptor genes in the fat of TallyHO mice. The inhibition of adipogenesis by leptin was restored by the treatment of inhibitors for extracellular-signal-regulated kinase (ERK) (PD98059) and signal transducer and activator of transcription-1 (STAT1) (fludarabine). Furthermore, in vivo intraperitoneal administration of PD98059 and fludarabine increased the PPAR{gamma} expression in the subcutaneous fat of TallyHO mice. These data suggest that leptin could inhibit the PPAR{gamma} expression and adipocyte differentiation in its physiological concentration in TallyHO mice.

  17. In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARgamma in L6 myotubes.

    PubMed

    Anandharajan, R; Jaiganesh, S; Shankernarayanan, N P; Viswakarma, R A; Balakrishnan, A

    2006-06-01

    The purpose of the present study is to investigate the effect of methanolic extracts of Aegles marmelos and Syzygium cumini on a battery of targets glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPARgamma) and phosphatidylinositol 3' kinase (PI3 kinase) involved in glucose transport. A. marmelos and S. cumini are anti-diabetic medicinal plants being used in Indian traditional medicine. Different solvent extracts extracted sequentially were analysed for glucose uptake activity at each step and methanol extracts were found to be significantly active at 100ng/ml dose comparable with insulin and rosiglitazone. Elevation of Glut-4, PPARgamma and PI3 kinase by A. marmelos and S. cumini in association with glucose transport supported the up-regulation of glucose uptake. The inhibitory effect of cycloheximide on A. marmelos- and S. cumini-mediated glucose uptake suggested that new protein synthesis is required for the elevated glucose transport. Current observation concludes that methanolic extracts of A. marmelos and S. cumini activate glucose transport in a PI3 kinase-dependent fashion.

  18. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings.

    PubMed

    Panebianco, Concetta; Oben, Jude A; Vinciguerra, Manlio; Pazienza, Valerio

    2017-08-01

    Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.

  19. Rosiglitazone promotes neurite outgrowth and mitochondrial function in N2A cells via PPARgamma pathway.

    PubMed

    Chiang, Ming-Chang; Cheng, Yi-Chuan; Chen, Han-Min; Liang, Yao-Jen; Yen, Chia-Hui

    2014-01-01

    Several pieces of evidence indicate that peroxisome proliferator-activated receptor gamma (PPARγ) stimulation promotes neuronal differentiation. However, to date, the effects of a synthetic PPARγ agonist (Rosiglitazone, Rosi) on neurite outgrowth have not yet been well described. Here we have evaluated the effects of Rosi on neurite outgrowth and mitochondrial function in the mouse neuroblastoma Neuro 2a (N2A) cell line. Our results show that Rosi promotes neurite outgrowth of N2A cells and significantly increases the population of neurite-bearing cells, with apparent increase of intracellular calcium and the expression of calmodulin-dependent kinase I (CaMKI). Rosi also increases the intracellular cAMP and expression of both protein kinase A (PKA) and cAMP response element binding protein (CREB). Phosphorylation of CREB was also detected in the Rosi treated N2A cells. Moreover, Rosi significantly increases the transcription of AMP-activated kinase (AMPK) and Sirtuin 1 (SIRT1). Besides, the expression of PPAR coactivator 1α (PGC1α), as well as the mRNA level its downstream genes, including nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (Tfam) were induced by Rosi treatments. Furthermore, Rosi increases the level of ATP, D-loop, and mitochondrial mass in N2A cells. Collectively, these findings provide an array of evidence that PPARγ activation provides beneficial neuronal networks within neurite outgrowth.

  20. Intact reading in patients with profound early visual dysfunction.

    PubMed

    Yong, Keir X X; Warren, Jason D; Warrington, Elizabeth K; Crutch, Sebastian J

    2013-10-01

    Despite substantial neuroscientific evidence for a region of visual cortex dedicated to the processing of written words, many studies continue to reject explanations of letter-by-letter (LBL) reading in terms of impaired word form representations or parallel letter processing in favour of more general deficits of visual function. In the current paper, we demonstrate that whilst LBL reading is often associated with general visual deficits, these deficits are not necessarily sufficient to cause reading impairment and have led to accounts of LBL reading which are based largely on evidence of association rather than causation. We describe two patients with posterior cortical atrophy (PCA) who exhibit remarkably preserved whole word and letter reading despite profound visual dysfunction. Relative to controls, both patients demonstrated impaired performance on tests of early visual, visuoperceptual and visuospatial processing; visual acuity was the only skill preserved in both individuals. By contrast, both patients were able to read aloud words with perfect to near-perfect accuracy. Reading performance was also rapid with no overall significant difference in response latencies relative to age- and education-matched controls. Furthermore, the patients violated a key prediction of general visual accounts of LBL reading - that pre-lexical impairments should result in prominent word length effects; in the two reported patients, evidence for abnormal word length effects was equivocal or absent, and certainly an order of magnitude different to that reported for LBL readers. We argue that general visual accounts cannot explain the pattern of reading data reported, and attribute the preserved reading performance to preserved direct access to intact word form representations and/or parallel letter processing mechanisms. The current data emphasise the need for much clearer evidence of causality when attempting to draw connections between specific aspects of visual processing and

  1. Core Cracking and Hydrothermal Circulation Profoundly Affect Ceres' Geophysical Evolution

    NASA Astrophysics Data System (ADS)

    Neveu, Marc; Desch, Steven J.; Castillo-Rogez, Julie C.

    2014-11-01

    The dwarf planet (1)Ceres is about to be visited by the Dawn spacecraft [1]. In addition to a recent report of water vapor emission [2], observations and models of Ceres suggest that its evolution was shaped by interactions between liquid water and silicate rock [3,4].Hydrothermal processes in a heated core require both fractured rock and liquid. Using a new core cracking model coupled to a thermal evolution code [5], we find volumes of fractured rock always large enough for significant interaction to occur. Therefore, liquid persistence is key. It is favored by antifreezes such as ammonia [4], by silicate dehydration which releases liquid, and by hydrothermal circulation itself, which enhances heat transport into the hydrosphere. The heating effect from silicate hydration seems minor. Hydrothermal circulation can profoundly affect Ceres' evolution: it prevents core dehydration via “temperature resets”, global cooling events lasting ~50 Myr, followed by ~1 Gyr periods during which Ceres' interior is nearly isothermal and its hydrosphere largely liquid. Whether Ceres has experienced such extensive hydrothermalism may be determined through examination of its present-day structure. A large, fully hydrated core (radius 420 km) suggests that extensive hydrothermal circulation prevented core dehydration. A small, dry core (radius 350 km) suggests early dehydration from short-lived radionuclides, with shallow hydrothermalism at best. Intermediate structures with a partially dehydrated core seem ambiguous, compatible both with late partial dehydration without hydrothermal circulation, and with early dehydration with extensive hydrothermal circulation. Thus, gravity measurements by the Dawn orbiter [1] could help discriminate between scenarios for Ceres' evolution.References:[1] Russell C. T. & Raymond C. A. (2011) Sp. Sci. Rev. 163, 3-23.[2] Küppers M. et al. (2014) Nature 505, 525-527.[3] Rivkin A. et al. (2011) Sp. Sci. Rev. 163, 95-116.[4] Castillo-Rogez J. C. & Mc

  2. Cochlear implantation in autistic children with profound sensorineural hearing loss.

    PubMed

    Lachowska, Magdalena; Pastuszka, Agnieszka; Łukaszewicz-Moszyńska, Zuzanna; Mikołajewska, Lidia; Niemczyk, Kazimierz

    2016-11-19

    Cochlear implants have become the method of choice for the treatment of severe-to-profound hearing loss in both children and adults. Its benefits are well documented in the pediatric and adult population. Also deaf children with additional needs, including autism, have been covered by this treatment. The aim of this study was to assess the benefits from cochlear implantation in deafened children with autism as the only additional disability. This study analyzes data of six children. The follow-up time was at least 43 months. The following data were analyzed: medical history, reaction to music and sound, Ling's six sounds test, onomatopoeic word test, reaction to spoken child's name, response to requests, questionnaire given to parents, sound processor fitting sessions and data. After cochlear implantation each child presented other communication skills. In some children, the symptoms of speech understanding were observed. No increased hyperactivity associated with daily use cochlear implant was observed. The study showed that in autistic children the perception is very important for a child's sense of security and makes contact with parents easier. Our study showed that oral communication is not likely to be a realistic goal in children with cochlear implants and autism. The implantation results showed benefits that varied among those children. The traditional methods of evaluating the results of cochlear implantation in children with autism are usually insufficient to fully assess the functional benefits. These benefits should be assessed in a more comprehensive manner taking into account the limitations of communication resulting from the essence of autism. It is important that we share knowledge about these complex children with cochlear implants. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  3. Cancer Prevention Knowledge of People with Profound Hearing Loss

    PubMed Central

    Meador, Helen E.; Reed, Barbara D.; Sen, Ananda; Gorenflo, Daniel W.

    2009-01-01

    BACKGROUND Deaf persons, a documented minority population, have low reading levels and difficulty communicating with physicians. The effect of these on their knowledge of cancer prevention recommendations is unknown. METHODS A cross-sectional study of 222 d/Deaf persons in Michigan, age 18 and older, chose one of four ways (voice, video of a certified American Sign Language interpreter, captions, or printed English) to complete a self-administered computer video questionnaire about demographics, hearing loss, language history, health-care utilization, and health-care information sources, as well as family and social variables. Twelve questions tested their knowledge of cancer prevention recommendations. The outcome measures were the percentage of correct answers to the questions and the association of multiple variables with these responses. RESULTS Participants averaged 22.9% correct answers with no gender difference. Univariate analysis revealed that smoking history, types of medical problems, last physician visit, and women having previous cancer preventive tests did not affect scores. Improved scores occurred with computer use (p = 0.05), higher education (p < 0.01) and income (p = 0.01), hearing spouses (p < 0.01), speaking English in multiple situations (p < 0.001), and in men with previous prostate cancer testing (p = 0.04). Obtaining health information from books (p = 0.05), physicians (p = 0.008), nurses (p = 0.03) or the internet (p = 0.02), and believing that smoking is bad (p < 0.001) also improved scores. Multivariate analysis revealed that English use (p = 0.01) and believing that smoking was bad (p = 0.05) were associated with improved scores. CONCLUSION Persons with profound hearing loss have poor knowledge of recommended cancer prevention interventions. English use in multiple settings was strongly associated with increased knowledge. PMID:19132325

  4. Intact reading in patients with profound early visual dysfunction

    PubMed Central

    Yong, Keir X.X.; Warren, Jason D.; Warrington, Elizabeth K.; Crutch, Sebastian J.

    2013-01-01

    Despite substantial neuroscientific evidence for a region of visual cortex dedicated to the processing of written words, many studies continue to reject explanations of letter-by-letter (LBL) reading in terms of impaired word form representations or parallel letter processing in favour of more general deficits of visual function. In the current paper, we demonstrate that whilst LBL reading is often associated with general visual deficits, these deficits are not necessarily sufficient to cause reading impairment and have led to accounts of LBL reading which are based largely on evidence of association rather than causation. We describe two patients with posterior cortical atrophy (PCA) who exhibit remarkably preserved whole word and letter reading despite profound visual dysfunction. Relative to controls, both patients demonstrated impaired performance on tests of early visual, visuoperceptual and visuospatial processing; visual acuity was the only skill preserved in both individuals. By contrast, both patients were able to read aloud words with perfect to near-perfect accuracy. Reading performance was also rapid with no overall significant difference in response latencies relative to age- and education-matched controls. Furthermore, the patients violated a key prediction of general visual accounts of LBL reading – that pre-lexical impairments should result in prominent word length effects; in the two reported patients, evidence for abnormal word length effects was equivocal or absent, and certainly an order of magnitude different to that reported for LBL readers. We argue that general visual accounts cannot explain the pattern of reading data reported, and attribute the preserved reading performance to preserved direct access to intact word form representations and/or parallel letter processing mechanisms. The current data emphasise the need for much clearer evidence of causality when attempting to draw connections between specific aspects of visual processing

  5. Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation.

    PubMed

    Maiuri, Luigi; Luciani, Alessandro; Giardino, Ida; Raia, Valeria; Villella, Valeria R; D'Apolito, Maria; Pettoello-Mantovani, Massimo; Guido, Stefano; Ciacci, Carolina; Cimmino, Mariano; Cexus, Olivier N; Londei, Marco; Quaratino, Sonia

    2008-06-01

    Cystic fibrosis (CF), the most common life-threatening inherited disease in Caucasians, is due to mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by airways chronic inflammation and pulmonary infections. The inflammatory response is not secondary to the pulmonary infections. Indeed, several studies have shown an increased proinflammatory activity in the CF tissues, regardless of bacterial infections, because inflammation is similarly observed in CFTR-defective cell lines kept in sterile conditions. Despite recent studies that have indicated that CF airway epithelial cells can spontaneously initiate the inflammatory cascade, we still do not have a clear insight of the molecular mechanisms involved in this increased inflammatory response. In this study, to understand these mechanisms, we investigated ex vivo cultures of nasal polyp mucosal explants of CF patients and controls, CFTR-defective IB3-1 bronchial epithelial cells, C38 isogenic CFTR corrected, and 16HBE normal bronchial epithelial cell lines. We have shown that a defective CFTR induces a remarkable up-regulation of tissue transglutaminase (TG2) in both tissues and cell lines. The increased TG2 activity leads to functional sequestration of the anti-inflammatory peroxisome proliferator-activated receptor gamma and increase of the classic parameters of inflammation, such as TNF-alpha, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-gamma and dampen down inflammation both in CF tissues and CFTR-defective cells. Our results highlight an unpredicted central role of TG2 in the mechanistic pathway of CF inflammation, also opening a possible new wave of therapies for sufferers of chronic inflammatory diseases.

  6. [Fertility decline in Colombia: expression of a profound social change].

    PubMed

    De Llinas, H M

    1983-01-01

    Demographers have identified 3 phases in the evolution of human population growth: 1) high mortality and high fertility resulting in very slow growth, 2) declining mortality and high fertility, resulting in rapid growth, and 3) declining mortality and fertility, resulting in slower growth. From the beginning of the century until the 1930s, Colombia was in the 1st phase, while the greatest mortality declines were registered from 1930-60. Fertility did not decline commensurately, and from 1951-64 the rate of population increase was 3.14%. The National Fertility Survey in 1969 and the 1973 census indicated that the country had at last begun its fertility decline. The 1969 survey showed that the total fertility rate (TFR) had dropped from 7.0 in the early 1960s to 6.0 in 1967-68, with fertility declining in both rural and urban areas. The 1973 census showed a rate of growth of 2.8% and an average number of children/woman of 4.7, showing that the fertility decline was structural and reflected profound changes in the values, norms, and attitudes regarding children of the Colombian population. Urbanization, the increased educational level and labor force participation of women, and the influence of the mass media in propagating the values of a consumer society are factors in the reduction of family size. Fertility differentials by region and social group have been declining progressively. The TFR in 1960-64 was 7.0 overall, 6.1 in urban areas, and 7.9 in rural areas, while in 1980 it was 3.6 overall, 3.0 in urban areas, and 5.1 in rural areas. In 1968-69, the TFR was 7.8 in the Atlantic region, 7.9 in the Oriental, 6.8 in the Central, 5.9 in the Pacific, and 4.5 in Bogota, while in 1980 it was 4.1 in the Atlantic, 4.0 in the Oriental, 3.5 in the Central, 3.3 in the Pacific, and 2.8 in Bogota. The number of women using family planning programs increased from 83 in 1965 to 1,790,484 in 1980. The proportion using contraception increased from 53% in 1976 to 55% in 1980. The

  7. Profound biotinidase deficiency: a rare disease among native Swedes.

    PubMed

    Ohlsson, Annika; Guthenberg, Claes; Holme, Elisabeth; von Döbeln, Ulrika

    2010-12-01

    Biotinidase deficiency is an autosomal recessive metabolic disorder included in many newborn screening programmes. Prior to the introduction of screening for biotinidase deficiency in Sweden in 2002, the disorder was almost unknown, with only one case diagnosed clinically. Biotinidase activity was measured in dried blood spots with a semiquantitative method using biotin-6-amidoquinoline as substrate. The cutoff value was set at 25% (later lowered to 20%) of the mean activity of all samples measured on that day. The disorder was confirmed by quantitative determination of biotinidase activity in plasma and DNA analyses. Over a period of 6 years, 13 patients were identified among 637,452 screened newborns and 5,068 adoptive/immigrant children. None of the patients had clinical symptoms at the time of diagnosis. Six patients had profound biotinidase deficiency, with an activity of 0-5% of normal in plasma. Four of these patients were born to parents who were first cousins of Middle Eastern or African origin. Eighteen gene alterations were identified, nine of which have not previously been described: seven mutations p.L83S (c.248T > C), p.R148H (c.443G > A), p.N202I (c.605A > T), p.I255T (c.764T > C), p.N402S (c.1205A > G), p.L405P (c.1214T > C), p.G445R (c.1333G > A) and two silent mutations p.L71L (c.211C > T) and p.L215L (c.645C > T). The predicted severity of the novel mutations was analyzed by sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), predicting p.L83S, p.L405P and p.G445R as severe mutations. Due to the high rate of immigrants since 1990 from non-Nordic countries, the incidence of biotinidase deficiency is similar to that found in many other Western countries.

  8. Taiwanofungus camphoratus activates peroxisome proliferator-activated receptors and induces hypotriglyceride in hypercholesterolemic rats.

    PubMed

    Suk, Fat-Moon; Lin, Shyr-Yi; Chen, Chien-Ho; Yen, Shish-Jung; Su, Ching-Hua; Liu, Der-Zen; Hou, Wen-Chi; Hung, Ling-Fang; Lin, Pei-Jung; Liang, Yu-Chih

    2008-07-01

    Taiwanofungus camphoratus (T. camphoratus), a fungus and a Taiwan-specific, well-known traditional Chinese medicine, has long been used to treat diarrhea, hypertension, itchy skin, and liver cancer. To gain a large amount of T. camphoratus, several culture techniques have been developed, including solid-state culture and liquid-state fermentation. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been described as a hypoglycemic agent that increases insulin sensitivity in peripheral tissues and results in reduced blood glucose, insulin, and triglyceride levels in insulin-resistant animals and in type-2 (non-insulin-dependent) diabetic patients. In this study, we investigate the possibility that T. camphoratus might activate PPARgamma in vitro and hypolipidemic activity in vivo. The results show that an aqueous extract of the wild fruiting bodies of T. camphoratus was able to increase the PPARgamma activity in cells transfected with the PPARgamma expression plasmid and the AOx-TK reporter plasmid. Based on the cell experiment, we examined the hypolipidemic effect of wild fruiting bodies (WFT) and a solid-state culture (SST) of T. camphoratus on SD rats fed on a high-cholesterol (HC) diet. The results show that WFT significantly decreased the serum triglyceride level, but could not affect the cholesterol level. SST only slightly decreased the serum triglyceride level. In addition, both WFT and SST significantly decreased the serum alanine transaminase (ALT) level and protected against the liver damage induced by the HC diet from the results of a histological examination. These results suggest that T. camphoratus might contain PPARgamma ligands and result in a hypotriglyceridemic effect, and that it also exhibits a liver protective activity.

  9. The effect of Saccharomyces boulardii on human colon cells and inflammation in rats with trinitrobenzene sulfonic acid-induced colitis.

    PubMed

    Lee, Sang Kil; Kim, Youn Wha; Chi, Sung-Gil; Joo, Yeong-Shil; Kim, Hyo Jong

    2009-02-01

    Saccharomyces boulardii (S. boulardii) has beneficial effects in the treatment of intestinal inflammation; however, little is known about the mechanisms by which these effects occur. We investigated the effects of S. boulardii on the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and interleukin-8 (IL-8), using human HT-29 colonocytes and a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. The effect of S. boulardii on gene expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Northern blot and Western blot assays. Pharmacological inhibitors for various signaling pathways were used to determine the signaling pathways implicated in the S. boulardii regulation of PPAR-gamma and IL-8. We found that S. boulardii up-regulated and down-regulated PPAR-gamma and IL-8 expression at the transcription level, both in vitro and in vivo (P < 0.05, respectively). Saccharomyces boulardii blocked tumor necrosis factor-alpha (TNF-alpha) regulation of PPAR-gamma and IL-8 through disruption of TNF-alpha-mediated nuclear factor kappa B (NF-kappaB) activation. Furthermore, S. boulardii suppressed colitis and expression of pro-inflammatory cytokine genes in vivo (P < 0.05, respectively). Our study demonstrated that S. boulardii reduces colonic inflammation and regulates inflammatory gene expression.

  10. PPAR-alpha and PPAR-beta expression changes in the hippocampus of rats undergoing global cerebral ischemia/reperfusion due to PPAR-gamma status

    PubMed Central

    2014-01-01

    Background Peroxisome proliferator-activated receptors (PPARs, including alpha, beta and gamma subtypes) and their agonists have a protective role in treatment of central nervous system (CNS) diseases. The present study was designed to investigate the expression changes of PPAR-alpha, -beta, -gamma and NF-kappa B in the hippocampus of rats with global cerebral ischemia/reperfusion injury (GCIRI) after treatment with agonists or antagonists of PPAR-gamma. Methods A rat GCIRI model was established by occlusion of bilateral common carotid arteries and cervical vena retransfusion. GW9662 (5 μg), a selective PPAR- gamma antagonist, was intraventricularly injected at 0.5 h before GCIR; Rosiglitazone (0.8, 2.4 and 7.2 mg/kg), a selective PPAR- gamma agonist, was injected intraperitoneally at 1 h before GCIRI. The expression changes of PPAR-alpha, -beta and -gamma at mRNA and protein levels were detected by RT-PCR and western blotting. The changes of spatial learning and memory (SLM) functions were assessed by using a Morris water maze; the pathohistological changes of hippocampal neurons were evaluated by hematoxylin-eosin (HE) staining; the contents of IL-1, IL-6, IL-10 and TNF-alpha, and the NF- kappa B expression were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were also detected. Results The SLM function and hippocampal neurons were significantly impaired after the occurrence of GCIRI. The MDA, IL-1, IL-6, IL-10, TNF-alpha content and expression of PPARs increased significantly, but the SOD activity and NF-kappa B expression were weakened in the hippocampus. Rosiglitazone treatment significantly protected rats from SLM function impairment and neuron death, and resulted in higher expressions of SOD activity and NF-kappa B, but lower contents of MDA and inflammatory factors. After treatment with rosiglitazone or GW9662, no significant change in PPAR

  11. Irreversible pulpitis and achieving profound anesthesia: Complexities and managements

    PubMed Central

    Modaresi, Jalil; Davoudi, Amin; Badrian, Hamid; Sabzian, Roya

    2016-01-01

    Dental pain management is one of the most critical aspects of modern dentistry. Irreversible pulpitis and further root canal therapy might cause an untolerated pain to the patients. The improvements in anesthetic agents and techniques were one of the advantages of studying nerve biology and stimulation. This article tried to overview of the nerve activities in inflammatory environments or induced pain. Furthermore, the proper advises, and supplementary techniques were reviewed for better pain management of irreversible pulpitis. PMID:26957681

  12. Hepatic inflammation and insulin resistance in pre-diabetes - further evidence for the beneficial actions of PPAR-gamma agonists and a role for SOCS-3 modulation.

    PubMed

    Chatterjee, Prabal K

    2010-08-01

    Pre-diabetes is a condition affecting increasing numbers of the population who find themselves caught in the grey area between normal glucose regulation and diabetes mellitus and who experience impaired glucose tolerance or fasting glucose. The ability of thiozolidinediones (TZDs) to ameliorate the clinical signs of diabetes mellitus is well-known but there is also emerging evidence for the benefits of PPAR-gamma agonists in pre-diabetes. In this issue of the British Journal of Pharmacology, Collino and colleagues report that pioglitazone can reduce hepatic inflammation and insulin resistance in rats administered a high cholesterol and fructose diet. Furthermore, pioglitazone reduced the expression of suppressor of cytokine signalling (SOCS)-3 - considered to be a key link between inflammation and insulin resistance. Although much work remains to be performed in fully understanding how TZDs modulate the cellular mechanisms which underlie pre-diabetes, these findings provide preliminary evidence that administration of TZDs to pre-diabetics could be beneficial.

  13. Profound Bilateral Sensorineural Hearing Loss in Nigerian Children: Any Shift in Etiology?

    ERIC Educational Resources Information Center

    Dunmade, A. D.; Segun-Busari, S.; Olajide, T. G.; Ologe, F. E.

