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Sample records for ppargamma induces profound

  1. Activation of PPAR{gamma} is not involved in butyrate-induced epithelial cell differentiation

    SciTech Connect

    Ulrich, S.; Waechtershaeuser, A.; Loitsch, S.; Knethen, A. von; Bruene, B.; Stein, J. . E-mail: j.stein@em.uni-frankfurt.de

    2005-10-15

    Histone deacetylase-inhibitors affect growth and differentiation of intestinal epithelial cells by inducing expression of several transcription factors, e.g. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) or vitamin D receptor (VDR). While activation of VDR by butyrate mainly seems to be responsible for cellular differentiation, the activation of PPAR{gamma} in intestinal cells remains to be elucidated. The aim of this study was to determine the role of PPAR{gamma} in butyrate-induced cell growth inhibition and differentiation induction in Caco-2 cells. Treatment with PPAR{gamma} ligands ciglitazone and BADGE (bisphenol A diglycidyl) enhanced butyrate-induced cell growth inhibition in a dose- and time-dependent manner, whereas cell differentiation was unaffected after treatment with PPAR{gamma} ligands rosiglitazone and MCC-555. Experiments were further performed in dominant-negative PPAR{gamma} mutant cells leading to an increase in cell growth whereas butyrate-induced cell differentiation was again unaffected. The present study clearly demonstrated that PPAR{gamma} is involved in butyrate-induced inhibition of cell growth, but seems not to play an essential role in butyrate-induced cell differentiation.

  2. 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.

  3. 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

  4. 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.

  5. PPARgamma mediates NSAIDs-induced upregulation of TFF2 expression in gastric epithelial cells.

    PubMed

    Shimada, Tadahito; Koitabashi, Ayako; Fujii, Yoichiro; Hashimoto, Takashi; Hosaka, Kumi; Tabei, Kyoko; Namatame, Takashi; Yoneda, Masashi; Hiraishi, Hideyuki; Terano, Akira

    2004-01-30

    Trefoil factor family (TFF) is a group of peptides that play critical roles in maintaining gastric mucosal integrity. In real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and reporter gene assays, we show that indomethacin and aspirin upregulate TFF2 expression in MKN45 gastric cells. These drugs also activated peroxisome proliferator-activated receptor gamma (PPARgamma) at concentration ranges that increase TFF2 expression, and upregulated TFF2 expression was suppressed by GW9662, a specific inhibitor of PPARgamma. These results suggest that indomethacin and aspirin upregulate gastric expression of TFF2 through activation of PPARgamma. This mechanism may be important in reducing the extent of gastric mucosal injury caused by the administration of non-steroidal anti-inflammatory drugs (NSAIDs).

  6. Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone.

    PubMed

    Artunc, Ferruh; Sandulache, Diana; Nasir, Omaima; Boini, Krishna M; Friedrich, Björn; Beier, Norbert; Dicks, Edith; Pötzsch, Sven; Klingel, Karin; Amann, Kerstin; Blazer-Yost, Bonnie L; Scholz, Wolfgang; Risler, Teut; Kuhl, Dietmar; Lang, Florian

    2008-05-01

    PPARgamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARgamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARgamma agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARgamma agonists. To test this hypothesis, food containing the PPARgamma agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1-/-, n=12) and their wild-type littermates (sgk1+/+), n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1+/+ mice. The treatment increased body weight significantly in both, sgk1+/+ mice (+2.2+/-0.3 g) and sgk-/- mice (+1.3+/-0.2 g), and decreased hematocrit significantly in sgk1+/+ mice (-6.5+/-1.0%) and sgk1-/- mice (-3.1+/-0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1+/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1+/+ mice (from 50.9+/-3.9 to 63.7+/-2.5 microl/g bw) but not in sgk-/- mice (from 46.8+/-3.8 to 48.3+/-5.2 microl/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPARgamma agonist pioglitazone. PMID:18172605

  7. 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

  8. The Effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice.

    PubMed

    Harrington, W Wallace; S Britt, Christy; G Wilson, Joan; O Milliken, Naphtali; G Binz, Jane; C Lobe, David; R Oliver, William; C Lewis, Michael; M Ignar, Diane

    2007-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR) alpha, delta, and gamma subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARgamma agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARalpha agonist, GW0742, a PPARdelta agonist, GW7845, a PPARgamma agonist), combination of PPARalpha and delta agonists, and PPARpan (PPARalpha/gamma/delta) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARalpha or PPARdelta agonist treatment induced a slight decrease in fat mass (FM) while a PPARgamma agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARalpha and delta agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARdelta, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARalpha and PPARdelta activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARgamma agonist while either maintaining weight or producing weight loss.

  9. 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.