    2007-01-01

    Deafness, profound hearing loss, is a global problem. However, the causes of, attitudes toward, and management options for deafness differ considerably from region to region. This study seeks to identify the present causes of profound sensorineural hearing loss in Nigeria, which in our environment is almost synonymous to a life sentence of silence…

  14. An Examination of Specific Daily Living Skills Deficits in Adults with Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Belva, Brian C.; Matson, Johnny L.

    2013-01-01

    While some researchers have investigated daily living skills deficits in individuals with intellectual disability (ID) as a whole, research on specific daily living skills in a profound ID population is limited. Two hundred and four adults with profound ID residing in two large developmental centers in the southeast portion of the United States…

  15. An Examination of Specific Daily Living Skills Deficits in Adults with Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Belva, Brian C.; Matson, Johnny L.

    2013-01-01

    While some researchers have investigated daily living skills deficits in individuals with intellectual disability (ID) as a whole, research on specific daily living skills in a profound ID population is limited. Two hundred and four adults with profound ID residing in two large developmental centers in the southeast portion of the United States…

  16. Teaching Individuals with Profound Multiple Disabilities to Access Preferred Stimuli with Multiple Microswitches

    ERIC Educational Resources Information Center

    Tam, Gee May; Phillips, Katrina J.; Mudford, Oliver C.

    2011-01-01

    We replicated and extended previous research on microswitch facilitated choice making by individuals with profound multiple disabilities. Following an assessment of stimulus preferences, we taught 6 adults with profound multiple disabilities to emit 2 different responses to activate highly preferred stimuli. All participants learnt to activate…

  17. Decreasing Self-Stimulating Behaviors with the Profoundly Mentally Retarded, While Acknowledging Obstacles and Frustrations.

    ERIC Educational Resources Information Center

    Smith, Susan J.; Solimani, Genevieve

    Two studies examined different treatment procedures to suppress self-stimulating behaviors with the profoundly mentally retarded. In experiment 1, a fine mist of cold water from a spray bottle was applied to the neck of a teenaged student in a class for the profoundly retarded. The intervention was very successful in reducing inappropriate humming…

  18. Assessing the Occurrence of Learning in Children with Profound Intellectual Disability: A Conditioning Approach.

    ERIC Educational Resources Information Center

    Remington, Bob

    1996-01-01

    This article discusses basic learning processes utilized by children with profound intellectual disabilities, including classical conditioning, operant conditioning, and habituation. The article also explores how these learning processes may be used in assessing the capabilities and preferences of children with profound intellectual disabilities.…

  19. Sleep Studies of Adults with Severe or Profound Mental Retardation and Epilepsy.

    ERIC Educational Resources Information Center

    Espie, Colin A.; Paul, Audrey; McFie, Joyce; Amos, Pat; Hamilton, David; McColl, John H.; And Others

    1998-01-01

    A study of the sleep patterns of 28 people with severe or profound mental retardation and epilepsy found atypical sleep stages with significant depletion of REM sleep and a predominance of indiscriminate non-REM sleep. Sleep diaries completed by caregivers reveal lengthy sleep periods, especially among those with profound mental retardation.…

  20. Identifying Expressions of Pleasure and Displeasure by Persons with Profound and Multiple Disabilities

    ERIC Educational Resources Information Center

    Petry, Katja; Maes, Bea

    2006-01-01

    Background: The aim of this study was to explore a procedure for drafting individualised profiles of how people with profound multiple disabilities express pleasure and displeasure. Method: There were 6 participants with profound multiple disabilities. The procedure involved an observational analysis of videotaped critical incidents by a…

  1. Diversity of Aspects on Play in Children with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Brodin, Jane

    2005-01-01

    Research on the meaning of play accelerated in the 1980s, but play in children with profound multiple disabilities is a topic, that is not discussed very often in research. In this article, play in children with profound multiple disabilities is in focus. The aim is to highlight studies on play as a tool for learning and early stimulation, and for…

  2. Profound Bilateral Sensorineural Hearing Loss in Nigerian Children: Any Shift in Etiology?

    ERIC Educational Resources Information Center

    Dunmade, A. D.; Segun-Busari, S.; Olajide, T. G.; Ologe, F. E.

    2007-01-01

    Deafness, profound hearing loss, is a global problem. However, the causes of, attitudes toward, and management options for deafness differ considerably from region to region. This study seeks to identify the present causes of profound sensorineural hearing loss in Nigeria, which in our environment is almost synonymous to a life sentence of silence…

  3. A Review of Curriculum Guides Developed for the Profoundly Mentally Handicapped (PMH) Population.

    ERIC Educational Resources Information Center

    Archer, Renee

    The monograph is intended to provide teachers of profoundly mentally handicapped students in South Carolina with a guide to ten existing curricula which were reviewed by the State Department of Education Consultant for the profoundly mentally handicapped. Usually included for each guide is title, information on curriculum components and…

  4. Assessing the Occurrence of Learning in Children with Profound Intellectual Disability: A Conditioning Approach.

    ERIC Educational Resources Information Center

    Remington, Bob

    1996-01-01

    This article discusses basic learning processes utilized by children with profound intellectual disabilities, including classical conditioning, operant conditioning, and habituation. The article also explores how these learning processes may be used in assessing the capabilities and preferences of children with profound intellectual disabilities.…

  5. Education Program and Guideline Booklet for The Severe/Profound, July 1976-June 1979.

    ERIC Educational Resources Information Center

    Hudspeth Retardation Center, Whitfield, MS.

    The education program for the severely and profoundly mentally retarded at the Hudspeth Retardation Center, a residential facility, is described. Specific objectives of the center are identified, including serving the 100 severely and profoundly retarded residents through initial evaluations, prescriptions of individualized education programs…

  6. Sleep Studies of Adults with Severe or Profound Mental Retardation and Epilepsy.

    ERIC Educational Resources Information Center

    Espie, Colin A.; Paul, Audrey; McFie, Joyce; Amos, Pat; Hamilton, David; McColl, John H.; And Others

    1998-01-01

    A study of the sleep patterns of 28 people with severe or profound mental retardation and epilepsy found atypical sleep stages with significant depletion of REM sleep and a predominance of indiscriminate non-REM sleep. Sleep diaries completed by caregivers reveal lengthy sleep periods, especially among those with profound mental retardation.…

  7. Decreasing Self-Stimulating Behaviors with the Profoundly Mentally Retarded, While Acknowledging Obstacles and Frustrations.

    ERIC Educational Resources Information Center

    Smith, Susan J.; Solimani, Genevieve

    Two studies examined different treatment procedures to suppress self-stimulating behaviors with the profoundly mentally retarded. In experiment 1, a fine mist of cold water from a spray bottle was applied to the neck of a teenaged student in a class for the profoundly retarded. The intervention was very successful in reducing inappropriate humming…

  8. Auditory/Vibratory Perception of Syllabic Structure in Words by Profoundly Hearing-Impaired Children.

    ERIC Educational Resources Information Center

    Zeiser, M. Lynn; Erber, Norman P.

    1977-01-01

    Sixty monosyllabic, disyllabic, and trisyllabic words were recorded and presented at different times through earphones and vibrators to 20 normal adults and 20 profoundly hearing impaired children (ages 8 to 15 years) to evaluate perception of number of syllables. Vibratory perception by profoundly hearing impaired and normal Ss and auditory…

  9. Joint Attention Behaviours in People with Profound Intellectual and Multiple Disabilities: The Influence of the Context

    ERIC Educational Resources Information Center

    Neerinckx, Heleen; Maes, Bea

    2016-01-01

    Background: In spite of the profound cognitive and physical problems, people with profound intellectual and multiple disabilities (PIMD) are able to develop joint attention behaviours (JAB) and benefit from positive interactions. Aims: To investigate which context factors influence the JAB of people with PIMD. Method: Based on video recordings of…

  10. Diversity of Aspects on Play in Children with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Brodin, Jane

    2005-01-01

    Research on the meaning of play accelerated in the 1980s, but play in children with profound multiple disabilities is a topic, that is not discussed very often in research. In this article, play in children with profound multiple disabilities is in focus. The aim is to highlight studies on play as a tool for learning and early stimulation, and for…

  11. The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1{alpha} expression

    SciTech Connect

    Xu, Wei; Guo, Ting; Zhang, Yan; Jiang, Xiaohong; Zhang, Yongxian; Zen, Ke; Yu, Bo; Zhang, Chen-Yu

    2011-05-01

    Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPAR{gamma}) coactivator-1 alpha (PGC-1{alpha}) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1{alpha} in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1{alpha} expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1{alpha} mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1{alpha} expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1{alpha} by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1{alpha} had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1{alpha} decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPAR{gamma} activation by a PPAR{gamma} antagonist GW9662 abolished the suppressive effects of PGC-1{alpha} on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1{alpha} were enhanced by a PPAR{gamma} agonist troglitazone. Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-1{alpha} expression. PGC-1{alpha} suppresses PDGF-induced VSMC migration through PPAR{gamma} coactivation and, consequently, p38 MAPK inhibition.

  12. No effect of isolated long-term supine immobilization or profound prolonged hypoxia on blood coagulation.

    PubMed

    Venemans-Jellema, A; Schreijer, A J M; Le Cessie, S; Emmerich, J; Rosendaal, F R; Cannegieter, S C

    2014-06-01

    Long-distance air travel is associated with an increased risk of venous thrombosis. The most obvious factor that can explain air travel-related thrombosis is prolonged seated immobilization. In addition, hypobaric hypoxia has been shown to affect coagulation, and the lowered atmospheric pressures present in the cabin during the flight may therefore play an etiologic role. Because immobilization and hypoxic conditions are usually present simultaneously in airplanes or hypobaric chambers, their separate effects on the coagulation system or on thrombosis risk have not been studied extensively. To investigate the separate effects of long-term immobilization and profound prolonged hypoxia on blood coagulation. We performed two studies in collaboration with European Space Agency/European Space Research and Technology Centre. In the first study, 24 healthy, non-smoking, adult women underwent 60 days of -6° head-down bed rest. In the second study, we took blood samples from 25 healthy men who participated during their stay in the Concordia station in Antarctica, where, due to the atmospheric conditions, continuous severe hypobaric hypoxia is present. In both studies, we measured markers of blood coagulation at baseline and at several time points during the exposures. We observed no increase in coagulation markers during immobilization or in the hypobaric environment, compared with baseline measurements. Our results indicate that neither immobilization nor hypoxia per se affects blood coagulation. These results implicate that a combination of risk factors is necessary to induce the coagulation system during air travel. © 2014 International Society on Thrombosis and Haemostasis.

  13. Shigella sonnei Bacteremia Presenting with Profound Hepatic Dysfunction

    PubMed Central

    Rettew, Andrew; Shaikh, Bilal; Abdulkareem, Abdullateef

    2017-01-01

    Worldwide, Shigellosis is a significant public health issue, associated with nearly one million deaths annually. About half a million cases of Shigella infection are reported annually in the United States. Shigella bacteremia is uncommon and generally seen in children and immunocompromised adults. We present a case of a Shigella sonnei bacteremia with marked hepatic derangement in a 27-year-old previously healthy homosexual male with history of Roux-en-Y gastric bypass, who presented to the emergency room with a 4-day history of loose watery stool, abdominal cramps, nausea and vomiting, and yellow skin of 2-day duration. He reports similar diarrhea illness in two close contacts in preceding days. On examination, he was fully oriented but dehydrated, icteric, and febrile. Laboratory data revealed WBC of 2200/μL, elevated AST and ALT (201 IU/L, 73 IU/L resp.), normal alkaline phosphatase, elevated total and direct bilirubin of 8.2 mg/dL and 4.4 mg/dL, albumin of 3.2 g/dL, INR of 2.9, prothrombin time of 31.7, and platelet of 96,000/μL. Workup for infectious, autoimmune and medication-induced hepatitis, Wilson's disease, and hemochromatosis was negative. Abdominal ultrasound and computed tomography of the abdomen showed hepatic steatosis and right-sided colitis. Stool and blood cultures were positive for Shigella sonnei. He was treated with ciprofloxacin with improvement in liver function. Follow-up blood test 4 months later was within normal limits. PMID:28326205

  14. Misperceiving Bullshit as Profound Is Associated with Favorable Views of Cruz, Rubio, Trump and Conservatism.

    PubMed

    Pfattheicher, Stefan; Schindler, Simon

    2016-01-01

    The present research investigates the associations between holding favorable views of potential Democratic or Republican candidates for the US presidency 2016 and seeing profoundness in bullshit statements. In this contribution, bullshit is used as a technical term which is defined as communicative expression that lacks content, logic, or truth from the perspective of natural science. We used the Bullshit Receptivity scale (BSR) to measure seeing profoundness in bullshit statements. The BSR scale contains statements that have a correct syntactic structure and seem to be sound and meaningful on first reading but are actually vacuous. Participants (N = 196; obtained via Amazon Mechanical Turk) rated the profoundness of bullshit statements (using the BSR) and provided favorability ratings of three Democratic (Hillary Clinton, Martin O'Malley, and Bernie Sanders) and three Republican candidates for US president (Ted Cruz, Marco Rubio, and Donald Trump). Participants also completed a measure of political liberalism/conservatism. Results revealed that favorable views of all three Republican candidates were positively related to judging bullshit statements as profound. The smallest correlation was found for Donald Trump. Although we observe a positive association between bullshit and support for the three Democrat candidates, this relationship is both substantively small and statistically insignificant. The general measure of political liberalism/conservatism was also related to judging bullshit statements as profound in that individuals who were more politically conservative had a higher tendency to see profoundness in bullshit statements. Of note, these results were not due to a general tendency among conservatives to see profoundness in everything: Favorable views of Republican candidates and conservatism were not significantly related to profoundness ratings of mundane statements. In contrast, this was the case for Hillary Clinton and Martin O'Malley. Overall, small

  15. Misperceiving Bullshit as Profound Is Associated with Favorable Views of Cruz, Rubio, Trump and Conservatism

    PubMed Central

    Pfattheicher, Stefan; Schindler, Simon

    2016-01-01

    The present research investigates the associations between holding favorable views of potential Democratic or Republican candidates for the US presidency 2016 and seeing profoundness in bullshit statements. In this contribution, bullshit is used as a technical term which is defined as communicative expression that lacks content, logic, or truth from the perspective of natural science. We used the Bullshit Receptivity scale (BSR) to measure seeing profoundness in bullshit statements. The BSR scale contains statements that have a correct syntactic structure and seem to be sound and meaningful on first reading but are actually vacuous. Participants (N = 196; obtained via Amazon Mechanical Turk) rated the profoundness of bullshit statements (using the BSR) and provided favorability ratings of three Democratic (Hillary Clinton, Martin O’Malley, and Bernie Sanders) and three Republican candidates for US president (Ted Cruz, Marco Rubio, and Donald Trump). Participants also completed a measure of political liberalism/conservatism. Results revealed that favorable views of all three Republican candidates were positively related to judging bullshit statements as profound. The smallest correlation was found for Donald Trump. Although we observe a positive association between bullshit and support for the three Democrat candidates, this relationship is both substantively small and statistically insignificant. The general measure of political liberalism/conservatism was also related to judging bullshit statements as profound in that individuals who were more politically conservative had a higher tendency to see profoundness in bullshit statements. Of note, these results were not due to a general tendency among conservatives to see profoundness in everything: Favorable views of Republican candidates and conservatism were not significantly related to profoundness ratings of mundane statements. In contrast, this was the case for Hillary Clinton and Martin O’Malley. Overall

  16. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene and risk of prostate cancer among men in a large cancer prevention study.

    PubMed

    Paltoo, Dina; Woodson, Karen; Taylor, Philip; Albanes, Demetrius; Virtamo, Jarmo; Tangrea, Joseph

    2003-02-28

    The nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) may play a role in prostate carcinogenesis. We examined the association between the PPAR-gamma Pro12Ala polymorphism and prostate cancer risk in a cohort of Finnish male smokers. In a nested case-control analysis that included 193 prostate cancer cases and 188 matched controls, we found no significant association between this polymorphism and prostate cancer risk (odds ratio, OR=1.27, 95% confidence interval, CI: 0.83-1.94), or significant trend or association with tumor stage (OR=1.28, 95% CI: 0.54-3.04 for metastatic disease) or grade (OR=1.57, 95% CI: 0.63-3.91 for poorly differentiated disease). The Pro12Ala polymorphism does not appear to play a significant role in prostate cancer risk in this cohort of men.

  17. Purified eicosapentaenoic acid induces prolonged survival of cardiac allografts and generates regulatory T cells.

    PubMed

    Iwami, D; Zhang, Q; Aramaki, O; Nonomura, K; Shirasugi, N; Niimi, M

    2009-06-01

    Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2(b)) mice were transplanted into CBA (H-2(k)) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4(+) and CD4(+)CD25(+) splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4(+)CD25(+) cells were Foxp3(+). In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA was upregulated by EPA treatment. A PPARgamma antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPARgamma activation.

  18. Gilles de la Tourette Disorder among Individuals with Severe or Profound Mental Retardation.

    ERIC Educational Resources Information Center

    Crews, W. David, Jr.; And Others

    1993-01-01

    Three case reports of people with severe or profound mental retardation and Tourette disorder are presented. Issues related to the diagnosis of Tourette disorder in this population are discussed. (Author)

  19. The Bivariate Plotting Procedure for Hearing Assessment of Adults Who Are Severely to Profoundly Mentally Retarded.

    ERIC Educational Resources Information Center

    Cattey, Tommy J.

    1985-01-01

    Puretone auditory assessment of 21 adults with severe to profound mental retardation indicated that a bivariate plotting procedure of predicting hearing sensitivity from the acoustic reflexes should be included in an audiological test battery for this population. (CL)

  20. The Bivariate Plotting Procedure for Hearing Assessment of Adults Who Are Severely to Profoundly Mentally Retarded.

    ERIC Educational Resources Information Center

    Cattey, Tommy J.

    1985-01-01

    Puretone auditory assessment of 21 adults with severe to profound mental retardation indicated that a bivariate plotting procedure of predicting hearing sensitivity from the acoustic reflexes should be included in an audiological test battery for this population. (CL)

  1. Reducing Stereotypic Handmouthing of a Child with Severe/Profound Retardation.

    ERIC Educational Resources Information Center

    Case-Holden, Vicki; Hupp, Susan C.

    1989-01-01

    A case study is presented of a seven-year-old girl with severe to profound mental retardation who exhibited excessive handmouthing. Contingent sensory reinforcement was successfully used to reduce her handmouthing to substantially lower levels. (Author/JDD)

  2. Grocery Shopping Skills for Persons with Moderate to Profound Intellectual Disabilities: A Review of the Literature.

    ERIC Educational Resources Information Center

    Morse, Timothy E.; And Others

    1996-01-01

    The published literature addressing grocery shopping instruction for individuals with moderate, severe, or profound intellectual disabilities was reviewed. Discussion focuses on variables associated with effective instructional programming, including maintenance, generalization, reliability, and social validity. (Author)

  3. Communication and special health care needs of a profoundly hearing impaired adolescent.

    PubMed

    Chacko, M R; Buttler, J T; Kirkland, R T

    1987-08-01

    This report describes the authors' experience in providing medical and contraceptive care to a profoundly hearing impaired adolescent in a hospital setting. Ways to communicate effectively with the hearing impaired are described.

  4. Allan-Herndon-Dudley syndrome with unusual profound sensorineural hearing loss.

    PubMed

    Gagliardi, Lucia; Nataren, Nathalie; Feng, Jinghua; Schreiber, Andreas W; Hahn, Christopher N; Conwell, Louise S; Coman, David; Scott, Hamish S

    2015-08-01

    The Allan-Herndon-Dudley syndrome is caused by mutations in the thyroid hormone transporter, Monocarboxylate transporter 8 (MCT8). It is characterized by profound intellectual disability and abnormal thyroid function. We report on a patient with Allan-Herndon-Dudley syndrome (AHDS) with profound sensorineural hearing loss which is not usually a feature of AHDS and which may have been due to a coexisting nonsense mutation in Microphthalmia-associated transcription factor (MITF).

  5. Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions.

    PubMed

    Sasso, Oscar; Bertorelli, Rosalia; Bandiera, Tiziano; Scarpelli, Rita; Colombano, Giampiero; Armirotti, Andrea; Moreno-Sanz, Guillermo; Reggiani, Angelo; Piomelli, Daniele

    2012-05-01

    Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund's adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund's adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions.

  6. Circulatory collapse following epidural bolus for Caesarean section a profound vasovagal reaction? A case report

    PubMed Central

    Oddby, Eva; Hein, Anette; Jakobsson, Jan G.

    2016-01-01

    Introduction Reduced blood pressure is commonly seen associated to spinal anaesthesia for Caesarean section and efforts to reduce its occurrence and its magnitude is common practice. Cardiovascular collapse requiring cardio-pulmonary resuscitation after putting the spinal/epidural block for Caesarean section is however a rare but most dramatic event. Presentation of case We describe a case with sudden short loss of circulation, circulatory collapse, short after start of emergency Caesarean section in top up epidural anaesthesia (3 + 12 ml ropivaciane 7.5 mg/ml), requiring CPR. The neonate was delivered during CPR with Apgar 1, 10, 10 at 1, 5 and 10 min. Circulation was restored following 60–90 s of CPR and administration of 0.5 mg adrenaline. No cardioversion was administered sinus rhythm was regained spontaneously. The mother and child had a further uncomplicated course. No signs of cardiac damage/anomaly, emboli, septicaemia, pereclampisa or local anaesthetic toxicity was found. The patient had prior to the decision about Caesarean section had fever and was subsequently relatively dehydrated. Discussion The patient had a fast return of sinus rhythm following birth of the child, without cardioversion. None of common causes for cardiac arrest was found and the patient an uncomplicated post Caesarean section course. The combination of epidural induced sympathetic block and reduced preload possibly triggered a Bezold-Jarisch reflex with a profound vasovagal reaction. Concluiosn A structured plan for the handling of cardiovascular crisis must be available wherever Caesarean section are performed. Adequate volume loading, left tilt and vigilant control of circulation following regional block performance is of outmost importance. PMID:27100952

  7. Profound changes in blood parameters during torpor in a South American marsupial.

    PubMed

    Franco, Marcela; Contreras, Carolina; Nespolo, Roberto F

    2013-10-01

    Seasonal torpor or hibernation is a phenomenon characterized by a physiological transition to dormancy (torpor) during challenging periods in terms of energy availability or metabolic load. Extensive physiological reprogramming and changes in gene-expression, immune function, oxygen transport and intermediate metabolism, occur during eutherian hibernation. Here we studied the seasonality of blood parameters, and during daily torpor, in a South American marsupial (Dromiciops gliroides). Seasonal trends in blood parameters showed an increase in hematological parameters during winter, and increases in total proteins, albumin and globulin during autumn. In contrast, torpor induced a drastic drop during most blood parameters. PCV dropped significantly 60%, as well as RBC (58%), hemoglobin concentration (58%), WBC (79%), including neutrophils (51%), eosinophils (84%) and lymphocytes (82%). Biochemical parameters also showed reductions: triglycerides (81%), proteins (32%), albumin (24%), globulins (38%), albumin (24%), creatinine (48%) and glucose (42%). Our results confirm some patterns observed in hibernating eutherians, such as leukopenia, probably caused by sequestration of white blood cells in organs. However, red blood cells and hemoglobin concentration also were reduced, which is to the best of our knowledge has not been reported for marsupials. The observed reduction in biochemical parameters suggests that marsupials, as in eutherians, change from carbohydrate-based to lipid-based metabolism during hibernation. However, the absence of increases in beta-hydroxybutyrate is puzzling. Finally, we found an increase (although non-significant after statistical correction for multiple comparisons) of creatine kinase which together with an increase in neutrophil/lymphocyte ratio could be indicative of muscle lysis and inflammation. These results indicate profound changes in standard physiological processes during torpor.

  8. [Experiment on inducing human periodontal ligament stem cells into adipose cells].

    PubMed

    He, Hui-xia; Liu, Hong-chen; Wang, Dong-sheng; Cao, Jun-kai; Zhang, Hai-zhong; E, Ling-ling

    2010-04-01

    To explore the capability of human periodontal ligament stem cells (PDLSCs) differentiating into adipose cells in vitro and to determine their changes in cell morphology, structure and function during differentiation. PDLSCs isolated by magnetic-activated cell selection were treated continuously with adipogenic medium for 21 d. Then the cell morphology, ultrastructure, adipose specific markers of low density lipoprotein (LPL) and peroxisome proliferator activated receptor-gamma (PPAR-gamma) were analyzed by inverted contrast microscope, trans mission electron microscope (TEM), flow cytometry, immunofluorescence, RT-PCR and Western blot, respectively. These adipose-like cells were also identified by oil red O staining to determine the formation of lipid droplet, and the non-induced cells were used as control. After continuous induction, the treated cells differentiated into adipose-like cells with round shape, and large amount of lipid drop in cytoplasm. 96.54% of the PDLSCs were found to differentiate into adipose cells as showed by flow cytometry, the specific markers of LPL mRNA and PPAR-gamma mRNA, and oil red O staining, respectively. Further, PPAR-gamma protein was detected in the induced cells in a time-dependent manner. Human PDLSCs have the potential of differentiating into adipose cells under appropriate condition, and the differentiated cells exhibited characteristics of adipose cells both from cell morphology and from their functions.

  9. Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARgamma2 and C/EBPalpha in 3T3-L1 cells.

    PubMed

    Furuyashiki, Takashi; Nagayasu, Hironobu; Aoki, Yukiko; Bessho, Hiroaki; Hashimoto, Takashi; Kanazawa, Kazuki; Ashida, Hitoshi

    2004-11-01

    Obesity is a serious health problem, and its prevention is promoted through life style including diet and exercise. In this study, we investigated the suppressive effects of tea catechin on the differentiation of 3T3-L1 preadipocytes to adipocytes. (-)-Catechin 3-gallate (CG), (-)-epigallocatechin (EGC), (-)-epicatechin 3-gallate, and (-)-epigallocatechin 3-gallate at 5 muM suppressed intracellular lipid accumulation. The suppressive effects of CG and EGC were stronger than the others, and CG and EGC also suppressed the activity of glycerol-3-phosphate dehydrogenase as a differentiation marker. These catechins inhibited the expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and CCAAT/enhancer-binding protein (C/EBP) alpha, both of which act as key transcription factors at an early stage of differentiation, followed by the expression of glucose transporter (GLUT) 4 at a later stage. In addition, the catechins did not affect the phosphorylation status of the insulin signal pathway. Thus, catechin suppressed adipocyte differentiation accompanied by the down-regulation of PPARgamma2, C/EBPalpha, and GLUT4. These results suggest that tea catechin prevents obesity through the suppression of adipocyte differentiation.

  10. Tracheostomies and assisted ventilation in children with profound disabilities: navigating family and professional values.

    PubMed

    Wilfond, Benjamin S

    2014-02-01

    Parental requests for gastrostomies, tracheostomies, or assisted ventilation in children with profound disabilities raise ethical concerns about children's interests, parental decision-making, and health care costs. The underlying concern for many relates to the perceived value of these children. Clinicians should make efforts to appreciate the family's perspective regarding children with profound disabilities who require respiratory and nutritional medical support. Finding opportunities to learn about the family members' lives outside of the health care setting may facilitate a deeper understanding of what it means to live with a child who has profound disabilities. In conversations with families, referring to interventions as futile and conditions as lethal will obscure the value-based nature of these decisions. Respiratory and nutritional interventions are not clearly against the interests of most children. Even for children with a limited life span, life-sustaining interventions may be important for the child and family. Health care costs are a serious societal issue; however, the costs associated with profound disabilities are not the most significant contributor. Societal decisions not to provide life-sustaining health care to children with profound disabilities would require a public process. Clinicians may have personal views regarding decisions for their own family or for their vision for society. However, clinicians have professional obligations to families who have different values. It is important to present balanced information and support parental decision-making so parents may decide to forgo or use life-sustaining interventions according to their values and goals.

  11. Assessing clinicians' consultation with people with profound learning disability: producing a rating scale.

    PubMed

    Kerr, M P; Evans, S; Nolan, M; Fraser, W I

    1995-06-01

    This paper describes the development of a scale for assessing clinicians' communication with people with profound learning disability. Four psychiatrists and four nurses were assessed completing three simple non-invasive clinical procedures--blood pressure, pulse and axillary temperature--with people with profound learning disability. Videotaped assessment of consultations was performed by three experienced speech and language therapists using a previously designed scale for analysing encounters with people with mild learning disability. This led to the production of a new scale specifically for people with profound learning disability. A significant inter-rater reliability was found between the three speech therapists for total scores (rater a-b, corr = 0.654, P = 0.006; rater a-c, corr = 0.795, P = 0.0001: rater b-c, corr = 0.673, P = 0.004). Significant reliability between raters was also found for the subsections of verbal behaviour and non-verbal behaviour.

  12. Attuning: A Communication Process between People with Severe and Profound Intellectual Disability and Their Interaction Partners.

    PubMed

    Griffiths, Colin; Smith, Martine

    2016-03-01

    People with severe and profound intellectual disability typically demonstrate a limited ability to communicate effectively. Most of their communications are non-verbal, often idiosyncratic and ambiguous. This article aims to identify the process that regulates communications of this group of people with others and to describe the methodological approach that was used to achieve this. In this qualitative study, two dyads consisting of a person with severe or profound intellectual and multiple disability and a teacher or carer were filmed as they engaged in school-based activities. Two 1-hour videotapes were transcribed and analysed using grounded theory. Attuning was identified within the theory proposed here as a central process that calibrates and regulates communication. Attuning is conceptualized as a bidirectional, dyadic communication process. Understanding this process may support more effective communication between people with severe or profound intellectual and multiple disability and their interaction partners. © 2015 John Wiley & Sons Ltd.

  13. Effects of three amplification strategies on speech perception by children with severe and profound hearing loss.

    PubMed

    Marriage, Josephine E; Moore, Brian C J; Stone, Michael A; Baer, Thomas

    2005-02-01

    Traditionally in the United Kingdom, children with severe and profound hearing loss have been fitted with linear, analog hearing aids. Fast-acting, wide-dynamic-range compression (WDRC) has been shown to give better discrimination of speech than linear amplification for moderately hearing-impaired young adults. For severe and profound hearing losses, higher compression ratios are needed. The resultant distortion of the temporal envelope and reduced modulation depth may offset improvements in audibility offered by WDRC. In this study, speech recognition and discrimination were assessed for severely and profoundly hearing-impaired children, using three different amplification strategies, including WDRC. Fifteen children (ages 7 to 15 yr) with severe and profound hearing loss were fitted bilaterally with high-power, multichannel compression hearing aids, incorporating one of three different amplification strategies: linear with peak clipping, linear with compression limiting, or WDRC. Output responses were matched to Desired Sensation Level (DSL i/o) targets. The children wore hearing aids programmed with each of the amplification strategies in turn, for at least 1 wk, in a counterbalanced order across children. After using a particular amplification strategy for at least 1 wk, speech perception tests were carried out. Speech scores on closed-set testing for the profound group showed significant benefit for WDRC over the other two algorithms. None of the other results showed a statistically significant effect of algorithm on speech performance. WDRC amplification sometimes led to better performance than linear amplification with peak clipping or output limiting, and it never led to poorer performance. Therefore, it appears to be safe to use well-designed WDRC for hearing-impaired children with severe or profound hearing loss.

  14. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations.

    PubMed

    Wiltink, Rachel C; Kruijshaar, Michelle E; van Minkelen, Rick; Onkenhout, Willem; Verheijen, Frans W; Kemper, Evelien A; van Spronsen, Francjan J; van der Ploeg, Ans T; Niezen-Koning, Klary E; Saris, Jasper J; Williams, Monique

    2016-10-01

    Biotinidase deficiency is a rare inherited metabolic disorder that can cause severe neurological symptoms. To prevent severe clinical presentations, it was included in the Dutch neonatal screening programme in 2007. Since then the number of cases detected has been high. This study set out to describe the incidence of the disease, the clinical and demographic characteristics of the neonates identified and the type of mutations found. In the south-western Netherlands, 304 982 neonates were screened between 2007 and 2012; and 92 were identified for further testing. Confirmatory testing revealed 6 (7%) with a profound biotinidase deficiency (<10% enzyme activity), 44 (48%) with a partial deficiency (10-30%) and 42 (46%) with normal activity (>30%). All six patients whose profound deficiency was confirmed had enzyme activities below 15% on neonatal screening. Mutation analysis was performed in 61 neonates: 5 'profound', 35 'partial' and 21 'normal'. All five 'profound' cases had two severe mutations. Comparison with the northern Netherlands showed that the frequency and types of mutation were representative for the Netherlands as a whole. The most common mutation detected was c.[1330G>C] (p.(Asp444His); 34%), which is considered to be mild, followed by three severe mutations c.[1368A>C], c.[1595C>T] and c.[1330G>C;511G>A]. Seven new mutations were identified. We conclude that neonatal screening for profound biotinidase produces a high number of false positives. Biotinidase deficiency was profound in less than 10% of cases identified. As biotinidase activity lay below 15% on neonatal screening in all such cases, the screening threshold might be reduced to 15%.

  15. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations

    PubMed Central

    Wiltink, Rachel C; Kruijshaar, Michelle E; van Minkelen, Rick; Onkenhout, Willem; Verheijen, Frans W; Kemper, Evelien A; van Spronsen, Francjan J; van der Ploeg, Ans T; Niezen-Koning, Klary E; Saris, Jasper J; Williams, Monique

    2016-01-01

    Biotinidase deficiency is a rare inherited metabolic disorder that can cause severe neurological symptoms. To prevent severe clinical presentations, it was included in the Dutch neonatal screening programme in 2007. Since then the number of cases detected has been high. This study set out to describe the incidence of the disease, the clinical and demographic characteristics of the neonates identified and the type of mutations found. In the south-western Netherlands, 304 982 neonates were screened between 2007 and 2012; and 92 were identified for further testing. Confirmatory testing revealed 6 (7%) with a profound biotinidase deficiency (<10% enzyme activity), 44 (48%) with a partial deficiency (10–30%) and 42 (46%) with normal activity (>30%). All six patients whose profound deficiency was confirmed had enzyme activities below 15% on neonatal screening. Mutation analysis was performed in 61 neonates: 5 ‘profound', 35 ‘partial' and 21 ‘normal'. All five ‘profound' cases had two severe mutations. Comparison with the northern Netherlands showed that the frequency and types of mutation were representative for the Netherlands as a whole. The most common mutation detected was c.[1330G>C] (p.(Asp444His); 34%), which is considered to be mild, followed by three severe mutations c.[1368A>C], c.[1595C>T] and c.[1330G>C;511G>A]. Seven new mutations were identified. We conclude that neonatal screening for profound biotinidase produces a high number of false positives. Biotinidase deficiency was profound in less than 10% of cases identified. As biotinidase activity lay below 15% on neonatal screening in all such cases, the screening threshold might be reduced to 15%. PMID:27329734

  16. Relationship of Piaget's sensorimotor period to language acquisition of profoundly retarded children.

    PubMed

    Kahn, J V

    1975-05-01

    The relationship of Stage 6 of Piaget's sensorimotor period and the acquisition of meaningful expressive language was investigated. The sample consisted of eight profoundly retarded children who exhibited some meaningful expressive language and eight profoundly retarded children who exhibited none. Chronological ages of the children ranged from 47 to 98 months. A strong relationship was found between meaningful expressive language and Stage 6 functioning as tested by the Uzgiris and Hunt (Note 1) instrument. The findings were discussed in terms of supporting Piaget's theory that cognitive structures exist which are prerequisites for the development of language.

  17. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California.

    PubMed

    Cowan, Tina M; Kazerouni, Niloufar Neely; Dharajiya, Nilesh; Lorey, Fred; Roberson, Marie; Hodgkinson, Christina; Schrijver, Iris

    2012-08-01

    We report population findings from newborn screening for biotinidase deficiency in California, representing over 2,000,000 newborns. The incidence of profound deficiency was 1/73,629, higher than in other reported populations. Out of 28 patients with profound biotinidase deficiency, 19 were of Hispanic descent, suggesting an increased frequency among this group. Of the 28 patients, 23 underwent mutation analysis of the BTD gene, with one common mutation, 528G>T, found in 43.3% of Hispanic alleles tested. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Atypical Ph negative chronic myeloid leukaemia presenting as sudden profound deafness.

    PubMed Central

    Smith, N; Bain, B; Michaels, L; Craven, E

    1991-01-01

    A patient with atypical Ph negative chronic myeloid leukaemia presented with the sudden onset of profound deafness. He survived only eight months. Detailed histological investigation performed at necropsy showed loss of ganglion cells and afferent nerve fibres in the cochlea and vestibule associated with extensive fibrosis and new bone formation in the labyrinthine spaces. Both leucophoresis and high dose chemotherapy capable of rapid cytoreduction are recommended in patients with chronic myeloid leukaemia with profound hearing loss, as conventional chemotherapy is rarely followed by recovery. Images PMID:1791207

  19. Synergistic interactions between heregulin and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist in breast cancer cells.

    PubMed

    Park, Bae-Hang; Lee, Sean-Bong; Stolz, Donna B; Lee, Yong J; Lee, Byeong-Chel

    2011-06-03

    Here, we demonstrate that troglitazone (Rezulin), a peroxisome proliferator-activated receptor agonist, acted in synergy with heregulin to induce massive cell death in breast cancer cells. Although the combination of heregulin and troglitazone (HRG/TGZ) induced both apoptosis and necrosis, the main mode of cell death was caspase-independent and occurred via necrosis. This combination increased generation of superoxide in mitochondria, which in turn destabilized mitochondria potential. Pretreatment with N-acetyl-l-cysteine and catalase expression ameliorated cell death induced by the combination treatment, indicating a role of oxidative stress in mediating HRG/TGZ-induced cell death. Notably, pretreatment with pyruvate significantly prevented the cell death, suggesting a potential mechanistic link between metabolic stress and HRG/TGZ-induced cell death. The activation of the HRG signaling axis has been considered as a poor prognostic factor in breast cancer and confers resistance to gefitinib (Iressa) and tamoxifen. However, our data presented here paradoxically suggest that HRG expression can actually be beneficial when it comes to treating breast cancer with peroxisome proliferator-activated receptor-γ ligands. Taken together, the combination of HRG and TGZ may provide a basis for the development of a novel strategy in the treatment of apoptosis-resistant and/or hormone-refractory breast cancer.

  20. Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines.

    PubMed

    Bae, Myung-Ae; Rhee, Herman; Song, Byoung J

    2003-03-20

    Rosiglitazone (RSG), an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma), induces minor toxicity in humans relative to another PPARgamma agonist, troglitazone (TRO). In contrast, recent reports suggest that RSG causes growth arrest and apoptosis of normal and cancerous cells. Therefore, in this study, we investigated the relative toxicities of TRO and RSG on three different hepatoma cell lines, and observed that TRO, but not RSG, was cytotoxic. Additionally, we studied the mechanism by which TRO induced damage to HepG2 hepatoma cells. Our results indicated that TRO increased the levels of p53, p27, and p21, while it reduced the levels of cyclin D1 and phospho-Rb in a time-dependent manner. Increased p27 and p21 levels coincided with reduced activities of cell cycle dependent kinases (cdk) such as cdk2- and cyclin A-protein kinases 24 h after TRO treatment. These results demonstrate that TRO, but not RSG, causes G1 arrest of hepatoma cells, most likely through changing the levels of cell cycle regulators. Furthermore, because RSG did not affect the levels of cell cycle regulators, TRO-mediated growth inhibition appears independent of PPARgamma activation.

  1. The Effects of Governing Board Configuration on Profound Organizational Change in Hospitals

    ERIC Educational Resources Information Center

    Alexander, Jeffrey A.; Ye, Yining; Lee, Shoou-Yih D.; Weiner, Bryan J.

    2006-01-01

    This study extends the literature on governing boards and organizational change by examining how governing board configurations have influenced profound organizational change in U.S. hospitals, and the conditions under which such change occurs. Hospitals governed by boards that more closely resembled a corporate governance model were more likely…

  2. The Development of Pragmatic Skills in Children Who Are Severely and Profoundly Deaf

    ERIC Educational Resources Information Center

    Toe, Dianne; Beattie, Rod; Barr, Megan

    2007-01-01

    The present study investigated the conversational skills of a group of 18 children (aged 6 to 16 years) with severe and profound hearing loss. Participants included both hearing aid users and cochlear implant users. All the children relied upon spoken English and were included in regular classroom settings for at least part of each school day.…

  3. Filling "Na Puka" with PUFM: Empowering Teachers with Profound Understanding of Fundamental Mathematics

    ERIC Educational Resources Information Center

    Monroe, Eula Ewing; Bailey, John; Mitchell, Barry; AhSue, Yvonne

    2011-01-01

    This paper reports results from a Mathematics and Science Partnership grant designed primarily to help teachers from six elementary schools on the North Shore of O'ahu develop a profound understanding of fundamental mathematics (PUFM) (Ma, 1999). Five of these schools had not met minimum requirements under the No Child Left Behind Act; among them…

  4. Attuning: A Communication Process between People with Severe and Profound Intellectual Disability and Their Interaction Partners

    ERIC Educational Resources Information Center

    Griffiths, Colin; Smith, Martine

    2016-01-01

    Background: People with severe and profound intellectual disability typically demonstrate a limited ability to communicate effectively. Most of their communications are non-verbal, often idiosyncratic and ambiguous. This article aims to identify the process that regulates communications of this group of people with others and to describe the…

  5. The Assessment Process in Recreation with Severely and Profoundly Retarded Populations.

    ERIC Educational Resources Information Center

    Crawford, Michael E.; And Others

    1978-01-01

    The article discusses approaches to the evaluation of severely and profoundly mentally retarded persons by recreational therapists. Considered are inventory assessments, medical profiles, interviews, and direct interactions with a client. The last phase of the evaluation process is summarizing and ordering the needs of the individual based on the…

  6. Interaction between Persons with Profound Intellectual and Multiple Disabilities and Their Partners: A Literature Review

    ERIC Educational Resources Information Center

    Hostyn, Ine; Maes, Bea

    2009-01-01

    Background: High quality interactions are of crucial importance for quality of life of persons with profound intellectual and multiple disabilities (PIMD). This literature review describes and synthesises studies addressing the interaction between persons with PIMD and their partners. Method: A computerised literature search using defined…

  7. Frequency and Severity of Challenging Behaviour in People with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Poppes, P.; van der Putten, A. J. J.; Vlaskamp, C.

    2010-01-01

    The main goals of this study were to determine the prevalence, frequency and severity of challenging behaviour in people with profound intellectual and multiple disabilities (PIMD). Because in the literature several health problems and sensory impairments are associated with the onset and existence of challenging behaviour, this relationship was…

  8. Low Mood and Challenging Behaviour in People with Severe and Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Hayes, S.; McGuire, B.; O'Neill, M.; Oliver, C.; Morrison, T.

    2011-01-01

    Background: We investigated the relationship between low mood and challenging behaviour in people in the severe and profound range of intellectual disability, while controlling for the presence of potentially confounding variables such as diagnosis of autism, physical and sensory problems and ill health. Methods: The key workers of 52 people with…

  9. Implementing AAC with Children with Profound and Multiple Learning Disabilities: A Study in Rationale Underpinning Intervention

    ERIC Educational Resources Information Center

    Harding, Celia; Lindsay, Gemma; O'Brien, Aoife; Dipper, Lucy; Wright, Julie

    2011-01-01

    There is a developing research base to support the rationale underpinning augmentative and alternative communication (AAC) for people with learning disabilities. However, there is a paucity of research examining the process involved in implementing AAC support for people who have profound disabilities. This paper seeks to explore the processes…

  10. Sensory Reinforcement of Head Turning with Nonambulatory, Profoundly Mentally Retarded Persons.

    ERIC Educational Resources Information Center

    Dewson, Michael R. J.; Whiteley, John H.

    1987-01-01

    Two experiments examined the reinforcing value of response contingent sensory events consisting of combinations of visual, auditory, and vibratory stimulation with 10 nonambulatory profoundly mentally retarded individuals. Results indicated that systematically varying a multimodal sensory event is an effective way to identify positive reinforcers…

  11. A Data Based Multidimensional Oral Hygiene Curriculum for the Severely and Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Feldman, David; Elliott, Thomas A.

    A multidimensional oral hygiene curriculum appropriate for the moderately to profoundly retarded and composed of tooth brushing, flossing, and gum stimulation/massage is proposed. Task analyses are included for manual tooth brushing, utilizing an oral irrigation appliance, manual flossing, and use of an adaptive aid for flossing. Also provided are…

  12. Behavioural and Emotional Problems in People with Severe and Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Forster, S.; Gray, K. M.; Taffe, J.; Einfeld, S. L.; Tonge, B. J.

    2011-01-01

    Background: People with severe and profound levels of intellectual disability (ID) are frequently examined as a single group in research. However, these two groups may be significantly different, particularly in the area of emotional and behavioural difficulties. Method: The Developmental Behaviour Checklist (DBC) was completed by parents and…

  13. A Data Based Multidimensional Oral Hygiene Curriculum for the Severely and Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Feldman, David; Elliott, Thomas A.

    A multidimensional oral hygiene curriculum appropriate for the moderately to profoundly retarded and composed of tooth brushing, flossing, and gum stimulation/massage is proposed. Task analyses are included for manual tooth brushing, utilizing an oral irrigation appliance, manual flossing, and use of an adaptive aid for flossing. Also provided are…

  14. School-Wide Positive Behavior Support for Individuals with Severe and Profound Disabilities

    ERIC Educational Resources Information Center

    Judge, Brittany A.

    2015-01-01

    One of the greatest challenges for alternative schools is to develop effective training programs for students with severe and profound developmental disabilities. School-wide positive behavior support (SWPBS) has been shown to decrease problematic behaviors in alternative schools and self-contained settings yet little is known about how effective…

  15. Visual Impairments in People with Severe and Profound Multiple Disabilities: An Inventory of Visual Functioning

    ERIC Educational Resources Information Center

    van den Broek, Ellen G. C.; Janssen, C. G. C.; van Ramshorst, T.; Deen, L.

    2006-01-01

    Background: The prevalence of visual impairments in people with severe and profound multiple disabilities (SPMD) is the subject of considerable debate and is difficult to assess. Methods: In a typical Dutch care organization, all clients with SPMD (n = 76) participated in the study and specific instruments adapted to these clients (requiring a…

  16. Day Services for People with Profound Intellectual and Multiple Disabilities: An Analysis of Thematically Organized Activities

    ERIC Educational Resources Information Center

    van der Putten, Annette; Vlaskamp, Carla

    2011-01-01

    One of the recent ideas to emerge in the Netherlands for improving the quality of activities provided for people with profound intellectual and multiple disabilities is to organize these activities thematically. Among the expected effects was that more activities with a greater variety would be provided and more attention would be offered to each…

  17. The Influence of Phonological Mechanisms in Written Spelling of Profoundly Deaf Children

    ERIC Educational Resources Information Center

    Colombo, Lucia; Arfe, Barbara; Bronte, Tiziana

    2012-01-01

    In the present study, the effect of phonological and working memory mechanisms involved in spelling Italian single words was explored in two groups of children matched for grade level: a group of normally hearing children and a group of pre-verbally deaf children, with severe-to-profound hearing loss. Three-syllable and four-syllable familiar…

  18. The Role of Attention in the Affective Life of People with Severe or Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Vos, Pieter; De Cock, Paul; Munde, Vera; Neerinckx, Heleen; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2013-01-01

    Although it is shown that attention plays an important role both in the onset and in the regulation of emotions in people without disabilities there is no information about how attention is related to emotions in people with severe or profound intellectual disability (ID). Therefore, in our study, we investigated the role of attention in the onset…

  19. Assessing the Balance Capabilities of People with Profound Intellectual Disabilities Who Have Experienced a Fall

    ERIC Educational Resources Information Center

    Hale, L.; Bray, A.; Littmann, A.

    2007-01-01

    Background: Although it is common for people with intellectual disability (ID) to fall, the reasons for this have not yet been identified. This pilot study aimed to explore the balance capabilities of a sample of adults with profound ID who had experienced a fall, in order to identify possible reasons for falling and to identify potential tests…

  20. The Influence of Computer Games on Visual-Motor Integration in Profoundly Deaf Children

    ERIC Educational Resources Information Center

    Radovanovic, Vesna

    2013-01-01

    The purpose of this research was to examine the influence of specialised software on the visual-motor integration of profoundly deaf children. The research sample was made up of 70 students aged from seven to 10, 43 of whom formed the experimental group and 27 the control group. The students in the experimental group used computers once a week…

  1. The Curriculum for Children with Severe and Profound Learning Difficulties at Stephen Hawking School

    ERIC Educational Resources Information Center

    Rayner, Matthew

    2011-01-01

    The increasing number of children with profound and multiple learning difficulties means that many schools for children with severe learning difficulties are having to review the curriculum that they offer. In addition, these schools are continuing to question whether a subject-based approach, in line with the National Curriculum, is the most…

  2. Using Environmental Design to Teach Ward Layout to Severely and Profoundly Retarded Blind Persons: A Proposal

    ERIC Educational Resources Information Center

    McGlinchey, Maureen A.; Mitala, Ronald F.