  10. Differential regulation of peroxisome proliferator activated receptor gamma1 (PPARgamma1) and PPARgamma2 messenger RNA expression in the early stages of adipogenesis.

    PubMed

    Saladin, R; Fajas, L; Dana, S; Halvorsen, Y D; Auwerx, J; Briggs, M

    1999-01-01

    Adipocyte differentiation is driven by the expression and activation of three transcription factor families: the differentially expressed CAAT/enhancer binding proteins (C/EBPs) alpha, beta, and delta; the helix-loop-helix adipocyte differentiation and determination factor-1; and peroxisome proliferator activated receptor gamma (PPARgamma), expressed as two isoforms, PPARgamma1 and the adipocyte-specific PPARgamma2. Overexpression of PPARgamma can induce adipocyte differentiation; therefore, we analyzed the expression of the two PPARgamma isoforms during early stages of differentiation to determine whether one was preferentially induced as an early determining event. Surprisingly, in the first 24 h, a 3-6-fold increase of PPARgamma2 mRNA was observed, whereas PPARgamma1 mRNA remained unchanged. PPARgamma1 was induced 1 day later. Overexpression of C/EBPbeta has also been shown to induce adipocyte differentiation. A C/EBP site was identified only in the human PPARgamma2 promoter. Its deletion blunted the response of PPARgamma2 promoter to cotransfected C/EBPbeta or methylisobutylxanthine treatment. We hypothesize that PPARgamma2 initiates adipocyte differentiation.

  11. 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

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

    PubMed

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

    2016-04-01

    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

  13. 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.

  14. 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.

  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. Acute profound abciximab induced thrombocytopenia: a correct management of a methodological error.

    PubMed

    Tanzilli, Gaetano; Sordi, Martina; Arrivi, Alessio; Mangieri, Enrico; Scappaticci, Massimiliano

    2009-01-01

    Thrombocytopenia is a rare complication of glycoprotein IIb/IIIa treatment. We report a case of an acute profound abciximab induced thrombocytopenia and its successful management. The patient, presenting with unstable angina, underwent percutaneous coronary intervention with implantation of three drug eluting stents without receiving a clopidogrel loading dose according to guidelines. The rapid drop in the platelet count after abciximab elastomeric pump infusion was treated with drug discontinuation and platelet transfusion. The high risk of stent thrombosis was avoided by a timely readministration of the dual antiplatelet treatment. PMID:21977060

  17. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.

    PubMed

    Choi, Jang Hyun; Banks, Alexander S; Estall, Jennifer L; Kajimura, Shingo; Boström, Pontus; Laznik, Dina; Ruas, Jorge L; Chalmers, Michael J; Kamenecka, Theodore M; Blüher, Matthias; Griffin, Patrick R; Spiegelman, Bruce M

    2010-07-22

    Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARgamma does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARgamma by Cdk5 is blocked by anti-diabetic PPARgamma ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARgamma phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARgamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARgamma.

  18. The NRIF3 Family of Transcriptional Coregulators Induces Rapid and Profound Apoptosis in Breast Cancer Cells

    PubMed Central

    Li, Dangsheng; Das, Sharmistha; Yamada, Tatsuya; Samuels, Herbert H.

    2004-01-01

    Many anticancer drugs kill cancer cells by inducing apoptosis. Despite the progress in understanding apoptosis, how to harness the cellular death machinery to selectively deliver tumor-specific cytotoxicity (while minimizing damage to other cells) remains an important challenge. We report here that expression of the NRIF3 family of transcriptional coregulators in a variety of breast cancer cell lines induces rapid and profound apoptosis (nearly 100% cell death within 24 h). A novel death domain (DD1) was mapped to a short 30-amino-acid region common to all members of the NRIF3 family. Mechanistic studies showed that DD1-induced apoptosis occurs through a novel caspase 2-mediated pathway that involves mitochondrial membrane permeabilization but does not require other caspases. Interestingly, the cytotoxicity of NRIF3 and DD1 appears to be cell type specific, as they selectively kill breast cancer or related cells but not other examined cells of different origins. Our study demonstrates the feasibility of selectively inducing cytotoxicity in a specific cancer and suggests that breast cancer cells contain a novel “death switch” that can be specifically triggered by NRIF3 or DD1. Strategies utilizing NRIF3 and/or DD1 and/or targeting this death switch may lead to the development of novel and more selective therapeutics against breast cancer. PMID:15082778

  19. 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.

  20. 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.

  1. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  2. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways.

  3. 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.

  4. 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}.

  5. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  7. 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.

  8. 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.

  9. 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.