    1975-01-01

    A team of behavior modification specialists observed the self-care behavior of 30 severely and profoundly retarded blind men (22-to 51-years-old) in a state institution prior to implementing training programs in basic self-care skills. (LH)

  3. Bereavement and Loss: Developing a Memory Box to Support a Young Woman with Profound Learning Disabilities

    ERIC Educational Resources Information Center

    Young, Hannah; Garrard, Brenda

    2016-01-01

    Supporting bereaved people with profound learning disabilities still remains an under-researched area. Moreover, the barriers of communication and disenfranchised grief mean that they often do not receive the support they require, leading to emotional and behavioural difficulties. This article describes research using a case study design, which…

  4. A Sensorial Approach to Art: Pre-Art Discovery with Severely and Profoundly Impaired Children.

    ERIC Educational Resources Information Center

    Lonker, Sherrie

    The booklet presents an art therapist's thoughts on contributions of art therapy to the development of severely and profoundly impaired students. She emphasizes the importance of sensory exploration as an introduction to the child's environment. Also stressed is the importance of positive and accepting attitudes on the part of teachers or…

  5. Speech Timing and Working Memory in Profoundly Deaf Children after Cochlear Implantation.

    ERIC Educational Resources Information Center

    Burkholder, Rose A.; Pisoni, David B.

    2003-01-01

    Compared speaking rates, digit span, and speech timing in profoundly deaf 8- and 9-year-olds with cochlear implants and normal-hearing children. Found that deaf children displayed longer sentence durations and pauses during recall and shorter digit spans than normal-hearing children. Articulation rates strongly correlated with immediate memory…

  6. Implementing AAC with Children with Profound and Multiple Learning Disabilities: A Study in Rationale Underpinning Intervention

    ERIC Educational Resources Information Center

    Harding, Celia; Lindsay, Gemma; O'Brien, Aoife; Dipper, Lucy; Wright, Julie

    2011-01-01

    There is a developing research base to support the rationale underpinning augmentative and alternative communication (AAC) for people with learning disabilities. However, there is a paucity of research examining the process involved in implementing AAC support for people who have profound disabilities. This paper seeks to explore the processes…

  7. Assistive Technology Programming for a Young Child with Profound Disabilities: A Single-Subject Study

    ERIC Educational Resources Information Center

    Shull, Jennifer; Deitz, Jean; Billingsley, Felix; Wendel, Sue; Kartin, Deborah

    2004-01-01

    Background and Purpose: The purpose of this study was to use single-subject research methods, combined with social validation procedures, as part of an evaluation/intervention process exploring the effects of adapted switch-operated devices on self-initiated behaviors of a 6-year-old child with profound multiple disabilities. Method: A…

  8. Communication Options for Persons with Severe and Profound Disabilities: State of the Art and Future Directions.

    ERIC Educational Resources Information Center

    Mirenda, Pat; And Others

    1990-01-01

    The paper reviews literature on communication augmentation for individuals with severe/profound intellectual disabilities, within the framework of the "Participation Model." The discussion covers communication opportunity, communication access, strategies for facilitating the use of natural speech, overview of unaided and aided…

  9. A Functionally Focused Curriculum for Children with Profound Multiple Disabilities: A Goal Analysis

    ERIC Educational Resources Information Center

    van der Putten, Annette; Reynders, Koop; Vlaskamp, Carla; Nakken, Han

    2004-01-01

    Background: This study analysed goals formulated in a functionally focused curriculum called Mobility Opportunities Via Education[TM] (MOVE). Method: The subjects were 49 children with profound multiple disabilities (PMD) who attended a centre for special education where the MOVE curriculum was implemented. Each goal was analysed to see whether or…

  10. The Curriculum for Children with Severe and Profound Learning Difficulties at Stephen Hawking School

    ERIC Educational Resources Information Center

    Rayner, Matthew

    2011-01-01

    The increasing number of children with profound and multiple learning difficulties means that many schools for children with severe learning difficulties are having to review the curriculum that they offer. In addition, these schools are continuing to question whether a subject-based approach, in line with the National Curriculum, is the most…

  11. Habituation and Generalization of Habituation by Nonambulatory, Profoundly Mentally Retarded Children.

    ERIC Educational Resources Information Center

    Kelman, William P.; Whiteley, John H.

    1986-01-01

    Generalization of habituation along a form dimension was investigated with 12 nonambulatory, profoundly mentally retarded children. Fixation times decreased over habituation trials and increased during test trials. No differences in fixation times to test stimuli were found in the group data, and analyses of individual subject data indicated that…

  12. Understanding the Diverse Literacy Needs of Profoundly Deaf Sign-Dominant Adults in Australia

    ERIC Educational Resources Information Center

    Furlonger, Brett; Rickards, Field

    2011-01-01

    This review explores the literacy difficulties experienced by prelingual, profoundly deaf, sign-dominant adults. A critical overview of the existing literature identifies the importance of understanding their language experiences and word-coding preferences. Findings challenge the notion that a permanent lack of audition from birth prevents…

  13. Constructing Adulthood in Discussions about the Futures of Young People with Moderate-Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Murphy, Elizabeth; Clegg, Jennifer; Almack, Kathryn

    2011-01-01

    Background: This study examines how those planning futures for young people with moderate-profound intellectual disabilities invoke, deploy and interpret contrasting definitions of adulthood and perceived capacity for autonomy and self-determination. Methods: Twenty-eight young people were followed through transition from children: s to adult…

  14. The Effects of Skill Training on Preference for Individuals with Severe to Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Dutt, Anuradha Salil Kumar

    2010-01-01

    Behavioral researchers have investigated procedures for identifying preferred items for individuals with varying levels of developmental disabilities. Some researchers in this area have reported difficulties in identifying preferred items for individuals with severe to profound multiple disabilities (SPMD), in part because the individuals may not…

  15. A Need for a Taxonomy for Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Nakken, H.; Vlaskamp, C.

    2007-01-01

    There is extensive discussion on the quality of education and support for individuals with profound intellectual and multiple disabilities (PIMD) in relation to inclusion and full citizenship. The discussions are complicated because of differences or lack of clarity in the description of the variations and types of PIMD. A description of the core…

  16. An Investigation of First-Order False Belief Understanding of Children with Congenital Profound Visual Impairment

    ERIC Educational Resources Information Center

    Green, Sarah; Pring, Linda; Swettenham, John

    2004-01-01

    This study assessed theory of mind understanding in children with congenital profound visual impairment (CPVI): children who have had no access to visual information throughout development. Participants were 18 children with CPVI and no other impairments, aged between 5 and 11 years, and 18 children with normal vision, matched individually on…

  17. Supporting Lifelong Learning for People with Profound and Multiple Learning Difficulties

    ERIC Educational Resources Information Center

    Nind, Melanie

    2007-01-01

    This article addresses the issue of supporting lifelong learning for individuals with profound and multiple learning difficulties. Lifelong learning is usually a more mainstream concept and is rarely applied to this marginalized group for whom learning "per se" is such a challenge. The paper debates whether the concept is a useful one, and what…

  18. Peer Interactions among Children with Profound Intellectual and Multiple Disabilities during Group Activities

    ERIC Educational Resources Information Center

    Nijs, Sara; Penne, Anneleen; Vlaskamp, Carla; Maes, Bea

    2016-01-01

    Background: Children with profound intellectual and multiple disabilities (PIMD) meet other children with PIMD in day care centres or schools. This study explores the peer-directed behaviours of children with PIMD, the peer interaction-influencing behaviour of the direct support workers and the children's positioning. Method: Group activities for…

  19. Systematic Dyskinesia Examination of Profoundly Mentally Retarded Persons: Cooperation and Assessment.

    ERIC Educational Resources Information Center

    Granger, Douglas A.; And Others

    1987-01-01

    Dyskinesia, abnormal involuntary movements associated with long-term neuroleptic drug use, was evaluated with 344 institutionalized profoundly mentally retarded adults using the Dyskinesia Identification System Condensed User Scale. Results indicated performance deficits on activation tasks associated with intelligence quotients, neuroleptic…

  20. Low Mood and Challenging Behaviour in People with Severe and Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Hayes, S.; McGuire, B.; O'Neill, M.; Oliver, C.; Morrison, T.

    2011-01-01

    Background: We investigated the relationship between low mood and challenging behaviour in people in the severe and profound range of intellectual disability, while controlling for the presence of potentially confounding variables such as diagnosis of autism, physical and sensory problems and ill health. Methods: The key workers of 52 people with…

  1. Normality and Impairment following Profound Early Institutional Deprivation: A Longitudinal follow-up into Early Adolescence

    ERIC Educational Resources Information Center

    Kreppner, Jana M.; Rutter, Michael; Beckett, Celia; Castle, Jenny; Colvert, Emma; Groothues, Christine; Hawkins, Amanda; O'Connor, Thomas G.; Stevens, Suzanne; Sonuga-Barke, Edmund J. S.

    2007-01-01

    Longitudinal analyses on normal versus impaired functioning across 7 domains were conducted in children who had experienced profound institutional deprivation up to the age of 42 months and were adopted from Romania into U.K. families. Comparisons were made with noninstitutionalized children adopted from Romania and with nondeprived within-U.K.…

  2. Assessing the Efficacy of an Academic Hearing Peer Tutor for a Profoundly Deaf Student.

    ERIC Educational Resources Information Center

    Burley, Suzanne; And Others

    1994-01-01

    Evaluation of using a hearing peer tutor to provide daily 20-minute math instruction for a profoundly deaf sixth-grade girl indicated that the peer tutoring intervention was highly successful, with the tutee meeting accuracy criteria for each of 4 curriculum objectives after only a brief period of intervention. (Author/DB)

  3. Investigating the Relationship between Observed Mood and Emotions in People with Severe and Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Vos, P.; De Cock, P.; Petry, K.; Van Den Noortgate, W.; Maes, B.

    2013-01-01

    Background: The measurement of subjective well-being in people with severe and profound intellectual disabilities (ID) is a difficult challenge. As they cannot self-report about their life satisfaction, because of severe communicative and cognitive limitations, behavioural observations of their emotions and moods are important in the measurement…

  4. Interaction between Persons with Profound Intellectual and Multiple Disabilities and Their Partners: A Literature Review

    ERIC Educational Resources Information Center

    Hostyn, Ine; Maes, Bea

    2009-01-01

    Background: High quality interactions are of crucial importance for quality of life of persons with profound intellectual and multiple disabilities (PIMD). This literature review describes and synthesises studies addressing the interaction between persons with PIMD and their partners. Method: A computerised literature search using defined…

  5. Let's Get Fit!: Fitness Activities for Children with Severe/Profound Disabilities.

    ERIC Educational Resources Information Center

    Modell, Scott J.; Cox, Thomas Alan

    1999-01-01

    Guidelines for developing a physical activity program for students with severe/profound disabilities address medical clearance; levels of participation; staffing; equipment; and program components, including warm-up, range of motion/flexibility activities, aerobics, resistance training, and cool-down. (DB)

  6. Phonological Decoding in Severely and Profoundly Deaf Children: Similarity Judgment between Written Pseudowords.

    ERIC Educational Resources Information Center

    Transler, C.; Gombert, J. E.; Leybaert, J.

    2001-01-01

    Examined whether phonological decoding could be observed among severely and profoundly deaf children during reading. The ability of 20 deaf children to detect phonological similarities between three written pseudo words was investigated. Results suggest a link between sensitivity to phonology in written language and speech skills. Implications of…

  7. Social Peer Interactions in Persons with Profound Intellectual and Multiple Disabilities: A Literature Review

    ERIC Educational Resources Information Center

    Nijs, Sara; Maes, Bea

    2014-01-01

    Social interactions may positively influence developmental and quality of life outcomes. Research in persons with profound intellectual and multiple disabilities (PIMD) mostly investigated interactions with caregivers. This literature review focuses on peer interactions of persons with PIMD. A computerized literature search of three databases was…

  8. The Ambiguities of Out-of-Home Care: Children with Severe or Profound Disabilities

    ERIC Educational Resources Information Center

    Roper, Susanne Olsen; Jackson, Jeffrey B.

    2007-01-01

    Ambiguous loss and boundary ambiguity experienced by families during the process of placing their child in out-of-home care was described by parents in 20 families raising a child with severe or profound developmental disabilities. In retrospective interviews, parents discussed their experiences before and after placing their child and how they…

  9. The Structure of Informal Social Networks of Persons with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Kamstra, A.; van der Putten, A. A. J.; Vlaskamp, C.

    2015-01-01

    Background: Persons with less severe disabilities are able to express their needs and show initiatives in social contacts, persons with profound intellectual and multiple disabilities (PIMD), however, depend on others for this. This study analysed the structure of informal networks of persons with PIMD. Materials and Methods: Data concerning the…

  10. Intraclassroom Comparison of Two Arrangements for Teaching Profoundly Mentally Retarded Children.

    ERIC Educational Resources Information Center

    Westling, David L.; And Others

    1982-01-01

    A one-to-one instructional arrangement appeared superior to a small group arrangement with nine profoundly mentally retarded students (3 to 9 years old) in terms of teacher on-task time and frequency of instructor turnaways per instructional minute. (CL)

  11. A Preliminary Evaluation of Training Parents to Use Facilitative Strategies with Their Children with Profound Disabilities.

    ERIC Educational Resources Information Center

    Fox, Lise; Westling, David

    1991-01-01

    This article describes an intervention in which three parents were taught to use facilitative strategies when interacting with their children with profound mental retardation. The intervention consisted of reinforcing appropriate parent behavior as it was being observed by them on prerecorded videotapes. Facilitative strategies included the use of…

  12. Competencies for Teachers of the Severely and Profoundly Handicapped. A Review.

    ERIC Educational Resources Information Center

    Whitten, Thomas M.; Westling, David L.

    1985-01-01

    A search of the literature of the past 10 years identified 59 competency statements for teachers of severely and profoundly handicapped students. Competencies fell into nine categories: general knowledge, planning, assessment, curriculum, behavior management, instruction, physical/medical, other personnel, and parents. Overwhelmingly, the…

  13. The Effects of Stimulus Modification on Putting Accuracy for Adults with Severe or Profound Mental Retardation.

    ERIC Educational Resources Information Center

    Bolton, Jenifer L.; And Others

    1994-01-01

    This study found that, following a systematic fading of putting guides, three adults with severe/profound mental retardation increased accuracy in making putts during posttraining assessments on a practice green. Results also maintained at, or increased above, posttraining levels at a two-week maintenance check and were generalized to a local golf…

  14. Developing Co-Active Imitative Behaviors with Profoundly Mentally Handicapped Students.

    ERIC Educational Resources Information Center

    Sternberg, Les; And Others

    1985-01-01

    The study examining effectiveness of prelanguage communication programming techniques on the development of imitative behaviors of three profoundly mentally handicapped students (10-21 years old) indicated that the procedures were effective and that the imitative behaviors generalized to other individuals. (Author/CL)

  15. Empirical Approach to Psychopharmacology for Institutionalized Individuals with Severe or Profound Mental Retardation.

    ERIC Educational Resources Information Center

    Bishop, Andrew C.

    1992-01-01

    A six-point program of diagnostic inquiry and treatment strategy for individuals with behavior disorders in addition to severe or profound mental retardation is presented, which allows alternate etiological hypotheses to be tested in a clinical setting. This format is intended to unify psychopharmacy practice in mental retardation and in general…

  16. Alertness in Individuals with Profound Intellectual and Multiple Disabilities: A Literature Review

    ERIC Educational Resources Information Center

    Munde, V. S.; Vlaskamp, C.; Ruijssenaars, A. J. J. M.; Nakken, H.

    2009-01-01

    Direct support persons (DSPs) often face problems in observing and determining alertness in individuals with profound intellectual and multiple disabilities (PIMD). A literature study was carried out to gather information about the problems just described. A search of two electronic databases and the references found in relevant hits revealed 42…

  17. Individual Focus in an Activity Centre: An Observational Study among Persons with Profound and Multiple Disabilities

    ERIC Educational Resources Information Center

    Hiemstra, S. J.; Vlaskamp, C.; Wiersma, L. A.

    2007-01-01

    Increasing numbers of adults with profound intellectual and multiple disabilities (PIMD) are being offered more--and more frequent--day services at activity centres. Little is known about the way direct support persons (DSP) in activity centres divide their time over the various tasks they have to perform and to what extent they are focused on…

  18. Intellectual Prosthesis: Reality or Dream for the Severely/Profoundly Retarded Person.

    ERIC Educational Resources Information Center

    Lent, James R.

    1982-01-01

    Developments in artificial intelligence have relevance for the education of severely/profoundly retarded persons by enhancing the learning of facts, principles, skills and concepts and by providing opportunities (via more portable equipment) for applications in a wide variety of settings. (CL)

  19. A Review of Biobehavioral State Assessment of Individuals with Profound Disabilities

    ERIC Educational Resources Information Center

    Richards, Stephen B.; Taylor, Ronald L.

    2005-01-01

    Assessment of individuals with profound disabilities is problematic, particularly when traditional approaches are used. As a result, alternate assessments have been attempted that better suit the needs of these students. One approach that has shown some promise is biobehavioral state assessment. Initially used with infants without disabilities,…

  20. Attuning: A Communication Process between People with Severe and Profound Intellectual Disability and Their Interaction Partners

    ERIC Educational Resources Information Center

    Griffiths, Colin; Smith, Martine

    2016-01-01

    Background: People with severe and profound intellectual disability typically demonstrate a limited ability to communicate effectively. Most of their communications are non-verbal, often idiosyncratic and ambiguous. This article aims to identify the process that regulates communications of this group of people with others and to describe the…

  1. The Effects of Governing Board Configuration on Profound Organizational Change in Hospitals

    ERIC Educational Resources Information Center

    Alexander, Jeffrey A.; Ye, Yining; Lee, Shoou-Yih D.; Weiner, Bryan J.

    2006-01-01

    This study extends the literature on governing boards and organizational change by examining how governing board configurations have influenced profound organizational change in U.S. hospitals, and the conditions under which such change occurs. Hospitals governed by boards that more closely resembled a corporate governance model were more likely…

  2. The Influence of Phonological Mechanisms in Written Spelling of Profoundly Deaf Children

    ERIC Educational Resources Information Center

    Colombo, Lucia; Arfe, Barbara; Bronte, Tiziana

    2012-01-01

    In the present study, the effect of phonological and working memory mechanisms involved in spelling Italian single words was explored in two groups of children matched for grade level: a group of normally hearing children and a group of pre-verbally deaf children, with severe-to-profound hearing loss. Three-syllable and four-syllable familiar…

  3. Teaching Adults with Severe and Profound Retardation to Exit Their Homes upon Hearing the Fire Alarm.

    ERIC Educational Resources Information Center

    Bannerman, Diane J.; And Others

    1991-01-01

    Prompting, modeling, and differential reinforcement were used to teach three nonverbal adults with severe to profound mental retardation to exit their group homes at the sound of the house fire alarm. All three learned to exit independently in less than two minutes in all or the majority of surprise fire drills. (Author/JDD)

  4. Interobserver Reliability Using the Phonetic Level Evaluation with Severely and Profoundly Hearing-Impaired Children.

    ERIC Educational Resources Information Center

    Shaw, Stephanie; Coggins, Truman E.

    1991-01-01

    This study, involving five experienced and trained speech language pathologists, categorized the elicited imitations of five profoundly and five severely prelingually hearing-impaired subjects using the Phonetic Level Evaluation. Failure to obtain acceptably high levels of reliability suggests that this measure may not yet be an accurate and…

  5. The Role of Attention in the Affective Life of People with Severe or Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Vos, Pieter; De Cock, Paul; Munde, Vera; Neerinckx, Heleen; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2013-01-01

    Although it is shown that attention plays an important role both in the onset and in the regulation of emotions in people without disabilities there is no information about how attention is related to emotions in people with severe or profound intellectual disability (ID). Therefore, in our study, we investigated the role of attention in the onset…

  6. Attentional Processes in Interactions between People with Profound Intellectual and Multiple Disabilities and Direct Support Staff

    ERIC Educational Resources Information Center

    Ine, Hostyn; Heleen, Neerinckx; Bea, Maes

    2011-01-01

    Few studies have examined joint attention in interactions with persons with profound intellectual and multiple disabilities (PIMD), despite its important role in high-quality interaction. The purpose of this study is to describe the attention-directing behaviours of persons with PIMD and their direct support staff and the attention episodes…

  7. Social Peer Interactions in Persons with Profound Intellectual and Multiple Disabilities: A Literature Review

    ERIC Educational Resources Information Center

    Nijs, Sara; Maes, Bea

    2014-01-01

    Social interactions may positively influence developmental and quality of life outcomes. Research in persons with profound intellectual and multiple disabilities (PIMD) mostly investigated interactions with caregivers. This literature review focuses on peer interactions of persons with PIMD. A computerized literature search of three databases was…

  8. Profound Hypotension after an Intradermal Injection of Indigo Carmine for Sentinel Node Mapping

    PubMed Central

    Jo, Youn Yi; Lee, Mi Geum; Yun, Soon Young

    2013-01-01

    Intradermal injections of indigo carmine for sentinel node mapping are considered safe and no report of an adverse reaction has been published. The authors described two cases of profound hypotension in women that underwent breast-conserving surgery after an intradermal injection of indigo carmine into the periareolar area for sentinel node mapping. PMID:23593094

  9. Profound hypotension after an intradermal injection of indigo carmine for sentinel node mapping.

    PubMed

    Jo, Youn Yi; Lee, Mi Geum; Yun, Soon Young; Lee, Kyung Cheon

    2013-03-01

    Intradermal injections of indigo carmine for sentinel node mapping are considered safe and no report of an adverse reaction has been published. The authors described two cases of profound hypotension in women that underwent breast-conserving surgery after an intradermal injection of indigo carmine into the periareolar area for sentinel node mapping.

  10. Bereavement and Loss: Developing a Memory Box to Support a Young Woman with Profound Learning Disabilities

    ERIC Educational Resources Information Center

    Young, Hannah; Garrard, Brenda

    2016-01-01

    Supporting bereaved people with profound learning disabilities still remains an under-researched area. Moreover, the barriers of communication and disenfranchised grief mean that they often do not receive the support they require, leading to emotional and behavioural difficulties. This article describes research using a case study design, which…

  11. Disability Support Workers' Experience of Interaction with a Person with Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Forster, Sheridan; Iacono, Teresa

    2008-01-01

    Background: The primary communication partner for many people with profound intellectual disability (PID) who are living in supported accommodation is their disability support worker (DSW). The experiences of DSWs in interacting with people with PID have received limited attention in the literature. Method: The nature of interactions between…

  12. Visual Preferences of Students with Profound Mental Retardation and Healthy, Full-Term Infants.

    ERIC Educational Resources Information Center

    Buhrow, Melissa; Bradley-Johnson, Sharon

    2003-01-01

    Thirty students (ages 3-20) with profound mental retardation and 30 healthy, full-term infants (5-8 months) were shown 12 patterned stimuli, three times each. Both groups looked significantly longer at face patterns than other patterns. However, the students with mental retardation looked longer at black and white patterns than colored patterns,…

  13. A Review of Research on the Educability of Profoundly Retarded Persons.

    ERIC Educational Resources Information Center

    Stainback, William; Stainback, Susan

    1983-01-01

    Research evidence regarding the educability of profoundly retarded persons is reviewed. Attention is focused on five areas of research: the development of motor skills, self-help skill training, social and communication behavior development, the reduction of severe maladaptive behaviors, and the impact of environmental factors on learning. (SEW)

  14. Habilitation of the Severely and Profoundly Retarded: Volume III. Reports from the Specialized Training Program.

    ERIC Educational Resources Information Center

    Horner, Robert H., Ed.; Bellamy, G. Thomas, Ed.

    Sixteen papers concerned with vocational habilitation of the severely and profoundly retarded are organized into three parts: issues in habilitation, stimulus control of vocational behavior, and instrumentation for program evaluation. Papers have the following titles and authors: "Structured Employment: Productivity and Productive Capacity" (R.…

  15. The Prevalence and Characteristics of Tinnitus with Profound Sensori-Neural Hearing Impairment.

    ERIC Educational Resources Information Center

    Drukier, Gale S.

    1989-01-01

    Of 331 children (aged 6-18) with profound hearing impairment, 96 were found to have tinnitus. More females than males reported tinnitus. Most of the children with tinnitus were bothered to some degree by it and indicated that the noises adversely affected their ability to hear voices. (JDD)

  16. The Impact of Medical Conditions on the Support of Children with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Zijlstra, H. P.; Vlaskamp, C.

    2005-01-01

    Background: The aim of this study was to analyse the impact of medical conditions of children with profound intellectual and multiple disabilities on the professional support they receive in centres for special education. Method: The medical files, the daily records and daily communication records between parents and professionals were reviewed…

  17. Visual Impairments in People with Severe and Profound Multiple Disabilities: An Inventory of Visual Functioning

    ERIC Educational Resources Information Center

    van den Broek, Ellen G. C.; Janssen, C. G. C.; van Ramshorst, T.; Deen, L.

    2006-01-01

    Background: The prevalence of visual impairments in people with severe and profound multiple disabilities (SPMD) is the subject of considerable debate and is difficult to assess. Methods: In a typical Dutch care organization, all clients with SPMD (n = 76) participated in the study and specific instruments adapted to these clients (requiring a…

  18. Peer Interactions among Children with Profound Intellectual and Multiple Disabilities during Group Activities

    ERIC Educational Resources Information Center

    Nijs, Sara; Penne, Anneleen; Vlaskamp, Carla; Maes, Bea

    2016-01-01

    Background: Children with profound intellectual and multiple disabilities (PIMD) meet other children with PIMD in day care centres or schools. This study explores the peer-directed behaviours of children with PIMD, the peer interaction-influencing behaviour of the direct support workers and the children's positioning. Method: Group activities for…

  19. Assessing the Balance Capabilities of People with Profound Intellectual Disabilities Who Have Experienced a Fall

    ERIC Educational Resources Information Center

    Hale, L.; Bray, A.; Littmann, A.

    2007-01-01

    Background: Although it is common for people with intellectual disability (ID) to fall, the reasons for this have not yet been identified. This pilot study aimed to explore the balance capabilities of a sample of adults with profound ID who had experienced a fall, in order to identify possible reasons for falling and to identify potential tests…

  20. Alertness in Individuals with Profound Intellectual and Multiple Disabilities: A Literature Review

    ERIC Educational Resources Information Center

    Munde, V. S.; Vlaskamp, C.; Ruijssenaars, A. J. J. M.; Nakken, H.

    2009-01-01

    Direct support persons (DSPs) often face problems in observing and determining alertness in individuals with profound intellectual and multiple disabilities (PIMD). A literature study was carried out to gather information about the problems just described. A search of two electronic databases and the references found in relevant hits revealed 42…

  1. Individual Focus in an Activity Centre: An Observational Study among Persons with Profound and Multiple Disabilities

    ERIC Educational Resources Information Center

    Hiemstra, S. J.; Vlaskamp, C.; Wiersma, L. A.

    2007-01-01

    Increasing numbers of adults with profound intellectual and multiple disabilities (PIMD) are being offered more--and more frequent--day services at activity centres. Little is known about the way direct support persons (DSP) in activity centres divide their time over the various tasks they have to perform and to what extent they are focused on…

  2. Habilitation of Severely and Profoundly Retarded Adults: Reports from the Specialized Training Program.

    ERIC Educational Resources Information Center

    Bellamy, G. Thomas, Ed.

    Presented are 11 reports resulting from applied research of the Specialized Training Program at the University of Oregon, a subcontract workshop for 15 severely and profoundly retarded adults which focuses on the areas of vocational potential and community program development. Entries include the following titles and authors: "Habilitation of the…

  3. A Preliminary Investigation of the Suitability of Aquatics for People with Severe and Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Aherne, Cian; Coughlan, Barry

    2017-01-01

    Background: Aquatics is an under-researched but possibly appropriate form of activity for people with severe to profound intellectual disabilities (SPIDs). Aim: The current pilot study investigates the suitability of an aquatics programme for service users with SPIDs. Method: Four service users with SPID completed an 8-12-session aquatics…

  4. The Structure of Informal Social Networks of Persons with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Kamstra, A.; van der Putten, A. A. J.; Vlaskamp, C.

    2015-01-01

    Background: Persons with less severe disabilities are able to express their needs and show initiatives in social contacts, persons with profound intellectual and multiple disabilities (PIMD), however, depend on others for this. This study analysed the structure of informal networks of persons with PIMD. Materials and Methods: Data concerning the…

  5. Group vs. Individual Training on a Self-Help Skill with the Profoundly Retarded.

    ERIC Educational Resources Information Center

    Elium, Michael D.; McCarver, Ronald B.

    The study compared the results of group and individual training methods on the acquisition of a roll-on-deodorant self care skill by 16 profoundly retarded adults residing at a residential institution for the mentally retarded. The deodorant skill was divided into 11 teaching steps and an initial performance baseline was obtained for each subject.…

  6. A Sensorial Approach to Art: Pre-Art Discovery with Severely and Profoundly Impaired Children.

    ERIC Educational Resources Information Center

    Lonker, Sherrie

    The booklet presents an art therapist's thoughts on contributions of art therapy to the development of severely and profoundly impaired students. She emphasizes the importance of sensory exploration as an introduction to the child's environment. Also stressed is the importance of positive and accepting attitudes on the part of teachers or…

  7. Assessment of Language Skills in Young Children with Profound Hearing Loss under Two Years of Age.

    ERIC Educational Resources Information Center

    Nott, Pauline; Cowan, Robert; Brown, P. Margaret; Cowan, Robert

    2003-01-01

    The validity of the Diary of Early Language (Di-EL), a parent report technique, was evaluated with nine children with profound hearing loss using cochlear implants or hearing aids. Lexical data, reported by parents using the Di-EL, agreed with results of the Mac Arthur Communicative Development Inventories and the Rossetti Infant Toddler Language…

  8. The Development of Pragmatic Skills in Children Who Are Severely and Profoundly Deaf

    ERIC Educational Resources Information Center

    Toe, Dianne; Beattie, Rod; Barr, Megan

    2007-01-01

    The present study investigated the conversational skills of a group of 18 children (aged 6 to 16 years) with severe and profound hearing loss. Participants included both hearing aid users and cochlear implant users. All the children relied upon spoken English and were included in regular classroom settings for at least part of each school day.…

  9. Therapy to Improve Pitch in Young Adults with Profound Hearing Loss.

    ERIC Educational Resources Information Center

    Subtelny, Joanne; And Others

    1989-01-01

    A voice training program to improve pitch register was developed for profoundly hearing-impaired young adults. Ten students of the National Technical Institute for the Deaf completed the program; results showed a significant reduction in pitch level, as well as improvement in pitch control and word intelligibility. (Author/JDD)

  10. Assessment of Language Skills in Young Children with Profound Hearing Loss under Two Years of Age.

    ERIC Educational Resources Information Center

    Nott, Pauline; Cowan, Robert; Brown, P. Margaret; Cowan, Robert

    2003-01-01

    The validity of the Diary of Early Language (Di-EL), a parent report technique, was evaluated with nine children with profound hearing loss using cochlear implants or hearing aids. Lexical data, reported by parents using the Di-EL, agreed with results of the Mac Arthur Communicative Development Inventories and the Rossetti Infant Toddler Language…

  11. Day Services for People with Profound Intellectual and Multiple Disabilities: An Analysis of Thematically Organized Activities

    ERIC Educational Resources Information Center

    van der Putten, Annette; Vlaskamp, Carla

    2011-01-01

    One of the recent ideas to emerge in the Netherlands for improving the quality of activities provided for people with profound intellectual and multiple disabilities is to organize these activities thematically. Among the expected effects was that more activities with a greater variety would be provided and more attention would be offered to each…

  12. The Impact of Medical Conditions on the Support of Children with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Zijlstra, H. P.; Vlaskamp, C.

    2005-01-01

    Background: The aim of this study was to analyse the impact of medical conditions of children with profound intellectual and multiple disabilities on the professional support they receive in centres for special education. Method: The medical files, the daily records and daily communication records between parents and professionals were reviewed…

  13. Sensorimotor Functioning and Prelinguistic Communication of Severely and Profoundly Retarded Individuals.

    ERIC Educational Resources Information Center

    Lobato, Debra; And Others

    1981-01-01

    In a study involving 40 institutionalized severely and profoundly retarded children and adolescents, more competent sensorimotor performance was associated with higher frequency of more sophisticated gestural communication, and Ss generally used more complex gestures to communicate in the imperative than in the declarative tasks. (Author/CL)

  14. Interaction, Inclusion and Students with Profound and Multiple Disabilities: Towards an Agenda for Research and Practice

    ERIC Educational Resources Information Center

    Arthur-Kelly, Michael; Foreman, Phil; Bennett, Deone; Pascoe, Sue

    2008-01-01

    The needs of students with profound and multiple disabilities (PMD) have received more attention in the educational research and best practice literature over the past decade, especially in relation to the importance of maximising their social and communicative engagement. However, perhaps as a function of their low incidence rate and resultant…

  15. The Leicestershire Intellectual Disability Tool: A Simple Measure to Identify Moderate to Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Tyrer, Freya; McGrother, Catherine W.; Thorp, Catherine F.; Taub, Nicholas A.; Bhaumik, Sabyasachi; Cicchetti, Domenic V.

    2008-01-01

    Background: It is often useful to ascertain whether adults have moderate to profound intellectual disability (approximate IQ less than 50; developmental age less than 108 months) when deciding whether to refer to specialist or mainstream services. The aim of the present study was to develop a simple measure to estimate moderate to profound…

  16. Intellectual Prosthesis: Reality or Dream for the Severely/Profoundly Retarded Person.

    ERIC Educational Resources Information Center

    Lent, James R.

    1982-01-01

    Developments in artificial intelligence have relevance for the education of severely/profoundly retarded persons by enhancing the learning of facts, principles, skills and concepts and by providing opportunities (via more portable equipment) for applications in a wide variety of settings. (CL)

  17. Teaching Persons with Profound Multiple Handicaps: A Review of the Effects of Behavioral Research.

    ERIC Educational Resources Information Center

    Reid, Dennis H.; And Others

    1991-01-01

    This review of behavioral research on teaching individuals with profound multiple handicaps found that behavior change has resulted from contingency management interventions, but the behavior changes cannot be described as beneficially affecting the individuals' quality of life. Explanations for this are offered, and suggestions for future…

  18. The Influence of Computer Games on Visual-Motor Integration in Profoundly Deaf Children

    ERIC Educational Resources Information Center

    Radovanovic, Vesna

    2013-01-01

    The purpose of this research was to examine the influence of specialised software on the visual-motor integration of profoundly deaf children. The research sample was made up of 70 students aged from seven to 10, 43 of whom formed the experimental group and 27 the control group. The students in the experimental group used computers once a week…

  19. Collaborative IEPs for the Education of Pupils with Profound and Multiple Learning Difficulties

    ERIC Educational Resources Information Center

    Stroggilos, Vasilis; Xanthacou, Yota

    2006-01-01

    Individual educational plans (IEPs) are considered to be more effective when designed and implemented by a multidisciplinary team. This paper deals with the IEP as a collaborative tool for the education of pupils with profound and multiple learning difficulties (PMLD). Ten pupils with PMLD and the people working around them (e.g. teacher, speech…

  20. The Prevalence of Students Who Are Profoundly Mentally Handicapped Receiving Medication in a School District.

    ERIC Educational Resources Information Center

    Fox, Lise; Westling, David L.

    1986-01-01

    A study of the prevalence of and factors (sex, age, race, residence) relating to prescribed medications for profoundly mentally retarded students (N=92) in a Florida school district revealed that 53 percent received medication. Anticonvulsants, prescribed to 44.56 percent of the students, accounted for 74 percent of all medications. (CB)

  1. Ciglitazone ameliorates homocysteine-mediated mitochondrial translocation and matrix metalloproteinase-9 activation in endothelial cells by inducing peroxisome proliferator activated receptor-gamma activity.

    PubMed

    Tyagi, N; Moshal, K S; Sen, U; Lominadze, D; Ovechkin, A V; Tyagi, S C

    2006-12-31

    The activation of peroxisome proliferator activated receptor-gamma (PPARgamma) ameliorates the homocysteine (Hcy)-induced matrix metalloproteinase (MMP) by decreasing reactive oxygen species (ROS) production. However, the mechanism by which Hcy induces ROS generation and MMP activation is unclear. We hypothesize that Hcy increases NADH oxidase (Nox-4) and decreases thioredoxin (Trx). This leads to translocation of Nox-4 into the mitochondria and decrease in Trx. In addition, activation of PPARgamma ameliorates the translocation of Nox-4 into mitochondria and MMP-9 activation. Mouse aortic vascular endothelial cells (MVEC) were cultured in the presence or absence of 100 microM Hcy. The cells were pre-treated with ciglitazone (CZ, 150 microM). Activity of PPARgamma activity was measured by electrophoretic mobility shift assay (EMSA) and antibody super shift assay. In situ generation of ROS was measured using 2,7-dichlorofluorescin (DCF) as a probe. The expression of Nox-4 and Trx were measured by quantitative real-time polymerase chain reaction (Q-RT-PCR). The translocation of Nox-4 was measured by 2-D gel analysis. To determine the levels of Nox-4 and Trx, the mitochondria and cytosol were separated and Western blot analysis was preformed. The MMP-9 activity was measured by gelatin-zymography. The results suggested that CZ activated endothelial PPARgamma in the presence of Hcy. Production of ROS was ameliorated by PPARgamma activation. Expression of Nox-4 was increased, while production of Trx was decreased by Hcy. However, the treatment with CZ normalized the levels of Nox-4 and Trx. Nox-4 was translocated into mitochondria in Hcy-treated endothelial cells. This translocation was associated with decreased production of Trx in mitochondria. The treatment with CZ blocked this translocation and increased Trx levels in mitochondria. Hcy-mediated MMP-9 activity was decreased in cells pre-treated with CZ. These results suggest that Hcy increases NADH oxidase and

  2. Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease.

    PubMed

    Chen, Yingjie; Guo, Haipeng; Xu, Dachun; Xu, Xin; Wang, Huan; Hu, Xinli; Lu, Zhongbing; Kwak, Dongmin; Xu, Yawei; Gunther, Roland; Huo, Yuqing; Weir, E Kenneth

    2012-06-01

    Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a ≤5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response.

  3. [Increasing alcohol-induced osteogenesis of human bone marrow-derived mesenchymal cells using siRNA transient suppression of peroxisome proliferator activated receptor gamma: an in vitro experiment study].

    PubMed

    Zhang, Hui; Cheng, Jing-Qiu; Huang, Qiang; Yang, Jing; Shen, Bin; Zhou, Zong-Ke; Kang, Peng-de; Lian, Yong-Yun; Pei, Fu-Xing

    2008-10-14

    To investigate the potential of small interfering RNA (siRNA) against human peroxisome proliferator activated receptor gamma (PPARgamma) to suppress the adipogenic effect of alcohol on human bone marrow-derived mesenchymal cells (hBMSCs) and increase osteogenesis. hBMSCs collected from joint replacement surgery were cultured, passaged, and transfected with PPARgamma-siRNA by using liposomal-based strategy. Then the cells were maintained in culture and treated with alcohol 50 mmol/L and dexamethasone, an osteogenic inducer, for 24 days. Oil red O staining was used to observe the fat drops in the cells so as to count the number of adipocytes. Histochemistry was performed to detect the protein expression of alkaline phosphatase, osteocalcium, and type 1 collagen on days 24 and 28 after treatment. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of osteoblast-specific transcription factor-2 (Osf2)/core-binding factor alpha subunit 1 (Cbfa1) on day 10. The adipocyte number of the PPARgamma-siRNA group was significantly lower than those of the alcohol-induced group and the controls (adipogenic group, liposomal group, and negative siRNA group) (all P < 0.05). The Calcium nodule formation rate of the PPARgamma-siRNA group was significantly higher than alcohol-induced group and the controls (adipogenic group, liposomal group, and negative siRNA group) (all P < 0.05). PCR and Western blotting showed significantly higher mRNA and protein expression of the human adipocyte-specific markers:Cbfa1, ALP, type 1 collagen, and osteocalcin, than the other groups. The adipogenic effect of alcohol on hBMSCs can be inhibited with a concomitant increase in osteogenesis by using siRNA technique to specific targeted human PPARgamma gene in vitro cell culture systems. PPARgamma-siRNA strategy may be a useful tool for studying the mechanisms of alcohol-induced osteoporosis and provides theoretical basis for its genetic therapy.

  4. PPAR-alpha L162V and PGC-1 G482S gene polymorphisms, but not PPAR-gamma P12A, are associated with alcohol consumption in a Spanish Mediterranean population.

    PubMed

    Francès, F; Verdú, F; Portolés, O; Castelló, A; Sorlí, J V; Guillen, M; Corella, D

    2008-12-01

    Peroxisome Proliferator-Activated Receptors (PPARs) and its co-activators are regulatory elements of the cellular lipid homeostasis and have been associated with feeding behavior modulation. Animal models suggest that these genes may be involved in alcohol consumption regulation. However, no studies in humans exist. Our aim is to estimate the possible association between polymorphisms in the PPAR-alpha, PPAR-gamma and PPAR-gamma co-activator 1A (PGC-1A) genes and alcohol consumption in humans. We have conducted a cross-sectional study between the PPAR-alpha L162V, PPAR-gamma P12A and PGC-1A G482S polymorphisms, and alcohol consumption in a general Mediterranean Spanish population (303 men and 443 women). We have found an association between the L162V polymorphism and alcohol consumption in which, carriers of the V allele were more prevalent among alcohol consumers (19.4% vs. 9.8%; OR 2.69; 95% CI: 1.31-5.54, p=0.007). The G482S polymorphism showed a significantly higher frequency in the group of high alcohol drinkers than in non-high alcohol drinkers (33.4% vs. 20.6%; OR 2.28; 95% CI: 1.07-4.88, p=0.034). Mean alcohol consumption was higher as the number of G alleles increased (GG 8.6+/-12.8 g/day, GS 6.6+/-9.2 g/day, SS 5.6+/-7.8 g/day, p=0.003). These results remained statistically significant after covariate adjustment. PPAR-alpha L162V and PGC-1A G482S polymorphisms are associated with alcohol consumption in the Mediterranean population.

  5. Does Aggressive Phototherapy Increase Mortality while Decreasing Profound Impairment among the Smallest and Sickest Newborns?

    PubMed Central

    Tyson, Jon E; Pedroza, Claudia; Langer, John; Green, Charles; Morris, Brenda; Stevenson, David; Van Meurs, Krisa P.; Oh, William; Phelps, Dale; O’Shea, Michael; McDavid, Georgia E.; Grisby, Cathy; Higgins, Rose

    2013-01-01

    Objective Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT. Study Design ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses. Results Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment. Conclusions Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing. PMID:22652561

  6. PPAR-gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double-blind randomized controlled pilot trial.

    PubMed

    Schmitz, Joy M; Green, Charles E; Hasan, Khader M; Vincent, Jessica; Suchting, Robert; Weaver, Michael F; Moeller, F Gerard; Narayana, Ponnada A; Cunningham, Kathryn A; Dineley, Kelly T; Lane, Scott D

    2017-10-01

    Pioglitazone (PIO), a potent agonist of PPAR-gamma, is a promising candidate treatment for cocaine use disorder (CUD). We tested the effects of PIO on targeted mechanisms relevant to CUD: cocaine craving and brain white matter (WM) integrity. Feasibility, medication compliance and tolerability were evaluated. Two-arm double-blind randomized controlled proof-of-concept pilot trial of PIO or placebo (PLC). Single-site out-patient treatment research clinic in Houston, TX, USA. Thirty treatment-seeking adults, 18 to 60 years old, with CUD. Eighteen participants (8 = PIO; 10 = PLC) completed diffusion tensor imaging (DTI) of WM integrity at pre-/post-treatment. Study medication was dispensed at thrice weekly visits along with once-weekly cognitive behavioral therapy for 12 weeks. Measures of target engagement mechanisms of interest included cocaine craving assessed by the Brief Substance Craving Scale (BSCS), the Obsessive Compulsive Drug Use Scale (OCDUS), a visual analog scale (VAS) and change in WM integrity. Feasibility measures included number completing treatment, medication compliance (riboflavin detection) and tolerability (side effects, serious adverse events). Target engagement change in mechanisms of interest, defined as a ≥ 0.75 Bayesian posterior probability of an interaction existing favoring PIO over PLC, was demonstrated on measures of craving (BSCS, VAS) and WM integrity indexed by fractional anisotropy (FA) values. Outcomes indicated greater decrease in craving and greater increase in FA values in the PIO group. Feasibility was demonstrated by high completion rates among those starting treatment (21/26 = 80%) and medication compliance (≥ 80%). There were no reported serious adverse events for PIO. Compared with placebo, patients receiving pioglitazone show a higher likelihood of reduced cocaine craving and improved brain white matter integrity as a function of time in treatment. Pioglitazone shows good feasibility as a treatment for cocaine

  7. Anti-inflammatory properties of a dual PPARgamma/alpha agonist muraglitazar in in vitro and in vivo models

    PubMed Central

    2013-01-01

    Introduction Peroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia. In addition to their metabolic effects, PPAR isoforms PPARα and PPARγ are also involved in the regulation of immune responses and inflammation. In the present study, we investigated the effects of a dual PPARγ/α agonist muraglitazar on inflammatory gene expression in activated macrophages and on carrageenan-induced inflammation in the mouse. Methods J774 murine macrophages were activated by lipopolysaccharide (LPS) and treated with dual PPARγ/α agonist muraglitazar, PPARγ agonist GW1929 or PPARα agonist fenofibrate. The effects of PPAR agonists on cytokine production and the activation of inducible nitric oxide synthase (iNOS) pathway were investigated by ELISA, Griess method, Western blotting and quantitative RT-PCR. Nuclear translocation, DNA-binding activity and reporter gene assays were used to assess the activity of nuclear factor kappa B (NF-kB) transcription factor. Carrageenan-induced paw oedema was used as an in vivo model of acute inflammation. Results Muraglitazar as well as PPARγ agonist GW1929 and PPARα agonist fenofibrate inhibited LPS-induced iNOS expression and NO production in activated macrophages in a dose-dependent manner. Inhibition of iNOS expression by muraglitazar included both transcriptional and post-transcriptional components; the former being shared by GW1929 and the latter by fenofibrate. All tested PPAR agonists also inhibited IL-6 production, while TNFα production was reduced by muraglitazar and GW1929, but not by fenofibrate. Interestingly, the anti-inflammatory properties of muraglitazar were also translated in vivo. This was evidenced by the finding that muraglitazar inhibited carrageenan-induced paw inflammation in a dose-dependent manner in mice as did iNOS inhibitor L-NIL and anti-inflammatory steroid dexamethasone. Conclusions These results show that muraglitazar has anti

  8. Peroxisome proliferator-activated receptors-alpha and gamma are targets to treat offspring from maternal diet-induced obesity in mice.

    PubMed

    Magliano, D'Angelo Carlo; Bargut, Thereza Cristina Lonzetti; de Carvalho, Simone Nunes; Aguila, Marcia Barbosa; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

    2013-01-01

    The aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma by Bezafibrate (BZ) could attenuate hepatic and white adipose tissue (WAT) abnormalities in male offspring from diet-induced obese dams. C57BL/6 female mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 49% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet) started at 12 weeks of age and was maintained for three weeks. The HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1) in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat. Diet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.

  9. Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

    PubMed Central

    Guasch, Laura; Sala, Esther; Castell-Auví, Anna; Cedó, Lidia; Liedl, Klaus R.; Wolber, Gerhard; Muehlbacher, Markus; Mulero, Miquel; Pinent, Montserrat; Ardévol, Anna; Valls, Cristina; Pujadas, Gerard; Garcia-Vallvé, Santiago

    2012-01-01

    Background Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. Methodology/Principal Findings We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. PMID:23226391

  10. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells.

    PubMed

    Jiang, W G; Redfern, A; Bryce, R P; Mansel, R E

    2000-02-01

    Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells.

  11. Chemerin, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) target gene that promotes mesenchymal stem cell adipogenesis.