  10. Structural insight into PPARgamma ligands binding.

    PubMed

    Farce, A; Renault, N; Chavatte, P

    2009-01-01

    Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetic efforts, more particularly PPARgamma. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARgamma. PMID:19442144

  11. Systemic PPARgamma ligation inhibits allergic immune response in the skin.

    PubMed

    Dahten, Anja; Koch, Christin; Ernst, Dennis; Schnöller, Corinna; Hartmann, Susanne; Worm, Margitta

    2008-09-01

    We have shown previously that specific ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit the systemic allergic immune response. The objective of this study was to investigate the impact of PPARgamma-ligand treatment on the local allergic immune response. We established a murine model exhibiting clinical and histological features of AD-like skin lesions with high reproducibility. In this model, the PPARgamma ligand was applied in an either preventive or therapeutic manner via systemic and local routes. The affected skin areas were assessed by standardized skin score, histological analyses, and immunohistochemical examinations. Our data show that systemic application of PPARgamma ligand by a preventive protocol led to significantly reduced onset of eczematous skin lesions. This was confirmed by histology, showing decreased skin thickness accompanied by significantly reduced infiltrations of CD4+ and CD8+ lymphocytes but also mast cells. Additionally, early allergen-specific IgE and IgG1 responses were reduced (day 21/35), whereas IgG2a levels remained unchanged. In conclusion, our results demonstrate that PPARgamma-ligand treatment inhibits not only systemic allergic immune response, but also local allergen-mediated dermatitis. Our findings point to therapeutic strategies, including a PPARgamma-ligand-based treatment. PMID:18401424

  12. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.

    PubMed

    Watkins, Steven M; Reifsnyder, Peter R; Pan, Huei-ju; German, J Bruce; Leiter, Edward H

    2002-11-01

    Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy. PMID:12401879

  13. Bilateral Entry and Release of Middle East Respiratory Syndrome Coronavirus Induces Profound Apoptosis of Human Bronchial Epithelial Cells

    PubMed Central

    Tao, Xinrong; Hill, Terence E.; Morimoto, Chikao; Peters, Clarence J.; Ksiazek, Thomas G.

    2013-01-01

    The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) infects human bronchial epithelial Calu-3 cells. Unlike severe acute respiratory syndrome (SARS)-CoV, which exclusively infects and releases through the apical route, this virus can do so through either side of polarized Calu-3 cells. Infection results in profound apoptosis within 24 h irrespective of its production of titers that are lower than those of SARS-CoV. Together, our results provide new insights into the dissemination and pathogenesis of MERS-CoV and may indicate that the virus differs markedly from SARS-CoV. PMID:23824802

  14. 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.

  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. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells

    PubMed Central

    Li, Robert W; Li, CongJun

    2006-01-01

    Background Global gene expression profiles of bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The bovine microarray with 86,191 distinct 60mer oligonucleotides, each with 4 replicates, was designed and produced with Maskless Array Synthesizer technology. These oligonucleotides represent approximately 45,383 unique cattle sequences. Results 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR) = 0 % were identified. The majority of these genes were repressed by butyrate and associated with cell cycle control. The expression levels of 30 selected genes identified by the microarray were confirmed using real-time PCR. The results from real-time PCR positively correlated (R = 0.867) with the results from the microarray. Conclusion This study presented the genes related to multiple signal pathways such as cell cycle control and apoptosis. The profound changes in gene expression elucidate the molecular basis for the pleiotropic effects of butyrate on biological processes. These findings enable better recognition of the full range of beneficial roles butyrate may play during cattle energy metabolism, cell growth and proliferation, and possibly in fighting gastrointestinal pathogens. PMID:16972989

  17. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.

    PubMed Central

    Schoonjans, K; Peinado-Onsurbe, J; Lefebvre, A M; Heyman, R A; Briggs, M; Deeb, S; Staels, B; Auwerx, J

    1996-01-01

    Increased activity of lipoprotein lipase (LPL) may explain the hypotriglyceridemic effects of fibrates, thiazolidinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator-activated receptors (PPARs). Treatment with compounds which activate preferentially PPARalpha, such as fenofibrate, induced LPL expression exclusively in rat liver. In contrast, the antidiabetic thiazolidinedione BRL 49653, a high affinity ligand for PPARgamma, had no effect on liver, but induced LPL expression in rat adipose tissue. In the hepatocyte cell line AML-12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3-L1 preadipocytes, the PPARgamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid. In both the in vivo and in vitro studies, inducibility by either PPARalpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte-restricted expression of PPARgamma, whereas PPARalpha was expressed predominantly in liver. A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolidinediones. Methylation interference and gel retardation assays demonstrated that a PPARalpha or gamma and the 9-cis retinoic acid receptor (RXR) heterodimers bind to this sequence -169 TGCCCTTTCCCCC -157. These data provide evidence that transcriptional activation of the LPL gene by fibrates and thiazolidinediones is mediated by PPAR-RXR heterodimers and contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPARgamma, fibrates exert their effects mainly in the liver via activation of PPARalpha. Images PMID:8895578

  18. Differential induction of PPAR-gamma by luminal glutamine and iNOS by luminal arginine in the rodent postischemic small bowel.

    PubMed

    Sato, N; Moore, F A; Kone, B C; Zou, L; Smith, M A; Childs, M A; Moore-Olufemi, S; Schultz, S G; Kozar, R A

    2006-04-01

    Using a rodent model of gut ischemia-reperfusion (I/R), we have previously shown that the induction of inducible nitric oxide synthase (iNOS) is harmful, whereas the induction of heme oxygenase 1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is protective. In the present study, we hypothesized that the luminal nutrients arginine and glutamine differentially modulate these molecular events in the postischemic gut. Jejunal sacs were created in rats at laparotomy, filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 min of superior mesenteric artery occlusion and 6 h of reperfusion, and compared with shams. The jejunum was harvested for histology or myeloperoxidase (MPO) activity (inflammation). Heat shock proteins and iNOS were quantitated by Western blot analysis and PPAR-gamma by DNA binding activity. In some experiments, rats were pretreated with the PPAR-gamma inhibitor G9662 or with the iNOS inhibitor N-[3(aminomethyl)benzyl]acetamidine (1400W). iNOS was significantly increased by arginine but not by glutamine following gut I/R and was associated with increased MPO activity and mucosal injury. On the other hand, PPAR-gamma was significantly increased by glutamine but decreased by arginine, whereas heat shock proteins were similarly increased in all experimental groups. The PPAR-gamma inhibitor G9662 abrogated the protective effects of glutamine, whereas the iNOS inhibitor 1400W attenuated the injurious effects of arginine. We concluded that luminal arginine and glutamine differentially modulate the molecular events that regulate injurious I/R-mediated gut inflammation and injury. The induction of PPAR-gamma by luminal glutamine is a novel protective mechanism, whereas luminal arginine appears harmful to the postischemic gut due to enhanced expression of iNOS.

  19. 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.

  20. Macrophage polarisation by fatty acids is PPARgamma-dependent.

    PubMed

    Pararasa, Chatyan; Bailey, Clifford; Griffiths, Helen

    2014-10-01

    Elevated plasma free fatty acids (FAs) are associated with increased risk of cardiovascular disease. We investigated the effects of the saturated FA palmitate and unsaturated FA oleate on monocyte phenotype and function. Palmitate increased cell surface expression of integrin CD11b and scavenger receptor CD36 in a concentration-dependent manner with some decrease in mitochondrial reducing capacity at high concentration (300µM). Monocytes incubated with palmitate, but not oleate, showed increased uptake of oxidized LDL and increased adhesion to rat aortic endothelium, particularly at bifurcations. The palmitate-induced increase in CD11b and CD36 expression was associated with increased cellular C16 ceramide and sphingomyelin, loss of reduced glutathione, and increased reactive oxygen species (ROS). Increased monocyte surface CD11b and CD36 was inhibited by fumonisin B1, an inhibitor of de novo ceramide synthesis, but not by the superoxide dismutase mimetic MnTBap. In contrast, MnTBap prevented the mitochondrial ROS increase and metabolic inhibition due to 300µM palmitate. This study demonstrates that in viable monocytes, palmitate but not oleate increases expression of surface CD11b and CD36. Palmitate increases monocyte adhesion to the aortic wall and promotes uptake of oxidized LDL and this involves de novo ceramide synthesis. We have also explored whether specific dietary fatty acids drive monocyte to macrophage polarisation via metabolic pathways. Here we show that monocytes pre-incubated with the saturated fatty acid palmitate increase production of inflammatory cytokines such as TNFa and IL-6 in response to a phorbol myristate differentiation trigger. This increases mitochondrial superoxide production, reduces dependency on oxidative phosphorylation through ceramide-dependent inhibition of PPARgamma activity and increases TNFa production, again via a mechanism that requires ceramide production. PMID:26461339

  1. 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 these…

  2. 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.

  3. 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.

  4. 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.

  5. [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)].