    PubMed

    Muruganandan, Shanmugam; Parlee, Sebastian D; Rourke, Jillian L; Ernst, Matthew C; Goralski, Kerry B; Sinal, Christopher J

    2011-07-08

    Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation of chemokine-like receptor 1 (CMKLR1). Herein we report the interaction of peroxisome proliferator-activated receptor γ (PPARγ) and chemerin in the context of adipogenesis. Knockdown of chemerin or CMKLR1 expression or antibody neutralization of secreted chemerin protein arrested adipogenic clonal expansion of bone marrow mesenchymal stem cells (BMSCs) by inducing a loss of G(2)/M cyclins (cyclin A2/B2) but not the G(1)/S cyclin D2. Forced expression of PPARγ in BMSCs did not completely rescue this loss of clonal expansion and adipogenesis following chemerin or CMKLR1 knockdown. However, forced expression and/or activation of PPARγ in BMSCs as well as non-adipogenic cell types such as NIH-3T3 embryonic fibroblasts and MCA38 colon carcinoma cells significantly induced chemerin expression and secretion. Sequence analysis revealed a putative PPARγ response element (PPRE) sequence within the chemerin promoter. This PPRE was able to confer PPARγ responsiveness on a heterologous promoter, and mutation of this sequence abolished activation of the chemerin promoter by PPARγ. Chromatin immunoprecipitation confirmed the direct association of PPARγ with this PPRE. Treatment of mice with rosiglitazone elevated chemerin mRNA levels in adipose tissue and bone marrow coincident with an increase in circulating chemerin levels. Together, these findings support a fundamental role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation as well as a role for PPARγ in regulating chemerin expression.

  12. An analysis of a partial task training strategy for profoundly retarded institutionalized clients.

    PubMed

    Cipani, E

    1985-03-01

    This study investigated the effects of a partial task training strategy on productivity and on-task behavior in three profoundly retarded institutionalized clients in a pre-skills workshop classroom. Partial task training consisted of the presentation of "mini-tasks," with reinforcement for completion of those tasks. Additionally, behavior monitors were used to provide the clients with further positive comments and prompts. The results indicated that this strategy was effective in decreasing high rates of off-task behavior and in substantially increasing the number of pieces completed during the session. However, the effect on other inappropriate behaviors was minimal. This strategy demonstrated that profoundly retarded clients could be taught to increase on-task behavior and productivity in pre-skills workshop classes.

  13. Defining, validating, and increasing indices of happiness among people with profound multiple disabilities.

    PubMed Central

    Green, C W; Reid, D H

    1996-01-01

    In this study we attempted to operationalize, measure, and increase happiness among people with profound disabilities. Happiness indices were defined and observed among 5 individuals. Validation measures indicated that (a) increases in happiness indices were observed when individuals were presented with most preferred stimuli relative to least preferred stimuli, (b) increases in unhappiness indices were observed when they were presented with least preferred relative to most preferred stimuli, and (c) practitioner ratings of participant happiness coincided with observed indices. Subsequently, classroom staff increased happiness indices through presentation and contingent withdrawal of activities. Results suggested that a behavioral approach can enhance happiness as one aspect of quality of life among people with profound disabilities. Research directions are offered that focus on using a behavioral approach to investigate other private events that are important among people with disabilities. PMID:8881345

  14. Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency.

    PubMed

    Ferreira, Patrick; Chan, Alicia; Wolf, Barry

    2017-02-21

    We report a 36-year-old woman who exhibited progressive optic atrophy at 13 years old, then stroke-like episodes and spastic diplegia in her 20s. Biotinidase deficiency was not readily considered in the differential diagnosis, and the definitive diagnosis was not made until pathological variants of the biotinidase gene (BTD) were found by exome sequencing. Profound biotinidase deficiency was confirmed by enzyme analysis. Unfortunately, her symptoms did not resolve or improve with biotin treatment. Biotin therapy is essential for all individuals with profound biotinidase deficiency and for preventing further damage in those who already exhibit irreversible neurological damage. Newborn screening for the disorder would have avoided years of clinical symptoms that now appear to be irreversible with biotin treatment.

  15. Profound suppression of kindled seizures by cysteamine: possible role of somatostatin to kindled seizures.

    PubMed

    Higuchi, T; Sikand, G S; Kato, N; Wada, J A; Friesen, H G

    1983-12-12

    Recently we reported significant increase in immunoreactive somatostatin content in various brain regions of amygdaloid-kindled rats. We report here that acute intraperitoneal administration of cysteamine, an agent reported to deplete brain and gastrointestinal immunoreactive somatostatin content in kindled rats, led to profound suppression of kindled seizures. Purified anti-somatostatin antibody injected intracerebroventricularly also blocked the kindled seizures. The results show that endogenous immunoreactive somatostatin has a role in the development of seizures in amygdaloid kindled rats.

  16. Epidemiology of fractures in people with severe and profound developmental disabilities

    USGS Publications Warehouse

    Glick, N.R.; Fischer, M.H.; Heisey, D.M.; Leverson, G.E.; Mann, D.C.

    2005-01-01

    Fractures are more prevalent among people with severe and profound developmental disabilities than in the general population. In order to characterize the tendency of these people to fracture, and to identify features that may guide the development of preventive strategies, we analyzed fracture epidemiology in people with severe and profound developmental disabilities who lived in a stable environment. Data from a 23-year longitudinal cohort registry of 1434 people with severe and profound developmental disabilities were analyzed to determine the effects of age, gender, mobility, bone fractured, month of fracture, and fracture history upon fracture rates. Eighty-five percent of all fractures involved the extremities. The overall fracture rate increased as mobility increased. In contrast, femoral shaft fracture risk was substantially higher in the least mobile [relative risk (RR), 10.36; 95% confidence interval (CI), 3.29-32.66] compared with the most mobile group. Although the overall fracture rate was not associated with age, the femoral shaft fractures decreased but hand/foot fractures increased with age. Overall fracture risk declined in August and September (RR, 0.70; 95% CI, 0.55-0.89), being especially prominent for tibial/fibular fractures (RR, 0.31; 95% CI, 0.13-0.70). Gender was not a factor in fracture risk. Two primary fracture mechanisms are apparent: one, largely associated with lack of weight-bearing in people with the least mobility, is exemplified by femoral fractures during non-traumatic events as simple as diapering or transfers; the other, probably due to movement- or fall-related trauma, is exemplified by hand/foot fractures in people who ambulate. The fracture experience of people with severe and profound developmental disabilities is unique and, because it differs qualitatively from postmenopausal osteoporosis, may require population-specific methods for assessing risk, for improving bone integrity, and for reduction of falls and accidents

  17. Prognostic factors for profound sudden idiopathic sensorineural hearing loss: a multicenter retrospective study.

    PubMed

    Lee, Ho Yun; Kim, Dong-Kee; Park, Yong-Ho; Cha, Wang Woon; Kim, Geun Jeon; Lee, Seung Hun

    2017-01-01

    The aim of this study was to assess the outcomes of various treatment modalities for profound idiopathic sudden sensorineural hearing loss (ISSNHL) and confirm the prognostic factors. In total, 191 patients were enrolled after a thorough medical chart review of patients diagnosed with unilateral, profound ISSNHL (≥90 dB). Epidemiological profiles, therapeutic regimens, and the results of pure tone audiometry tests were recorded for all patients. Final recovery was assessed according to Siegel's criteria and by comparing the final hearing level of the affected ear with that of the unaffected ear. The mean follow-up duration and the final hearing level were 75 ± 54 days and 77 ± 24 dB, respectively. None of the evaluated prognostic factors were significantly associated with complete recovery (<25 dB). However, improved hearing in both ears, the absence of dizziness, the use of lipo-prostaglandin E1 (lipo-PGE1), and the use of plasma volume expanders were independently associated with a final hearing level of up to 45 dB (p < 0.05). Steroid dose reduction, worse initial hearing, and non-use of lipo-PGE1 increased the possibility of no recovery. Although the efficacy of oral steroid treatment for profound ISSNHL has been questioned, steroid dose reduction was significantly associated with no recovery. Therefore, adequate oral corticosteroid doses should be considered in the absence of contraindications. In addition, the use of lipo-PGE1 and/or a plasma volume expander seems preferable for better recovery, and their use for the management of profound ISSNHL should be considered.

  18. Agreement between whole blood and plasma sodium measurements in profound hyponatremia.

    PubMed

    Geoghegan, Pierce; Koch, Christopher D; Wockenfus, Amy M; Harrison, Andrew M; Dong, Yue; Kashani, Kianoush B; Karon, Brad S

    2015-05-01

    We compared two different methods of whole blood sodium measurement to plasma sodium measurement using samples in the profoundly hyponatremic range (Na < 120 mmol/L). Whole blood pools with a range of low sodium values were generated using combinations and dilutions of pooled electrolyte-balanced lithium heparin samples submitted for arterial blood gas analysis. Each pool was analyzed five times on a Radiometer 827 blood gas analyzer and iSTAT analyzer. Pools were centrifuged to produce plasma, which was analyzed five times on a Roche Cobas c501 chemistry analyzer. An additional 40 fresh (analyzed on day of collection) excess lithium heparin arterial blood gas samples from 36 patients were analyzed on the Radiometer 827, iSTAT, and Cobas c501 as described above. The setting was a tertiary referral center. Blood samples were collected from a combination of patients in the intensive care unit, operating theaters and emergency room. All methods demonstrated excellent precision, even in the profoundly hyponatremic measurement range (Na < 120 mmol/L using a plasma reference method). However, agreement between the methods varied with the degree of hyponatremia. In the profoundly hyponatremic range, Radiometer whole blood sodium values were nearly identical to plasma reference sodium, while iSTAT whole blood sodium showed a consistent positive bias relative to plasma sodium in this range. If whole blood direct sodium measurements are compared with plasma sodium in profoundly hyponatremic patients consideration should be given to the use of Radiometer blood gas analyzers over iSTAT since the latter shows a positive bias relative to a plasma comparative method. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  19. Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.

    PubMed

    Sadleir, Lynette G; Mountier, Emily I; Gill, Deepak; Davis, Suzanne; Joshi, Charuta; DeVile, Catherine; Kurian, Manju A; Mandelstam, Simone; Wirrell, Elaine; Nickels, Katherine C; Murali, Hema R; Carvill, Gemma; Myers, Candace T; Mefford, Heather C; Scheffer, Ingrid E

    2017-09-05

    To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  20. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency.

    PubMed

    Wolf, Barry; Spencer, Robert; Gleason, Tucker

    2002-02-01

    Sensorineural hearing loss occurs in approximately 75% of symptomatic children with profound biotinidase deficiency, which is more common than originally thought. The hearing loss varies in severity and is usually irreversible. The biochemical, genotype, and clinical variations do not correlate with the development of hearing loss. Thus, it is very important to diagnose the disorder early, especially by newborn screening, to prevent the hearing loss.

  1. Localization training results in individuals with unilateral severe to profound hearing loss.

    PubMed

    Firszt, Jill B; Reeder, Ruth M; Dwyer, Noël Y; Burton, Harold; Holden, Laura K

    2015-01-01

    Adults with unilateral hearing loss often demonstrate decreased sound localization ability and report that situations requiring spatial hearing are especially challenging. Few studies have evaluated localization abilities combined with training in this population. The present pilot study examined whether localization of two sound types would improve after training, and explored the relation between localization ability or training benefit and demographic factors. Eleven participants with unilateral severe to profound hearing loss attended five training sessions; localization cues gradually decreased across sessions. Localization ability was assessed pre- and post-training. Assessment stimuli were monosyllabic words and spectral and temporal random spectrogram sounds. Root mean square errors for each participant and stimulus type were used in group and correlation analyses; individual data were examined with ordinary least squares regression. Mean pre-to post-training test results were significantly different for all stimulus types. Among the participants, eight significantly improved following training on at least one localization measure, whereas three did not. Participants with the poorest localization ability improved the most and likewise, those with the best pre-training ability showed the least training benefit. Correlation results suggested that test age, age at onset of severe to profound hearing loss and better ear high frequency audibility may contribute to localization ability. Results support the need for continued investigation of localization training efficacy and consideration of localization training within rehabilitation protocols for individuals with unilateral severe to profound hearing loss. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening.

    PubMed

    Wolf, Barry

    2017-04-01

    We began screening newborns for biotinidase deficiency disorder in 1984, and now all states in the United States and many countries perform this screening. The purpose of this study was to determine the outcomes of older adolescent and adult individuals with the disorder identified by newborn screening. We located and surveyed, by questionnaire and telephone interviews, 44 individuals with profound biotinidase deficiency identified by newborn screening with a mean age of 23.1 years. All individuals had successfully completed high school, and many were attending or had completed college or graduate school. Compliance in using biotin has been excellent. Several individuals developed a variety of symptoms when they discontinued biotin for days or weeks. These features readily resolved when biotin was resumed. In addition, five treated women had nine uneventful pregnancies and deliveries. Newborn screening for profound biotinidase deficiency and early treatment with biotin result in excellent outcomes for older adolescents and adults with the disorder. In addition, mothers with profound biotinidase deficiency who were treated with biotin had pregnancies with good outcomes. These outcome results indicate that newborn screening for biotinidase deficiency is one of the most successful newborn screening programs.Genet Med 19 4, 396-402.

  3. Severe to profound deafness may be associated with MYH9-related disease: report of 4 patients.

    PubMed

    Canzi, P; Pecci, A; Manfrin, M; Rebecchi, E; Zaninetti, C; Bozzi, V; Benazzo, M

    2016-10-01

    MYH9-related disease (MYH9-RD) is a rare genetic syndromic disorder characterised by congenital thrombocytopenia and is associated with the risk of developing progressive sensorineural hearing loss, nephropathy and presenile cataracts during childhood or adult life. All consecutive patients enrolled in the Italian Registry for MYH9-RD with severe to profound deafness were included in a retrospective study. The study population involved 147 Italian patients with MYH9-RD: hearing loss was identified in 52% of cases and only 4 patients (6%) presented severe to profound deafness at a mean age of 33 years. Deafness was associated with mild spontaneous bleeding in all patients and with kidney involvement in 3 cases. Cochlear implantation was carried out in 3 cases with benefit, and no major complications were observed. Diagnosis was performed about 28 years after the first clinical manifestation of MYH9-RD, which was never suspected by an otolaryngologist. The clinical and diagnostic aspects of 4 patients with severe to profound deafness are discussed with a focus on therapeutic implications.

  4. Localization Training Results in Individuals with Unilateral Severe to Profound Hearing Loss

    PubMed Central

    Firszt, Jill B.; Reeder, Ruth M.; Dwyer, Noël Y.; Burton, Harold; Holden, Laura K.

    2014-01-01

    Adults with unilateral hearing loss often demonstrate decreased sound localization ability and report that situations requiring spatial hearing are especially challenging. Few studies have evaluated localization abilities combined with training in this population. The present pilot study examined whether localization of two sound types would improve after training, and explored the relation between localization ability or training benefit and demographic factors. Eleven participants with unilateral severe to profound hearing loss attended five training sessions; localization cues gradually decreased across sessions. Localization ability was assessed pre- and post-training. Assessment stimuli were monosyllabic words and spectral and temporal random spectrogram sounds. Root mean square errors for each participant and stimulus type were used in group and correlation analyses; individual data were examined with ordinary least squares regression. Mean pre- to post-training test results were significantly different for all stimulus types. Among the participants, eight significantly improved following training on at least one localization measure, whereas three did not. Participants with the poorest localization ability improved the most and likewise, those with the best pre-training ability showed the least training benefit. Correlation results suggested that test age, age at onset of severe to profound hearing loss and better ear high frequency audibility may contribute to localization ability. Results support the need for continued investigation of localization training efficacy and consideration of localization training within rehabilitation protocols for individuals with unilateral severe to profound hearing loss. PMID:25457655

  5. Intratympanic methylprednisolone perfusion as a salvage treatment for profound idiopathic sudden sensorineural hearing loss.

    PubMed

    Dai, Y; Lu, L; Hou, J; Yang, X; Li, H; Yang, Y; She, W

    2017-05-01

    This study aimed to examine the effectiveness of intratympanic methylprednisolone perfusion as salvage treatment for profound idiopathic sudden sensorineural hearing loss. A retrospective clinical study of 97 patients with unilateral profound idiopathic sudden sensorineural hearing loss was performed. In all, 83 patients who received salvage intratympanic methylprednisolone perfusion plus conventional treatment (except for steroids) as the second-line therapy were assigned to the study group, while 14 patients who received conventional treatment alone were assigned to the comparison group. In the study group, treatments in patients with a shorter interval from disease onset to intratympanic methylprednisolone perfusion (up to 15 days) had significantly greater improvements in the overall effective rate and pure tone average compared with patients with a longer interval (over 15 days). For patients with a short interval from disease onset to intratympanic methylprednisolone perfusion, those in the study group had significantly greater improvements in the overall effective rate and pure tone average compared with those in the comparison group. In both the study and comparison groups, hearing improvements were greater at low frequencies than at medium and high frequencies. The interval from disease onset to intratympanic methylprednisolone perfusion was the major factor affecting hearing recovery. Early second-line salvage intratympanic methylprednisolone perfusion significantly improved the degree of hearing recovery in profound idiopathic sudden sensorineural hearing loss patients after failure of systemic steroid treatment.

  6. Like cognitive function, decision making across the life span shows profound age-related changes

    PubMed Central

    Tymula, Agnieszka; Rosenberg Belmaker, Lior A.; Ruderman, Lital; Glimcher, Paul W.; Levy, Ifat

    2013-01-01

    It has long been known that human cognitive function improves through young adulthood and then declines across the later life span. Here we examined how decision-making function changes across the life span by measuring risk and ambiguity attitudes in the gain and loss domains, as well as choice consistency, in an urban cohort ranging in age from 12 to 90 y. We identified several important age-related patterns in decision making under uncertainty: First, we found that healthy elders between the ages of 65 and 90 were strikingly inconsistent in their choices compared with younger subjects. Just as elders show profound declines in cognitive function, they also show profound declines in choice rationality compared with their younger peers. Second, we found that the widely documented phenomenon of ambiguity aversion is specific to the gain domain and does not occur in the loss domain, except for a slight effect in older adults. Finally, extending an earlier report by our group, we found that risk attitudes across the life span show an inverted U-shaped function; both elders and adolescents are more risk-averse than their midlife counterparts. Taken together, these characterizations of decision-making function across the life span in this urban cohort strengthen the conclusions of previous reports suggesting a profound impact of aging on cognitive function in this domain. PMID:24082105

  7. Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis.

    PubMed

    Chang, Wan-Chun; Jan Wu, Yeong-Jian; Chung, Wen-Hung; Lee, Yun-Shien; Chin, See-Wen; Chen, Ting-Jui; Chang, Yu-Sun; Chen, Der-Yuan; Hung, Shuen-Iu

    2017-03-01

    Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. We enrolled 448 gout patients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3 , caspase 1, peroxisome proliferator-activated receptor-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1β ( PPARGC1B ). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B , which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10 -9 ; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from gout patients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1β (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1β. Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1β expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.

  8. PPAR-gamma agonist rosiglitazone attenuates the inflammation caused by carrageenan in the mouse model of pleurisy.

    PubMed

    Buss, Ziliani da Silva; Medeiros, Yara S; Fröde, Tania S

    2012-02-01

    The aim of this study was to investigate the anti-inflammatory efficacy of rosiglitazone (ROSI) in a pleurisy model of carrageenan-induced inflammation. Efficacy was monitored in the mouse pleural cavity by evaluating leukocyte migration, exudate concentration, and myeloperoxidase (MPO) and adenosine deaminase (ADA) activities concomitantly with nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-17A (IL-17A), and vascular endothelial growth factor-alpha (VEGF-α) levels 4 and 48 h after pleurisy induction. In both phases (4 and 48 h) of pleurisy, ROSI inhibited all the inflammation parameters that were tested (p<0.05). These results provide evidence that ROSI was efficacious in inhibiting pro-inflammatory mediators. These anti-inflammatory effects are assumed to mainly result from the inhibition of products released from activated leukocytes, such as MPO, ADA, NOx, TNF-α, IL-1β, IL-17A, and VEGF-α.

  9. Behavioral and Psychosocial Outcomes of a 16-Week Rebound Therapy-Based Exercise Program for People with Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Jones, Martyn C.; Walley, Robert M.; Leech, Amanda; Paterson, Marion; Common, Stephanie; Metcalf, Charlotte

    2007-01-01

    People with profound intellectual disabilities rarely experience a physically active lifestyle, and their long-term physical inactivity likely contributes to poor health. The authors developed and implemented a pilot exercise program for persons with a profound intellectual disability and conducted a study to evaluate the effort. The development…

  10. The Deaf-Blind/Severely-Profoundly Handicapped: Proceedings from the 1978 Nebraska Statewide Conference, Nebraska Diagnostic Resource Center, Cozad, Nebraska.

    ERIC Educational Resources Information Center

    Clark, Douglas H., Ed.

    The report presents the proceedings of a 1978 Nebraska statewide conference intitled "The Education and Training of the Deaf-Blind/Severely-Profoundly Handicapped." Titles and authors of the 13 papers presented include "Considerations for Full Educational Service for the Severely and Profoundly Handicapped" (N. Haring);…

  11. The Deaf-Blind/Severely-Profoundly Handicapped: Proceedings from the 1978 Nebraska Statewide Conference, Nebraska Diagnostic Resource Center, Cozad, Nebraska.

    ERIC Educational Resources Information Center

    Clark, Douglas H., Ed.

    The report presents the proceedings of a 1978 Nebraska statewide conference intitled "The Education and Training of the Deaf-Blind/Severely-Profoundly Handicapped." Titles and authors of the 13 papers presented include "Considerations for Full Educational Service for the Severely and Profoundly Handicapped" (N. Haring);…

  12. Research Ethics Committees and the Benefits of Involving People with Profound and Multiple Learning Disabilities in Research

    ERIC Educational Resources Information Center

    Boxall, Kathy; Ralph, Sue

    2011-01-01

    Although there is increasing interest in service user involvement in research, such involvement rarely extends to people with profound and multiple learning disabilities. New developments in visual methodologies offer the potential for people with profound and multiple learning disabilities to be included in research. At the same time, however,…

  13. Behavioral and Psychosocial Outcomes of a 16-Week Rebound Therapy-Based Exercise Program for People with Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Jones, Martyn C.; Walley, Robert M.; Leech, Amanda; Paterson, Marion; Common, Stephanie; Metcalf, Charlotte

    2007-01-01

    People with profound intellectual disabilities rarely experience a physically active lifestyle, and their long-term physical inactivity likely contributes to poor health. The authors developed and implemented a pilot exercise program for persons with a profound intellectual disability and conducted a study to evaluate the effort. The development…

  14. Domains of Quality of Life of People with Profound Multiple Disabilities: The Perspective of Parents and Direct Support Staff

    ERIC Educational Resources Information Center

    Petry, Katja; Maes, Bea; Vlaskamp, Carla

    2005-01-01

    Background: This study considered the general validity of the basic domains of quality of life that appear in theoretical models, in relation to people with profound multiple disabilities. The authors examined how parents and direct support staff operationalized these basic domains for people with profound multiple disabilities. They investigated…

  15. Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT.

    PubMed

    De Cosmo, Salvatore; Motterlini, Nicola; Prudente, Sabrina; Pellegrini, Fabio; Trevisan, Roberto; Bossi, Antonio; Remuzzi, Giuseppe; Trischitta, Vincenzo; Ruggenenti, Piero

    2009-12-01

    Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)-a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20-200 microg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 microg/min at inclusion. Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1-51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21-0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 +/- 9.1 vs. 10.5 +/- 24.9 microg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29-0.72]; P < 0.001). In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy.

  16. Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes

    SciTech Connect

    Rachek, Lyudmila I.; Yuzefovych, Larysa V.; LeDoux, Susan P.; Julie, Neil L.; Wilson, Glenn L.

    2009-11-01

    Thiazolidinediones (TZDs), such as troglitazone (TRO) and rosiglitazone (ROSI), improve insulin resistance by acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). TRO was withdrawn from the market because of reports of serious hepatotoxicity. A growing body of evidence suggests that TRO caused mitochondrial dysfunction and induction of apoptosis in human hepatocytes but its mechanisms of action remain unclear. We hypothesized that damage to mitochondrial DNA (mtDNA) is an initiating event involved in TRO-induced mitochondrial dysfunction and hepatotoxicity. Primary human hepatocytes were exposed to TRO and ROSI. The results obtained revealed that TRO, but not ROSI at equimolar concentrations, caused a substantial increase in mtDNA damage and decreased ATP production and cellular viability. The reactive oxygen species (ROS) scavenger, N-acetyl cystein (NAC), significantly diminished the TRO-induced cytotoxicity, suggesting involvement of ROS in TRO-induced hepatocyte cytotoxicity. The PPARgamma antagonist (GW9662) did not block the TRO-induced decrease in cell viability, indicating that the TRO-induced hepatotoxicity is PPARgamma-independent. Furthermore, TRO induced hepatocyte apoptosis, caspase-3 cleavage and cytochrome c release. Targeting of a DNA repair protein to mitochondria by protein transduction using a fusion protein containing the DNA repair enzyme Endonuclease III (EndoIII) from Escherichia coli, a mitochondrial translocation sequence (MTS) and the protein transduction domain (PTD) from HIV-1 TAT protein protected hepatocytes against TRO-induced toxicity. Overall, our results indicate that significant mtDNA damage caused by TRO is a prime initiator of the hepatoxicity caused by this drug.

  17. Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes.

    PubMed

    Rachek, Lyudmila I; Yuzefovych, Larysa V; Ledoux, Susan P; Julie, Neil L; Wilson, Glenn L

    2009-11-01

    Thiazolidinediones (TZDs), such as troglitazone (TRO) and rosiglitazone (ROSI), improve insulin resistance by acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). TRO was withdrawn from the market because of reports of serious hepatotoxicity. A growing body of evidence suggests that TRO caused mitochondrial dysfunction and induction of apoptosis in human hepatocytes but its mechanisms of action remain unclear. We hypothesized that damage to mitochondrial DNA (mtDNA) is an initiating event involved in TRO-induced mitochondrial dysfunction and hepatotoxicity. Primary human hepatocytes were exposed to TRO and ROSI. The results obtained revealed that TRO, but not ROSI at equimolar concentrations, caused a substantial increase in mtDNA damage and decreased ATP production and cellular viability. The reactive oxygen species (ROS) scavenger, N-acetyl cystein (NAC), significantly diminished the TRO-induced cytotoxicity, suggesting involvement of ROS in TRO-induced hepatocyte cytotoxicity. The PPARgamma antagonist (GW9662) did not block the TRO-induced decrease in cell viability, indicating that the TRO-induced hepatotoxicity is PPARgamma-independent. Furthermore, TRO induced hepatocyte apoptosis, caspase-3 cleavage and cytochrome c release. Targeting of a DNA repair protein to mitochondria by protein transduction using a fusion protein containing the DNA repair enzyme Endonuclease III (EndoIII) from Escherichia coli, a mitochondrial translocation sequence (MTS) and the protein transduction domain (PTD) from HIV-1 TAT protein protected hepatocytes against TRO-induced toxicity. Overall, our results indicate that significant mtDNA damage caused by TRO is a prime initiator of the hepatoxicity caused by this drug.

  18. Coping with post-lingual severe-profound hearing impairment: a grounded theory study.

    PubMed

    Hallberg, L R; Påsse, U; Ringdahl, A

    2000-02-01

    The purpose of this study was to describe the experiences of coping with demanding auditory situations in everyday life from the perspective of individuals with severe-profound hearing impairment. Seventeen individuals (11 women and 6 men), with post-lingual severe-profound hearing impairment participated in the study. All were patients at the Department of Audiology, Sahlgrenska University Hospital in Göteborg, Sweden. Inclusion criteria were a hearing impairment exceeding 70 dB HL at the frequency of 1 kHz in the better ear, and full-time employment. Data were assessed by in-depth interviews lasting about one hour. The interviews were transcribed verbatim and analysed line-by-in line in accordance with the grounded theory tradition. Six theoretical constructs, or categories, were grounded in the data. These categories were labelled 'coaching', 'belonging to two worlds', 'self-efficacy', 'hardiness' and 'directing coping strategies'. In a grounded theory the central phenomenon on which all the other categories are integrated is known as the 'core category'. The core category, which emerged in the present study, was labelled 'finding flow and entering a positive circle'. This was described as a condition necessary for successful coping with the demanding situation of being a profoundly hearing-impaired person working full-time. According to the core category, there is a small 'margin' within the positive circle (a space where smaller mistakes may occur). However, if mistakes are too severe, or too many, individuals will no longer find flow in the positive circle, rather they enter a negative circle. In the present study subjects' personalities were characterized by hardiness. It is suggested that coaching behaviour and the hearing-impaired individuals' personality dispositions of hardiness and self-efficacy function as resistance resources, buffering stressful events in everyday life.

  19. Profound Amnesia after Temporal Lobectomy: An Autoimmune Process Resembling Patient H.M.?

    PubMed Central

    Bonello, Michael; Larner, Andrew J.; Marson, Anthony G.

    2014-01-01

    We describe a patient who developed significant cognitive decline with profound amnesia following non-dominant temporal lobectomy for refractory seizures, in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation, neuropsychological evidence of bilateral involvement, and high titres of antibodies directed against glutamic acid decarboxylase (GAD). This case adds to the evidence that the diagnosis of non-paraneoplastic anti-GAD limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline. PMID:25473398

  20. Spider silk violin strings with a unique packing structure generate a soft and profound timbre.

    PubMed

    Osaki, Shigeyoshi

    2012-04-13

    We overcome the difficulties in pulling long draglines from spiders, twist bundles of dragline filaments, and succeed in preparing violin strings. The twisting is found to change the cross section shapes of filaments from circular to polygonal and to optimize the packing structure with no openings among filaments providing mechanically strong and elastic strings. The spider string signal peaks of overtones for the violin are relatively large at high frequencies, generating a soft and profound timbre. Such a preferable timbre is considered to be due to the unique polygonal packing structure which provides valuable knowledge for developing new types of materials.

  1. Right ventricular diastolic dysfunction and patent foramen ovale causing profound cyanosis

    PubMed Central

    Shnaider, H; Shiran, A; Lorber, A

    2004-01-01

    A 73 year old woman presented with profound central cyanosis and a history of a minor stroke. She had normal heart morphology, normal pulmonary artery pressure, and a normal coronary angiography. A patent foramen ovale (PFO) with a massive right to left shunt was demonstrated at the atrial level, with normal pulmonary venous saturations and Po2 values. This rare, age related case of right ventricular diastolic dysfunction in a normotensive patient revealed a generous PFO allowing a pronounced right to left shunt. PMID:15145895

  2. Spider Silk Violin Strings with a Unique Packing Structure Generate a Soft and Profound Timbre

    NASA Astrophysics Data System (ADS)

    Osaki, Shigeyoshi

    2012-04-01

    We overcome the difficulties in pulling long draglines from spiders, twist bundles of dragline filaments, and succeed in preparing violin strings. The twisting is found to change the cross section shapes of filaments from circular to polygonal and to optimize the packing structure with no openings among filaments providing mechanically strong and elastic strings. The spider string signal peaks of overtones for the violin are relatively large at high frequencies, generating a soft and profound timbre. Such a preferable timbre is considered to be due to the unique polygonal packing structure which provides valuable knowledge for developing new types of materials.

  3. Profound vision loss impairs psychological well-being in young and middle-aged individuals

    PubMed Central

    Garcia, Giancarlo A; Khoshnevis, Matin; Gale, Jesse; Frousiakis, Starleen E; Hwang, Tiffany J; Poincenot, Lissa; Karanjia, Rustum; Baron, David; Sadun, Alfredo A

    2017-01-01

    Purpose The aim of this study was to evaluate the effects of profound vision loss on psychological well-being in adolescents, young adults, and middle-aged adults with regard to mood, interpersonal interactions, and career-related goals. In addition, we assessed the significance of the resources that may be used to enhance psychological well-being in cases of profound vision loss, and in particular, examined the utility of low vision aids and the role of the ophthalmologist as a provider of emotional support. Methods A questionnaire was issued to individuals aged 13–65 years with profound vision loss resulting from Leber’s hereditary optic neuropathy (LHON). Depression prevalence was evaluated with questions regarding major depressive disorder symptomatology. Participants appraised the effects of vision loss on their interpersonal interactions and career goals by providing an impact rating (IR) on a 21-point psychometric scale from −10 to +10. Social well-being index was defined as the average of interpersonal IR and career IR. Subjects were additionally asked about the use of low vision aids and sources of emotional support. Results A total of 103 participants (mean age =26.4±11.2 years at LHON diagnosis; mean ± standard deviation) completed the questionnaire. Nearly half (49.5%) met the depression criteria after vision loss. Negative impacts on interpersonal interactions (median IR = −5) and career goals (median IR = −6) were observed; both ratings were worse (P<0.001) for depressed versus nondepressed subjects. Older age at diagnosis corresponded to higher depression prevalence and increased incidence of negative interpersonal IR and career IR. Sixty-eight percent of subjects used electronic vision aids; controlling for age, social well-being index was higher among these individuals than for those who did not use electronic aids (P=0.03). Over half of the participants (52.4%) asserted that they derived emotional support from their ophthalmologist

  4. The effects of governing board configuration on profound organizational change in hospitals.

    PubMed

    Alexander, Jeffrey A; Ye, Yining; Lee, Shoou-Yih D; Weiner, Bryan J

    2006-09-01

    This study extends the literature on governing boards and organizational change by examining how governing board configurations have influenced profound organizational change in U.S. hospitals, and the conditions under which such change occurs. Hospitals governed by boards that more closely resembled a corporate governance model were more likely to experience positive changes such as diversification and merger and less likely to undergo negative changes such as closure. Organizational performance influenced change, but largely independent of governance configurations. Only in the case of closure did we find that governance configuration operated jointly with organizational performance.

  5. Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPAR{gamma}-LXR{alpha}-ABCA1 pathway

    SciTech Connect

    Xu, Yanni; Lai, Fangfang; Xu, Yang; Wu, Yexiang; Liu, Qi; Li, Ni; Wei, Yuzhen; Feng, Tingting; Zheng, Zhihui; Jiang, Wei; Yu, Liyan; Hong, Bin; Si, Shuyi

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Using an ABCA1p-LUC HepG2 cell line, we found that MPA upregulated ABCA1 expression. Black-Right-Pointing-Pointer MPA induced ABCA1 and LXR{alpha} protein expression in HepG2 cells. Black-Right-Pointing-Pointer PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. Black-Right-Pointing-Pointer The effect of MPA upregulating ABCA1 was due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 pathway. -- Abstract: ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I and plays an important role in atherosclerosis. In a previous study, we developed a high-throughput screening method using an ABCA1p-LUC HepG2 cell line to find upregulators of ABCA1. Using this method in the present study, we found that mycophenolic acid (MPA) upregulated ABCA1 expression (EC50 = 0.09 {mu}M). MPA upregulation of ABCA1 expression was confirmed by real-time quantitative reverse transcription-PCR and Western blot analysis in HepG2 cells. Previous work has indicated that MPA is a potent agonist of peroxisome proliferator-activated receptor gamma (PPAR{gamma}; EC50 = 5.2-9.3 {mu}M). Liver X receptor {alpha} (LXR{alpha}) is a target gene of PPAR{gamma} and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXR{alpha} protein expression in HepG2 cells. Addition of PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPAR{gamma}. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism.

  6. Terpene metabolic engineering via nuclear or chloroplast genomes profoundly and globally impacts off-target pathways through metabolite signalling.

    PubMed

    Pasoreck, Elise K; Su, Jin; Silverman, Ian M; Gosai, Sager J; Gregory, Brian D; Yuan, Joshua S; Daniell, Henry

    2016-09-01

    The impact of metabolic engineering on nontarget pathways and outcomes of metabolic engineering from different genomes are poorly understood questions. Therefore, squalene biosynthesis genes FARNESYL DIPHOSPHATE SYNTHASE (FPS) and SQUALENE SYNTHASE (SQS) were engineered via the Nicotiana tabacum chloroplast (C), nuclear (N) or both (CN) genomes to promote squalene biosynthesis. SQS levels were ~4300-fold higher in C and CN lines than in N, but all accumulated ~150-fold higher squalene due to substrate or storage limitations. Abnormal leaf and flower phenotypes, including lower pollen production and reduced fertility, were observed regardless of the compartment or level of transgene expression. Substantial changes in metabolomes of all lines were observed: levels of 65-120 unrelated metabolites, including the toxic alkaloid nicotine, changed by as much as 32-fold. Profound effects of transgenesis on nontarget gene expression included changes in the abundance of 19 076 transcripts by up to 2000-fold in CN; 7784 transcripts by up to 1400-fold in N; and 5224 transcripts by as much as 2200-fold in C. Transporter-related transcripts were induced, and cell cycle-associated transcripts were disproportionally repressed in all three lines. Transcriptome changes were validated by qRT-PCR. The mechanism underlying these large changes likely involves metabolite-mediated anterograde and/or retrograde signalling irrespective of the level of transgene expression or end product, due to imbalance of metabolic pools, offering new insight into both anticipated and unanticipated consequences of metabolic engineering.

  7. Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

    SciTech Connect

    Scherzberg, Maria-Christina; Kiehl, Andreas; Zivkovic, Aleksandra; Stark, Holger; Stein, Jürgen; Fürst, Robert; Steinhilber, Dieter; Ulrich-Rückert, Sandra

    2015-08-15

    (Z)-3,5,4′-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC{sub 50} values for Z-TMS between 0.115 μM and 0.473 μM (resveratrol: 110.7 μM to 190.2 μM). Flow cytometric analysis revealed a G{sub 2}/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. - Highlights: • Methylation of resveratrol leads to profound changes in biologic activity. • Z-TMS does not prevent hepatic steatosis, but inhibits tubulin polymerization. • Resveratrol analog Z-TMS does not influence known targets like

  8. Over-expression of C/EBP-{alpha} induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-{gamma}

    SciTech Connect

    Wang Xueqing; Huang Guangcun; Mei Shuang; Qian Jin; Ji Juling; Zhang Jinsheng

    2009-03-06

    Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-{alpha} (C/EBP-{alpha}) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-{alpha} gene (Ad-C/EBP-{alpha}) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/EBP-{alpha} resulted in the up-regulation of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) and P53, while P53 expression was regulated by PPAR-{gamma}. In addition, Fas, FasL, DR4, DR5, and TRAIL were studied. The results indicated that the death receptor pathway was mainly involved and regulated by PPAR-{gamma} and p53 in the process of apoptosis triggered by C/EBP-{alpha} in HSCs.

  9. Over-expression of C/EBP-alpha induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-gamma.

    PubMed

    Wang, Xueqing; Huang, Guangcun; Mei, Shuang; Qian, Jin; Ji, Juling; Zhang, Jinsheng

    2009-03-06

    Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-alpha (C/EBP-alpha) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-alpha gene (Ad-C/EBP-alpha) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/EBP-alpha resulted in the up-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and P53, while P53 expression was regulated by PPAR-gamma. In addition, Fas, FasL, DR4, DR5, and TRAIL were studied. The results indicated that the death receptor pathway was mainly involved and regulated by PPAR-gamma and p53 in the process of apoptosis triggered by C/EBP-alpha in HSCs.

  10. An examination of specific daily living skills deficits in adults with profound intellectual disabilities.

    PubMed

    Belva, Brian C; Matson, Johnny L

    2013-01-01

    While some researchers have investigated daily living skills deficits in individuals with intellectual disability (ID) as a whole, research on specific daily living skills in a profound ID population is limited. Two hundred and four adults with profound ID residing in two large developmental centers in the southeast portion of the United States were studied. Data were collected on these individuals' daily living skills, utilizing the Vineland Adaptive Behavior Scales (VABS). Three dependent t-tests were conducted comparing the proportion of items endorsed by informants on each of the three subdomains of daily living skills on the VABS (personal, domestic, and community). A significantly larger proportion of Personal Subdomain items were endorsed compared to Domestic or Community Subdomain items. Additionally, participants exhibited a significantly larger proportion of Domestic Skills Subdomain items compared to Community Skills Subdomain items which is consistent with theoretical models suggesting that institutional living may curb broader community skill sets. No gender differences were found in daily living skills. Lastly, individuals between the ages 30 and 39 exhibited significantly more Personal Subdomain skills than individuals who were 60 or older, while participants between the ages 30 and 39 exhibited significantly more Domestic Subdomain skills than individuals between the ages 60 and 69. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Profound microcephaly, primordial dwarfism with developmental brain malformations: a new syndrome.

    PubMed

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Saleem, Sahar N; Ahmed, Mahmoud K H; Issa, Mahmoud; Effat, Laila K; Kayed, Hisham F; Zaki, Maha S; Gaber, Khaled R

    2012-08-01

    We describe two sibs with a lethal form of profound congenital microcephaly, intrauterine and postnatal growth retardation, subtle skeletal changes, and poorly developed brain. The sibs had striking absent cranial vault with sloping of the forehead, large beaked nose, relatively large ears, and mandibular micro-retrognathia. Brain magnetic resonance imaging (MRI) revealed extremely simplified gyral pattern, large interhemispheric cyst and agenesis of corpus callosum, abnormally shaped hippocampus, and proportionately affected cerebellum and brainstem. In addition, fundus examination showed foveal hypoplasia with optic nerve atrophy. No abnormalities of the internal organs were found. This profound form of microcephaly was identified at 17 weeks gestation by ultrasound and fetal brain MRI helped in characterizing the developmental brain malformations in the second sib. Molecular analysis excluded mutations in potentially related genes such as RNU4ATAC, SLC25A19, and ASPM. These clinical and imaging findings are unlike that of any recognized severe forms of microcephaly which is believed to be a new microcephalic primordial dwarfism (MPD) with developmental brain malformations with most probably autosomal recessive inheritance based on consanguinity and similarly affected male and female sibs.

  12. A quantitative review of self-help research with the severely and profoundly mentally retarded.

    PubMed

    Konarski, E A; Diorio, M S

    1985-01-01

    Eighty-seven studies published since 1964 through 1982 on training self-help skills to severely and profoundly mentally retarded persons were analyzed according to 19 parameters reflecting their methodological details. The results showed a steady interest in this research area over time, but 63% of the studies focused on toileting and feeding with fewer studies looking at other self-help skills. Package treatments composed primarily of accelerative techniques were most frequently used to train these skills. Methodologically, it was found that these studies typically involved profoundly mentally retarded people (33% of studies) who were trained by residential staff (69% of studies) in institutional settings (63% of studies). The results also indicated an increase over time in the number of studies rated acceptable on the reliability and design parameters. Finally, very few studies reported assessments of generalization, maintenance, or social validity. It was concluded that, (a) researchers need to broaden their interests in terms of settings, trainers, and behaviors studied to best meet the needs of this population, (b) the experimental quality of this literature is improving, and (c) the social impact of observed behavior changes has yet to be fully explored.

  13. Profound effects of population density on fitness-related traits in an invasive freshwater snail.

    PubMed

    Zachar, Nicholas; Neiman, Maurine

    2013-01-01

    Population density can profoundly influence fitness-related traits and population dynamics, and density dependence plays a key role in many prominent ecological and evolutionary hypotheses. Here, we evaluated how individual-level changes in population density affect growth rate and embryo production early in reproductive maturity in two different asexual lineages of Potamopyrgus antipodarum, a New Zealand freshwater snail that is an important model system for ecotoxicology and the evolution of sexual reproduction as well as a potentially destructive worldwide invader. We showed that population density had a major influence on individual growth rate and early-maturity embryo production, effects that were often apparent even when comparing treatments that differed in population density by only one individual. While individual growth rate generally decreased as population density increased, we detected a hump-shaped relationship between embryo production and density, with females from intermediate-density treatments producing the most embryos and females from low- and high-density treatments producing the fewest embryos. The two lineages responded similarly to the treatments, indicating that these effects of population density might apply more broadly across P. antipodarum. These results indicate that there are profound and complex relationships between population density, growth rate, and early-maturity embryo production in at least two lineages of this important model system, with potential implications for the study of invasive populations, research on the maintenance of sex, and approaches used in ecotoxicology.

  14. Profound Effects of Population Density on Fitness-Related Traits in an Invasive Freshwater Snail

    PubMed Central

    Zachar, Nicholas; Neiman, Maurine

    2013-01-01

    Population density can profoundly influence fitness-related traits and population dynamics, and density dependence plays a key role in many prominent ecological and evolutionary hypotheses. Here, we evaluated how individual-level changes in population density affect growth rate and embryo production early in reproductive maturity in two different asexual lineages of Potamopyrgus antipodarum, a New Zealand freshwater snail that is an important model system for ecotoxicology and the evolution of sexual reproduction as well as a potentially destructive worldwide invader. We showed that population density had a major influence on individual growth rate and early-maturity embryo production, effects that were often apparent even when comparing treatments that differed in population density by only one individual. While individual growth rate generally decreased as population density increased, we detected a hump-shaped relationship between embryo production and density, with females from intermediate-density treatments producing the most embryos and females from low- and high-density treatments producing the fewest embryos. The two lineages responded similarly to the treatments, indicating that these effects of population density might apply more broadly across P. antipodarum. These results indicate that there are profound and complex relationships between population density, growth rate, and early-maturity embryo production in at least two lineages of this important model system, with potential implications for the study of invasive populations, research on the maintenance of sex, and approaches used in ecotoxicology. PMID:24278240

  15. Biochemical and immunological characterization of serum biotinidase in profound biotinidase deficiency.

    PubMed Central

    Hart, P S; Hymes, J; Wolf, B

    1992-01-01

    The biochemical and immunological characterization of biotinidase was performed in sera from 100 normal individuals, 68 children with profound biotinidase deficiency (less than 10% of mean normal activity) who were identified symptomatically and by newborn screening, and 63 of their parents. On isoelectric focusing, serum enzyme from normal individuals exhibits extensive microheterogeneity, consisting of at least four major and five minor isoforms at pH 4.15-4.35. Patients with profound biotinidase deficiency can be classified into at least nine distinct biochemical phenotypes, on the basis of (a) the presence or absence of cross-reacting material (CRM) to biotinidase, (b) the number of isoforms, and (c) the distribution frequency of the isoforms. None of the patients with CRM had an abnormal Km of the substrate for the enzyme. All of the parents had normal isoform patterns. The mean activities, CRM concentrations, and specific activities were not significantly different between parents of CRM-positive children and parents of CRM-negative children. There is no relationship between either the age at onset or the severity of symptoms and the isoform patterns or CRM status of the symptomatic children. The isoform patterns of children identified by newborn screening are not different from those of symptomatic children. Images Figure 3 PMID:1729884

  16. [Economic benefits of the cochlear implant for treating profound sensorineural hearing loss].

    PubMed

    Peñaranda, Augusto; Mendieta, Juan Carlos; Perdomo, Jorge Andrés; Aparicio, María Leonor; Marín, Lina Marcela; García, Juan Manuel; Barón, Clemencia

    2012-04-01

    Evaluate the cost-benefit, cost-utility, and cost-effectiveness of cochlear implantation, comparing it to the use of hearing aids in children with profound bilateral sensorineural hearing loss. The nonparametric propensity score matching method was used to carry out an economic and impact assessment of the cochlear implant and then perform cost-benefit, cost-utility, and cost-effectiveness analyses. Primary information was used, taken randomly from 100 patients: 62 who received cochlear implants (treatment group) and 38 belonging to the control group who used hearing aids to treat profound sensorineural hearing loss. An economic cost differential was found-to the advantage of the cochlear implant-of close to US$ 204,000 between the implant and the use of hearing aids over the expected life span of the patients analyzed. This amount refers to the greater expenses that hearing-aid patients will have. With this adjusted figure, the cost-benefit indicator shows that for each dollar invested to treat the cochlear-implant patient, there is a return on the investment of US$ 2.07. The cochlear implant produces economic benefits for the patient. It also produces health utilities since positive cost-utility (gain in decibels) and cost-effectiveness (gain in language discrimination) ratios were found.

  17. Cochlear ossification in patients with profound hearing loss following bacterial meningitis.

    PubMed

    Caye-Thomasen, Per; Dam, Mikkel Seidelin; Omland, Silje Haukali; Mantoni, Margit

    2012-07-01

    Cochlear ossification following bacterial meningitis is related to causative pathogen, but not age at disease or time point of evaluation. However, progression may occur over time, especially in case of primary signs of ossification. To investigate the occurrence and degree of cochlear ossification on CT and MRI in patients with bilateral profound hearing loss following bacterial meningitis, in relation to causative pathogen, age at disease, and time point of evaluation. Progression of ossification in cases that underwent more than one scan was evaluated. In the period 1982-2008, 47 cochlear implantations were performed in 34 consecutive candidates suffering from bilateral profound hearing loss following bacterial meningitis. A retrospective review of patient files and preoperative CT and MR images was performed. Cochlear ossification was observed in 35% of patients and 26% of ears on CT. The corresponding values for MRI were 44 and 30% (difference not significant). Streptococcus pneumoniae infection caused ossification more frequently than Neisseria meningitidis. No difference was found between pediatric and adult cases, and the occurrence of ossification was not related to the time point of evaluation. Signs of progressive ossification were found in cases with two CT scans, especially if ossification was present at the first scan.

  18. Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells.