    PubMed

    Dubois, M; Vantyghem, M-C; Schoonjans, K; Pattou, F

    2002-12-01

    Thiazolidinediones (TZDs) form a new class of oral antidiabetic agents. They improve insulin sensitivity and reduce glycemia, lipidemia and insulinemia in patients with type 2 diabetes. Their mechanism is original, since they activate the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), altering the expression of genes involved in glucose and lipid homeostasis. Stimulating PPARgamma improves insulin sensitivity via several mechanisms: 1) it raises the expression of GLUT4 glucose transporter; 2) it regulates release of adipocyte-derived signaling factors that affect insulin sensitivity in muscle, and 3) it contributes to a turn-over in adipose tissue, inducing the production of smaller, more insulin sensitive adipocytes. TZDs also affect free fatty acids (FFA) lipotoxicity on islets, improving pancreatic B-cell function. In addition, triglycerides and FFA levels are lowered by TZDs. Two TZDs, rosiglitazone and pioglitazone, have recently obtained the European commercial licence, but their use is restricted to the association with metformin or sulfonylureas. At the moment, they are indicated in type 2 diabetes but could be of interest in a broader array of diseases related to insulin resistance. As for side effects, rosiglitazone and pioglitazone may cause increased plasma volume, edema and dose-related weight gain. TZDs offer an attractive option in the treatment of type 2 diabetes, though it may be too soon to determine if they prevent vascular complications, as do other oral antidiabetic agents. An important issue for the future will be to assess the influence of weight gain in the long time. PMID:12527853

  6. 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.

  7. PPARgamma1 synthesis and adipogenesis in C3H10T1/2 cells depends on S-phase progression, but does not require mitotic clonal expansion.

    PubMed

    Cho, Young C; Jefcoate, Colin R

    2004-02-01

    sensitivity to G1/S, but not G2/M inhibitors. Importantly, growth arrest occurred in all differentiating cells, while continuous mitotic clonal expansion occurred in non-differentiating cells. Irrespective of confluence level, 10T1/2 cells differentiate after progression through S-phase, where adipogenic commitment induced by IDM stimulation is a prerequisite for PPARgamma synthesis and subsequent adipocyte differentiation.

  8. 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.

  9. 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.

  10. 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. PMID:10383160

  11. 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.

  12. The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPARgamma.

    PubMed

    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 PPARgamma. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPARgamma in a dose-dependent manner. DAX-1 directly competed with the PPARgamma coactivator (PGC)-1alpha for binding to PPARgamma. 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 PPARgamma target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPARgamma and performs a potential function in the regulation of PPARgamma-mediated cellular differentiation. PMID:18381063

  13. 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.

  14. 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.

  15. 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.

  16. Peroxisome proliferator-activated receptor gamma ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia.

    PubMed

    Zang, Chuanbing; Liu, Hongyu; Posch, Maximilian G; Waechter, Maries; Facklam, Margit; Fenner, Martin H; Ruthardt, Martin; Possinger, Kurt; Phillip Koeffler, H; Elstner, Elena

    2004-04-01

    This study examined the expression and structural intactness of peroxisome proliferator-activated receptor gamma (PPARgamma) in human acute lymphocytic leukemia (ALL) cells and determined the effect of PPARgamma ligands on growth and apoptosis of these cells. We noted that all lymphocytic leukemia cell lines expressed PPARgamma and no PPARgamma mutations were found in these cell lines as indicated by SSCP analysis. Effect of the PPARgamma ligands on the proliferation, differentiation and apoptosis of B type ALL cells was further examined. Treatment of these cells with the PPARgamma ligands Pioglitazone (PGZ) and 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) resulted in growth inhibition in a dose-dependent manner which was associated with a G1 to S cell cycle arrest. However, this effect appeared to be PPARgamma-independent since several PPARgamma antagonists could not reverse this effect. No differentiation was induced by this treatment. Four out of five cell lines underwent apoptosis after culture with the PPARgamma ligands. This effect was partially caspase-dependent because a pan-caspase inhibitor partially reversed this effect. In conclusion, our results suggest that PPARgamma ligands may offer a new therapeutic approach to aid in the treatment of ALL. PMID:15109539

  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. 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.

  19. 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.

  20. Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid.

    PubMed

    Tsukahara, Tamotsu; Tsukahara, Ryoko; Fujiwara, Yuko; Yue, Junming; Cheng, Yunhui; Guo, Huazhang; Bolen, Alyssa; Zhang, Chunxiang; Balazs, Louisa; Re, Fabio; Du, Guangwei; Frohman, Michael A; Baker, Daniel L; Parrill, Abby L; Uchiyama, Ayako; Kobayashi, Tetsuyuki; Murakami-Murofushi, Kimiko; Tigyi, Gabor

    2010-08-13

    Cyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARgamma with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARgamma target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARgamma inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARgamma, revealing that PPARgamma is regulated by endogenous agonists as well as by antagonists. PMID:20705243

  1. PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

    SciTech Connect

    Lee, Seong-Ryong; Kim, Hahn-Young; Hong, Jung-Suk; Baek, Won-Ki; Park, Jong-Wook

    2009-02-27

    Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

  2. 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. PMID:27225220

  3. 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.

  4. 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}.

  5. 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

  6. 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.

  7. 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

    2015-11-01

    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.

  8. 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.

  9. 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.

  10. Discrimination Learning in Profoundly Retarded Children.

    ERIC Educational Resources Information Center

    Suib, Michael R.; And Others

    1980-01-01

    A study investigating the discrimination abilities of two crib-bound, cerebral palsied, profoundly retarded females demonstrates the importance of individual differences among such children and suggests that discriminative responding may be demonstrated by at least some profoundly retarded children, particularly if distributed practice is employed…

  11. Rapid endovascular warming for profound hypothermia.

    PubMed

    Laniewicz, Megan; Lyn-Kew, Kenneth; Silbergleit, Robert

    2008-02-01

    Profound hypothermia is associated with high mortality and morbidity. Optimal outcomes have been reported with invasive extracorporeal warming techniques not readily available in most hospitals. Endovascular warming devices may provide a less invasive alternative. A 68-year-old woman developed profound hypothermia after environmental exposure. On arrival, she was comatose, severely bradycardic, without palpable pulses, and with a core body temperature of 23.0 degrees C (72 degrees F). Attempts to warm her with traditional methods during 2 hours were ineffective. An endovascular temperature control system was placed and effectively warmed the patient at about 3 degrees C (4.5 degrees F) per hour, with return of hemodynamic stability. When hypothermia is profound, surface warming works poorly and invasive strategies, including cardiopulmonary bypass, are recommended. Rapid warming from profound hypothermia can be accomplished with endovascular systems, and these may be an effective alternative to more invasive extracorporeal methods. PMID:17681640

  12. 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.

  13. 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}.

  14. 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…

  15. 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.

  16. 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.

  17. 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.

  18. 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}.

  19. 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.

  20. Constitutive Ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra.

    PubMed

    Mijatovic, Jelena; Airavaara, Mikko; Planken, Anu; Auvinen, Petri; Raasmaja, Atso; Piepponen, T Petteri; Costantini, Frank; Ahtee, Liisa; Saarma, Mart

    2007-05-01

    Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system. PMID:17475787

  1. Profound duodenogastric reflux causes pancreatic growth in rats.

    PubMed Central

    Gasslander, T; Mukaida, H; Herrington, M K; Hinder, R A; Adrian, T E

    1995-01-01

    Although duodenogastric reflux is a physiological event, excessive reflux may be a pathogenetic factor in several diseases of the foregut, including cancer. Long term profound duodenogastric reflux produces pancreatic and gastric tumours in rats. The trophic effect of surgically induced duodenogastric reflux on the pancreas was investigated and the mechanisms involved were examined. Rats with profound reflux from a split gastroenterostomy were compared with sham operated and unoperated controls after two and six weeks. In the six week experiment, one reflux and one sham group were given the cholecystokinin (CCK) receptor antagonist devazepide (25 nmol/kg/h). Duodenogastric reflux caused a significant increase in pancreatic weight, DNA, and plasma CCK and gastrin concentrations at both two and six weeks. Devazepide substantially reduced the pancreatic weight increase after six weeks but did not abolish it completely. CCK and gastrin were not affected by devazepide. These results suggest that CCK is largely responsible for the pancreatic growth induced by reflux but another factor may also be involved. The trophic effect of duodenogastric reflux may contribute to the increased incidence of pancreatic cancer reported after gastric surgery. PMID:7890218

  2. Management of Children with Severe, Severe-profound, and Profound Sensorineural Hearing Loss.

    PubMed

    Iseli, Claire; Buchman, Craig A

    2015-12-01

    Management of children with severe, severe-profound, and profound sensorineural hearing loss is best achieved using a family-centered approach by a team of health professionals, including audiologists, speech pathologists, otolaryngologists, pediatricians, genetic counselors, and early intervention programs. Early diagnosis and intervention offers the best chance for speech and language acquisition. Although hearing aids can provide some of the needed information, they are often not sufficient for spoken language development and a cochlear implant is needed. This must be combined with a strong audiology and speech therapy rehabilitation program.

  3. 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.

  4. Personality study in profoundly deaf adults.

    PubMed

    Sánchez Galán, L; Díez Sánchez, M A; Llorca Ramón, G; del Cañizo Fernández-Roldán, A