    PubMed

    Lapillonne, Helene; Konopleva, Marina; Tsao, Twee; Gold, David; McQueen, Teresa; Sutherland, Robert L; Madden, Timothy; Andreeff, Michael

    2003-09-15

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormonal receptor superfamily expressed in a large number of human cancers. Here, we demonstrate that PPARgamma is expressed and transcriptionally active in breast cancer cells independent of their p53, estrogen receptor, or human epidermal growth factor receptor 2 status. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a novel synthetic triterpenoid, is a ligand for PPARgamma. We investigated the molecular mechanisms of CDDO on proliferation and apoptosis in breast cancer cells. In all breast cancer cell lines studied, CDDO transactivated PPARgamma, induced dose- and time-dependent cell growth inhibition, cell cycle arrest in G(1)-S and G(2)-M, and apoptosis. We then used differential cDNA array analysis to investigate the molecular changes induced by CDDO. After 16-h exposure of MCF-7 and MDA-MB-435 cells to CDDO, we found genes encoding the following proteins to be up-regulated in both cell lines: p21(Waf1/CIP1); GADD153; CAAT/enhancer binding protein transcription factor family members; and proteins involved in the ubiquitin-proteasome pathway. Among the down-regulated genes, we focused on the genes encoding cyclin D1, proliferating cell nuclear antigen, and the insulin receptor substrate 1. Using Western blot analysis and/or real-time PCR, we confirmed that CDDO regulated the expression of cyclin D1, p21(Waf1/CIP1), and Bcl-2. Cyclin D1 and p21(Waf1/CIP1) were additionally confirmed as important mediators of CDDO growth inhibition in genetically modified breast cancer cell lines. CDDO was able to significantly reduce the growth of MDA-MB-435 tumor cells in immunodeficient mice in vivo. The finding that CDDO can target genes critical for the regulation of cell cycle, apoptosis, and breast carcinogenesis suggests usage of CDDO as novel targeted therapy in breast cancer.

  19. Use of a Treatment Package in the Management of a Profoundly Mentally Retarded Girl's Pica and Self-Stimulation.

    ERIC Educational Resources Information Center

    Paniagua, Freddy A.; And Others

    1986-01-01

    Treatment involving verbal reprimands, physical restraint, response interruption, and positive practice overcorrection resulted in rapid and dramatic decreases in the levels of pica and self-stimulation of a 4-year-old profoundly retarded girl. (CL)

  20. Dickens for All: Inclusive Approaches to Literature and Communication with People with Severe and Profound Learning Disabilities.

    ERIC Educational Resources Information Center

    Park, Keith

    1998-01-01

    Discusses the potential uses of literature with people with severe and profound learning disabilities and describes a series of multisensory interactive drama games re-telling the story of "A Christmas Carol" by Charles Dickens. (Author/DB)

  1. Use of a Treatment Package in the Management of a Profoundly Mentally Retarded Girl's Pica and Self-Stimulation.

    ERIC Educational Resources Information Center

    Paniagua, Freddy A.; And Others

    1986-01-01

    Treatment involving verbal reprimands, physical restraint, response interruption, and positive practice overcorrection resulted in rapid and dramatic decreases in the levels of pica and self-stimulation of a 4-year-old profoundly retarded girl. (CL)

  2. The Effect of Contingent Music on the In-Seat Behavior of a Blind Young Woman with Profound Mental Retardation.

    ERIC Educational Resources Information Center

    Hill, Jane; And Others

    1989-01-01

    The study found significant improvements in behavior when a profoundly mentally retarded blind subject was reinforced with music. The young woman also discriminated among different types of music, and behavior rates varied accordingly. (Author/DB)

  3. Dickens for All: Inclusive Approaches to Literature and Communication with People with Severe and Profound Learning Disabilities.

    ERIC Educational Resources Information Center

    Park, Keith

    1998-01-01

    Discusses the potential uses of literature with people with severe and profound learning disabilities and describes a series of multisensory interactive drama games re-telling the story of "A Christmas Carol" by Charles Dickens. (Author/DB)

  4. Limitations of Mild, Moderate, and Profound Hypothermia in Protecting Developing Hippocampal Neurons After Simulated Ischemia.

    PubMed

    Gregersen, Maren; Lee, Deok Hee; Gabatto, Pablo; Bickler, Philip E

    2013-12-01

    Mild hypothermia (33°C-34°C) after cerebral ischemia in intact animals or ischemia-like conditions in vitro reduces neuron death. However, it is now clear that more profound hypothermia or delayed hypothermia may not provide significant protection. To further define the limitations of hypothermia after cerebral ischemia, we used hippocampal slice cultures to examine the effects of various degrees, durations, and delays of hypothermia on neuron death after an ischemia-like insult. Organotypic cultures of the hippocampus from 7- to 8 day-old rat pups were cooled to 32°C, 23°C, 17°C, or 4°C immediately or after a 2-4 hour delay from an injurious insult of oxygen and glucose deprivation (OGD). Cell death in CA1, CA3 and dentate regions of the cultures was assessed 24 hours later with SYTOX(®) or propidium iodide, both of which are fluorescent markers labeling damaged cells. OGD caused extensive cell death in CA1, CA3, and dentate regions of the hippocampal cultures. Hypothermia (32°C, 23°C and 17°C) for 4-6 hours immediately after OGD was protective at 24 hours, but when hypothermia was applied for longer periods or delayed after OGD, no protection or increased death was seen. Ultra-profound hypothermia (4°C) increased cell death in all cell areas of the hippocampus even when after a milder insult of only hypoxia. In an in vitro model of recovery after an ischemia-like insult, mild to profound hypothermia is protective only when applied without delay and for limited periods of time (6-8 hours). Longer durations of hypothermia, or delayed application of the hypothermia can increase neuron death. These findings may have implications for clinical uses of therapeutic hypothermia after hypoxic or ischemic insults, and suggest that further work is needed to elucidate the limitations of hypothermia as a protective treatment after ischemic stress.

  5. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians.

    PubMed

    Ek, J; Andersen, G; Urhammer, S A; Hansen, L; Carstensen, B; Borch-Johnsen, K; Drivsholm, T; Berglund, L; Hansen, T; Lithell, H; Pedersen, O

    2001-09-01

    We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians. The Pro12Ala polymorphism was examined using PCR-RFLP Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex. Whole-body insulin sensitivity was significantly improved in carriers compared with non-carriers of the Ala-allele of the codon 12 polymorphism in Swedish Caucasian men (6.0+/-2.5 vs 5.6+/-2.5 mg kg(-1) x min(-1) x mU/l](-1) x 100, p = 0.044). The same tendency, but not significant, was observed in the insulin sensitivity index among the group of young healthy Danish Caucasians. The incidence of Type II diabetes and IGT among the Swedish subjects at the age of 70 was similar in the three genotype-groups of the Pro12Ala variant and the Ala-allele was not related to a lower prevalence of Type II diabetes in Danish Caucasians. The Ala-allele of the PPAR-gamma2 polymorphism is associated with improved whole body insulin sensitivity among Swedish Caucasians.

  6. Use of teacher prompts to increase social behavior: generalization effects with severely and profoundly retarded adolescents.

    PubMed

    Petersen, G A; Austin, G J; Lang, R P

    1979-07-01

    In a single-subject design with replication across subjects, teacher prompts were used in an attempt to increase the rate of social behavior of three severely and profoundly retarded adolescents who were legally blind. Training took place in the classroom on successive school days with the teacher prompting each subject to engage in positive social interaction with each peer. Observations for generalization effects immediately followed each training session. The remaining class members were brought into the room, and social interactions were observed in a free-play setting while the teacher was absent. During both phases, observers recorded the behavior of the three subjects for 5 minutes and recorded all units of social exchange that each subject initiated or responded to. Increased rates of social behavior were obtained for all three subjects during both training and generalization. Major factors that contributed to the generalization effects were discussed.

  7. Successful life outcome and management of real-world memory demands despite profound anterograde amnesia

    PubMed Central

    Duff, Melissa C.; Wszalek, Tracey; Tranel, Daniel; Cohen, Neal J.

    2010-01-01

    We describe the case of Angie, a 50 year-old woman with profound amnesia (General Memory Index = 49, Full Scale IQ = 126) following a closed head injury in 1985. This case is unique in comparison to other cases reported in the literature in that, despite the severity of her amnesia, she has developed remarkable real-world life abilities, shows impressive self awareness and insight into the impairment and sparing of various functional memory abilities, and exhibits ongoing maturation of her identity and sense of self following amnesia. The case provides insights into the interaction of different memory and cognitive systems in handling real-world memory demands, and has implications for rehabilitation and for successful life outcome after amnesia. PMID:18608659

  8. Survival from profound metabolic acidosis due to hypovolaemic shock. A world record?

    PubMed

    Di Rollo, Nicola; Caesar, David; Ferenbach, David A; Dunn, Mark J G

    2013-01-30

    This case describes the unexpected survival of an adult man who presented to the emergency department with hypovolaemic shock secondary to a splenic haemorrhage. Before surgery he had a pH 6.527, base excess (BE) -34.2 mmol/l and lactate 15.6 mmol/l. He underwent a splenectomy after which his condition stabilised. He was managed in the intensive care unit postoperatively where he required organ support including renal replacement therapy but was subsequently discharged home with no neurological or renal deficit. Although there are case reports of patients surviving such profound metabolic acidosis these have mainly been cases of near drowning or toxic alcohol ingestion. To the best of our knowledge this is the first reported case of survival after a pH of 6.5 secondary to hypovolaemic shock.

  9. Care versus treatment at the end of life for profoundly disabled persons.

    PubMed

    Spike, Jeffrey P

    2012-01-01

    Individuals who are profoundly mentally handicapped do not have the capacity to make their own decisions and also do not have a past record of decisions, from when they had capacity, to guide us in making decisions for them. They represent a difficult group, ethically, for surrogate decision making. Here I propose some guidelines, distinguishing between these patients and patients in a persistent vegetative state (PVS). As the life span of patients becomes shorter, or their level of consciousness becomes permanently impaired, the presumption for comfort care should become an imperative, and the standard of evidence to justify any invasive intervention should become higher. For members of this population, who have no more ability to refuse treatment than to consent to it, protection of the vulnerable must mean allowing a peaceful death as well as a comfortable life. Reasonable legal safeguards are also proposed to allow improved end-of-life decisions to be made for this population.

  10. RNA diversity has profound effects on the translation of neuronal nitric oxide synthase.

    PubMed

    Wang, Y; Newton, D C; Robb, G B; Kau, C L; Miller, T L; Cheung, A H; Hall, A V; VanDamme, S; Wilcox, J N; Marsden, P A

    1999-10-12

    A comprehensive analysis of the structure of neuronal nitric oxide synthase (nNOS; EC 1.14.13.39) mRNA species revealed NOS1 to be the most structurally diverse human gene described to date in terms of promoter usage. Nine unique exon 1 variants are variously used for transcript initiation in diverse tissues, and each is expressed from a unique 5'-flanking region. The dependence on unique genomic regions to control transcription initiation in a cell-specific fashion burdens the transcripts with complex 5'-mRNA leader sequences. Elaborate splicing patterns that involve alternatively spliced leader exons and exon skipping have been superimposed on this diversity. Highly structured nNOS mRNA 5'-untranslated regions, which have profound effects on translation both in vitro and in cells, contain cis RNA elements that modulate translational efficiency in response to changes in cellular phenotype.

  11. The structure of informal social networks of persons with profound intellectual and multiple disabilities.

    PubMed

    Kamstra, A; van der Putten, A A J; Vlaskamp, C

    2015-05-01

    Persons with less severe disabilities are able to express their needs and show initiatives in social contacts, persons with profound intellectual and multiple disabilities (PIMD), however, depend on others for this. This study analysed the structure of informal networks of persons with PIMD. Data concerning the number, type and frequency of contacts were collected in 205 persons with PIMD. The mean number of contact persons was 5.1 (range: 0-26, SD: 4.2) per year. 79.4% of the contact persons are family, with an average of 72.3 contacts per year. Parents had significantly more contact compared to the other informal contact persons. In 2.2% of the sample contacts with peers were seen. The informal networks of persons with PIMD consist mainly of family. The question arises how informal networks can be expanded and which role professionals have in this process. © 2014 John Wiley & Sons Ltd.

  12. Increasing habilitative services for persons with profound handicaps: an application of structural analysis to staff management.

    PubMed

    Green, C W; Reid, D H; Perkins, L I; Gardner, S M

    1991-01-01

    We evaluated a structural analysis methodology for enhancing the utility of a staff management program. In Experiment 1, a structural analysis of direct-care staff behavior in a mental retardation facility revealed differences in work patterns over time. Specific times were identified when few basic care duties were necessary and staff engaged in nonwork activity. In Experiment 2, a management program was implemented to increase staff members' training activities during periods identified through the structural analysis. The program was accompanied by increases in training activities and decreases in nonwork behavior. The improvements were maintained during a 43-week period while the most labor-intensive component of the program was withdrawn. Staff acceptability measures indicated a positive response to the management intervention, although responses varied across components within the multifaceted program. The increased training was accompanied by beneficial changes among clients with profound handicaps. Results are discussed regarding practical considerations for improving staff performance and for adopting innovations resulting from applied research.

  13. Profound hypoglycemia-ınduced by vaccinium corymbosum juice and laurocerasus fruit.

    PubMed

    Aktan, Ahmet Hamdi; Ozcelik, Abdullah; Cure, Erkan; Cure, Medine Cumhur; Yuce, Suleyman

    2014-01-01

    An emergency intervention was performed in a 75-year-old male patient with hypoglycemic attack and blackout. Although he was diagnosed with prediabetes before 2 years, he did not take any anti-diabetic drug or follow dietary advice. He drank Vaccinium corymbosum L (VC) juice daily with a belief that it increases sexual potency. Before the development of hypoglycemia, the patient had consumed about 500 ml VC juice in addition to eating 200-300 gram of Laurocerasus officinalis (LO) fruit. The measured plasma glucose (PG) level during loss of consciousness was 30 mg/dl. The profound hypoglycemia may be an unexpected side effect of an interaction between the chemical compositions of the two plants, occurred as a result of LO fruit intake that may have a strong PG-lowering effect or related to excessive intake of VC juice. Both plants may be considered in the alternative treatment of diabetes.

  14. Peer Interactions among Children with Profound Intellectual and Multiple Disabilities during Group Activities.

    PubMed

    Nijs, Sara; Penne, Anneleen; Vlaskamp, Carla; Maes, Bea

    2016-07-01

    Children with profound intellectual and multiple disabilities (PIMD) meet other children with PIMD in day care centres or schools. This study explores the peer-directed behaviours of children with PIMD, the peer interaction-influencing behaviour of the direct support workers and the children's positioning. Group activities for children with PIMD initiated by a direct support worker were video-recorded. The behaviour and positioning of the children and the behaviour of the direct support workers were coded. Limited peer-directed behaviour of the children with PIMD and peer interaction-influencing behaviour of the direct support workers are observed. Weak associations were found between the positioning or peer interaction-influencing behaviours and the behaviour of children with PIMD. Children with PIMD show social interest in each other during group activities. More knowledge is needed to create an environment which facilitates peer-directed behaviours of persons with PIMD. © 2015 John Wiley & Sons Ltd.

  15. Interaction between persons with profound intellectual and multiple disabilities and their partners: a literature review.

    PubMed

    Hostyn, Ine; Maes, Bea

    2009-12-01

    High quality interactions are of crucial importance for quality of life of persons with profound intellectual and multiple disabilities (PIMD). This literature review describes and synthesises studies addressing the interaction between persons with PIMD and their partners. A computerised literature search using defined inclusion criteria yielded 15 articles. The literature analysis revealed four components important in interactions: sensitive responsiveness, joint attention, co-regulation, and an emotional component. The abilities and disabilities, interactive behaviours, and personality of persons with PIMD influence these interactions. Additional influences are the partners' interactive strategies, knowledge, and perceptions and the context of the interaction. An overview model integrates the results and forms a vehicle to facilitate our understanding of interactions with persons with high support needs. Methodological analyses of the studies show lacunae in current research. This review offers a starting point to guide future research and intervention.

  16. Cochlear Implantation for Profound Hearing Loss After Multimodal Treatment for Neuroblastoma in Children

    PubMed Central

    Ryu, Nam-Gyu; Chang, Young Soo; Kim, Byoung Kil; Chung, Won-Ho; Cho, Yang-Sun; Hong, Sung Hwa

    2015-01-01

    Objectives Neuroblastoma (NBL) predominantly affects children under 5 years of age. Through multimodal therapy, including chemotherapy, radiotherapy, surgery, and peripheral blood stem cell transplantation, the survival rate in patients with NBL have improved while treatment-related complications have also increased. Treatment-related ototoxicity, mainly from cisplatin, can result in profound hearing loss requiring cochlear implantation (CI). We analyzed the effectiveness and hearing preservation of CI recipients who had treated with multimodal therapy due to NBL. Methods Patients who received multimodal therapy for NBL and subsequent CIs were enrolled. A detailed review of the perioperative hearing test, speech evaluation, and posttreatment complications was conducted. Speech performance was analyzed using the category of auditory performance (CAP) score and the postoperative hearing preservation of low frequencies was also compared. Patients who were candidates for electro-acoustic stimulation (EAS) used an EAS electrode for low frequency hearing preservation. Results Three patients were identified and all patients showed improvement of speech performance after CI. The average of CAP score improved from 4.3 preoperatively to 5.8 at 1 year postoperatively. Two patients who were fitted with the Flex electrode showed complete hearing preservation and the preserved hearing was maintained over 1 year. The one remaining patient was given the standard CI-512 electrode and showed partial hearing preservation. Conclusion Patients with profound hearing loss resulting from NBL multimodal therapy can be good candidates for CI, especially for EAS. A soft surgical technique as well as a specifically designed electrode should be applied to this specific population during the CI operation in order to preserve residual hearing and achieve better outcomes. PMID:26622949

  17. [The use of hearing aids in children with profound deafness. Methodology and results].

    PubMed

    Tranchino, G; Motta, G; Covino, A; De Orsi, F; Moccia, G; Motta, S; Salzano, F

    1995-10-01

    The early application of hearing aids in children with severe and profound hearing loss is rather an hard problem that has to be solved, according to the Authors, by taking care of several factors. Usually, as far as these patients concern, two kinds of hearings aids are used. The first one emphasizes all the frequencies in the same way, including low tones that, in the early ages, are very important for improving prosodic pattern, occlusive and liquid phonemas, primary words and sentences. The second type, emphasizing only medium and high frequencies, is useful for discrimination processes. The Authors suggest to applicate the hearing aids in these patients, following a behavior be themselves named "dynamic application". In the first phase the Authors use hearing aids emphasizing also low tones; in the second one they modify the device, according more precise data turning out form audiometric evaluation and speech therapy. The results concerning a research on 27 children with profound hearing loss are debated; the application of hearing aids occurred in early age and the speech therapy followed the same criteria for all patients. The subjects were divided in two groups, homogeneous for age, degree of hearing loss and social environment. For the 12 children of groups A the "dynamic application" was used. For the 15 patients of group B the traditional strategy, using only devices for the amplification of medium and high tones, was applied. The best results concerning voice intonation and learning occlusive phonemas were obtained in group A subjects. The Authors, introducing their results and discussion, compare them with references data. In conclusion, the "dynamic application" is effective because of the better results in speech therapy and also because its ratio permits the application of hearing aids in children with hearing loss of different degrees, especially in the most difficult cases.

  18. Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia.

    PubMed

    Braithwaite, Steven P; Xu, Jian; Leung, John; Urfer, Roman; Nikolich, Karoly; Oksenberg, Donna; Lombroso, Paul J; Shamloo, Mehrdad

    2008-05-01

    Striatal enriched protein tyrosine phosphatase (STEP) acts in the central nervous system to dephosphorylate a number of important proteins involved in synaptic function including ERK and NMDA receptor subunits. These proteins are also linked to stroke, in which cerebral ischemia triggers a complex cascade of events. Here we demonstrate that STEP is regulated at both the transcriptional and the post-transcriptional levels in rat models of cerebral ischemia and that its regulation may play a role in the outcome of ischemic insults. After transient middle cerebral artery occlusion, there are profound decreases in the levels of STEP mRNA, whilst in global ischemia STEP mRNA is selectively down-regulated in areas susceptible to ischemic damage. In a neuroprotective preconditioning paradigm, and in regions of the brain that are relatively resistant to ischemic damage, STEP mRNA levels are increased. Furthermore, there is a significant processing of STEP after ischemia to generate a novel species, STEP(33), resulting in a redistribution of STEP from membrane-bound to soluble compartments. Concomitant with the cleavage of mature forms of STEP, there are changes in the phosphorylation state of ERK. We show that the cleavage of STEP leads to a catalytically active form, but this cleaved form no longer binds to and dephosphorylates its substrate pERK. Therefore, in response to ischemic insults, there are profound reductions in both the amount and the activity of STEP, its localization, as well as the activity of one of its key substrates, pERK. These changes in STEP may reflect a critical role in the outcomes of ischemic brain injury.

  19. Arogenate dehydratase isoenzymes profoundly and differentially modulate carbon flux into lignins.

    PubMed

    Corea, Oliver R A; Ki, Chanyoung; Cardenas, Claudia L; Kim, Sung-Jin; Brewer, Sarah E; Patten, Ann M; Davin, Laurence B; Lewis, Norman G

    2012-03-30

    How carbon flux differentially occurs in vascular plants following photosynthesis for protein formation, phenylpropanoid metabolism (i.e. lignins), and other metabolic processes is not well understood. Our previous discovery/deduction that a six-membered arogenate dehydratase (ADT1-6) gene family encodes the final step in Phe biosynthesis in Arabidopsis thaliana raised the fascinating question whether individual ADT isoenzymes (or combinations thereof) differentially modulated carbon flux to lignins, proteins, etc. If so, unlike all other lignin pathway manipulations that target cell wall/cytosolic processes, this would be the first example of a plastid (chloroplast)-associated metabolic process influencing cell wall formation. Homozygous T-DNA insertion lines were thus obtained for five of the six ADTs and used to generate double, triple, and quadruple knockouts (KOs) in different combinations. The various mutants so obtained gave phenotypes with profound but distinct reductions in lignin amounts, encompassing a range spanning from near wild type levels to reductions of up to ∼68%. In the various KOs, there were also marked changes in guaiacyl:syringyl ratios ranging from ∼3:1 to 1:1, respectively; these changes were attributed to differential carbon flux into vascular bundles versus that into fiber cells. Laser microscope dissection/pyrolysis GC/MS, histochemical staining/lignin analyses, and pADT::GUS localization indicated that ADT5 preferentially affects carbon flux into the vascular bundles, whereas the adt3456 knock-out additionally greatly reduced carbon flux into fiber cells. This plastid-localized metabolic step can thus profoundly differentially affect carbon flux into lignins in distinct anatomical regions and provides incisive new insight into different factors affecting guaiacyl:syringyl ratios and lignin primary structure.

  20. The 'placement' of people with profound impairments across the lifespan: re-thinking age criteria.

    PubMed

    Gibson, Barbara E; King, Gillian; Kingsnorth, Shauna; McKeever, Patricia

    2014-05-21

    Advances in lifesaving technologies and treatments make it possible for children with profound physical and cognitive impairments to survive into adulthood. Questions regarding how and where they should live are discussed rarely and, when they are, primarily focus on safety and/or containing costs. Since models of long-term care provision are age-based, children who reside in institutions are 'discharged' to adult facilities when they reach an arbitrary age. Such transfers may not be in the best interests of these young people or their families. Our aim in this debate is to highlight why age is a problematic criterion for placement decisions, with the goal of stimulating further research and inquiry. Transfers from pediatric to adult institutions are driven primarily by funding arrangements and underpinned by stage-based theories of human development. Arguments supporting such transfers point to the value of communal living with same age peers, and engagement in age-appropriate activities. These goals are questionable for individuals who are minimally interactive and/or where equally worthy interactions are feasible in intergenerational settings. Instead their accommodation needs might more closely align with palliative care principles of supporting individuals and families to enjoy what they bring to each other's lives and minimize suffering. Innovative models of 'vertical care' and 'lifetime homes', which enable continuous flexible services across the lifespan, are discussed as examples of alternative approaches requiring further debate and research. Entrenched funding and service models that require the transfer of profoundly impaired young people from pediatric to adult facilities need to be re-examined with considerations of best interests, needs, and preferences of individuals and their families. Questions of what constitutes a 'good life' for these individuals are tenacious and require further thought and research. Nevertheless, they need to be regarded as