    2000-01-01

    The difference with which the pre-lingual and post-lingual profoundly deaf confront their deafness is evident: the reticence of many pre-lingual deaf persons when faced with technological advances and genetic investigations is not present among the post-lingual deaf. This article looks at this difference from the person as a whole, and aims to carry out a comparative study of the personalities of both groups and of the non-deaf. To this end, three samples were taken (one of pre-lingual deaf persons, one of post-lingual deaf persons and a third of non-deaf persons) and the Mini-Mult personality questionnaire was employed as a measuring instrument. Significant differences were found in 5 clinical scales: Hs (hypochondria), Hy (hysteria), Pa (paranoia), Pt (psychastenia), Sc (schizophrenia). The differences between the deaf and the non-deaf are statistically significant. The profile obtained for the pre-lingual deaf is high on the schizophrenia scale (Sc), and suggests a kind of person where the said scale might detect isolation derived from deafness. The profile of the post-lingual deaf, marked by the hypochondria scale, shows persons with severe hypersensibility and fears regarding their state of health. The significant influence of variables such as level of education and state of employment on the post-lingual deaf and, in particular, on his feeling of loneliness and his worries regarding his deafness, his state of mind and his possible paranoiac tendencies, makes them factors that must be taken into consideration when fundamentally evaluating the personality of a post-lingual deaf person. These personality traits influence the way a profoundly deaf person confronts his deafness. PMID:11387661

  5. Autoradiographical imaging of PPARgamma agonist effects on PBR/TSPO binding in TASTPM mice.

    PubMed

    Roberts, Jennifer C; Friel, Sarah L; Roman, Shilina; Perren, Marion; Harper, Alex; Davis, John B; Richardson, Jill C; Virley, David; Medhurst, Andrew D

    2009-04-01

    Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD. An age dependent increase in specific [3H](R)-PK11195 binding to peripheral benzodiazepine receptors (PBR)/translocator protein (18 kDa) (TSPO) was observed in the cortex of TASTPM mice compared to wild type mice, indicative of microglial activation. This was consistent with immunohistochemical data showing age-dependent increases in CD68 immunoreactivity co-localised with amyloid beta (Abeta) deposits. In 10 month old TASTPM mice, pioglitazone (20 mg/kg) and ciglitazone (50 mg/kg) significantly reduced [3H](R)-PK11195 and [3H]DPA-713 binding in cortex and hippocampus, indicative of reduced microglial activation. In AD brain, significant [3H](R)-PK11195 and [3H]DPA-713 binding was observed across all stages of the disease. These results support the use of PBR/TSPO autoradiography in TASTPM mice as a functional readout of microglial activation to assess anti-inflammatory drugs prior to evaluation in AD patients.

  6. Investigation of the lipophilic behaviour of some thiazolidinediones. Relationships with PPAR-gamma activity.

    PubMed

    Giaginis, Costas; Theocharis, Stamatios; Tsantili-Kakoulidou, Anna

    2007-10-01

    Various lipophilicity aspects of five well-known PPAR-gamma ligands, belonging to the thiazolidinedione (TZD) class, ciglitazone (CSZ), troglitazone (TGZ), netoglitazone (NGZ) and the ampholytic pioglitazone (PGZ) and rosiglitazone (RGZ), have been explored. The compounds were found to be highly lipophilic as assessed by direct octanol-water partitioning experiments and further confirmed by reversed phase HPLC measurements under different conditions. Immobilised artificial membrane (IAM) chromatographic indices were also determined as an alternative expression of lipophilicity. They were found to show less diversity forming two clusters. Experimental logD/logP values were compared to those predicted by three widely used calculation systems. For the two ampholytic TZDs, the lipophilicity and retention/pH profiles were established over a broad pH range and compared to the corresponding calculated profiles. Lipophilicity indices derived under the different conditions were further compared to biological activity, concerning in vitro transactivation (pEC(50)) and binding affinity (pK(i)) data, taken from literature. The most active TZD (RGZ) in both transactivation and binding assay proved to be the less lipophilic analogue. An equation relating pEC(50) data to experimental logD(7.4) or reversed-phase logk(w) values could be established, while pK(i) data did not lead to satisfactory correlation.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

  12. M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles.

    PubMed

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

    2013-02-01

    Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point toward 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 toward 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 micro 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 were made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 vs. 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

  13. 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

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

    PubMed

    Zhang, Yanqiong; Mao, Xia; Guo, Qiuyan; Bai, Ming; Zhang, Bo; Liu, Chunfang; Sun, Yanqun; Li, Shao; Lin, Na

    2016-03-29

    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

  15. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats.

    PubMed

    Tanaka, T; Kohno, H; Yoshitani, S; Takashima, S; Okumura, A; Murakami, A; Hosokawa, M

    2001-03-15

    The biological role of the peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARgamma ligands have been found to inhibit mammary carcinogenesis in rodents, the effects on colon tumorigenesis are controversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPARalpha and PPARgamma) on colitis and an early phase of colitis-related colon carcinogenesis in male F344 rats. In the first experiment, gastric gavage of troglitazone (PPARgamma ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPARalpha ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextran sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic mucosa. In the second experiment, dietary administration (0.01 or 0.05% in diet) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxymethane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced formation of aberrant crypts foci, which are precursor lesions for colon carcinoma. In the third experiment, dietary administration (0.01% in diet for 6 weeks) of pioglitazone (PPARgamma ligand), troglitazone, and bezafibrate effectively suppressed DSS/AOM-induced ACF. Administration of both ligands significantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPARalpha and PPARgamma) can inhibit the early stages of colon tumorigenesis with or without colitis.

  16. Epilepsy: Impact upon Severely and Profoundly Handicapped Persons.

    ERIC Educational Resources Information Center

    Spooner, Fred; Dykes, Mary K.

    1982-01-01

    The paper synthesizes information about epilepsy (definition and categories of seizures, types of seizures, and treatment) and notes its impact upon persons with severe/profound handicaps. The need for a transdisciplinary team in case management is cited. (CL)

  17. Metabolic Surgery Profoundly Influences Gut Microbial-Host Metabolic Crosstalk

    PubMed Central

    Li, Jia V.; Ashrafian, Hutan; Bueter, Marco; Kinross, James; Sands, Caroline; le Roux, Carel W; Bloom, Stephen R.; Darzi, Ara; Athanasiou, Thanos; Marchesi, Julian R.; Nicholson, Jeremy K.; Holmes, Elaine

    2013-01-01

    Background and Aims Bariatric surgery is increasingly performed worldwide to treat morbid obesity and is also known as metabolic surgery to reflect its beneficial metabolic effects especially with respect to improvement in type 2 diabetes. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. Methods We apply a parallel and statistically integrated metagenomic and metabonomic approach to characterize Roux-en-Y gastric bypass (RYGB) effects in a rat model. Results We show substantial shifts of the main gut phyla towards higher levels of Proteobacteria (52-fold) specifically Enterobacter hormaechei. We also find low levels of Firmicutes (4.5-fold) and Bacteroidetes (2-fold) in comparison to sham-operated rats. Faecal extraction studies reveal a decrease in faecal bile acids and a shift from protein degradation to putrefaction through decreased faecal tyrosine with concomitant increases in faecal putrescine and diamnoethane. We find decreased urinary amines and cresols and demonstrate indices of modulated energy metabolism post-RYGB including decreased urinary succinate, 2-oxoglutarate, citrate and fumarate. These changes could also indicate renal tubular acidosis, which associates with increased flux of mitochondrial tricarboxylic acid cycle intermediates. A surgically-induced effect on the gut-brain-liver metabolic axis is inferred by increased neurotropic compounds; faecal γ-aminobutyric acid (GABA) and glutamate. Conclusion This profound co-dependence of mammalian and microbial metabolism, which is systematically altered following RYGB surgery, suggests that RYGB exerts local and global metabolic activities. The effect of RYGB surgery on the host metabolic-microbial crosstalk augments our understanding of the metabolic phenotype of bariatric procedures and can facilitate enhanced treatments for obesity-related diseases. PMID:21572120

  18. 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.

  19. 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.

  20. 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.

  1. Catalase potentiates retinoic acid-induced THP-1 monocyte differentiation into macrophage through inhibition of peroxisome proliferator-activated receptor gamma.

    PubMed

    Ding, Qiurong; Jin, Ting; Wang, Zhenzhen; Chen, Yan

    2007-06-01

    Macrophage differentiation plays a pivotal role in cardiovascular diseases and many other physiological processes. However, the role of reaction oxygen species in macrophage differentiation has not been elucidated. Here, we report functional characterization of catalase, an enzyme that degrades hydrogen peroxide (H(2)O(2)), in THP-1 monocyte differentiation. Treatment of THP-1 cells with catalase was able to synergize with all-trans retinoic acid (ATRA) to enhance macrophage differentiation, demonstrated by changes of cell adherence, cell cycle arrest, nitroblue tetrazolium reduction, and expression of differentiation markers including CD68, CD11b, and matrix metalloproteinase 9 (MMP9). ATRA could stimulate retinoic acid (RA) receptor-mediated transcription, but this was not affected by catalase. However, ATRA and catalase were capable of reducing transcriptional activity mediated by peroxisome proliferator-activated receptor gamma (PPARgamma). Consistently, PPARgamma antagonists enhanced, and PPARgamma agonists inhibited MMP9 expression stimulated by ATRA and catalase in THP-1 cells. Therefore, these data indicate that catalase is able to potentiate ATRA-induced macrophage differentiation by inhibition of PPARgamma activity, underscoring an important interplay between H(2)O(2), RA, and PPARgamma in macrophages.

  2. 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.

  3. 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…

  4. 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…

  5. 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…

  6. Evaluating Optic Microswitches with Students with Profound Multiple Disabilities.

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Oliva, Doretta

    2003-01-01

    Two students (ages 7 and 8) who were totally blind with profound motor impairments and mental retardation were provided with optic microswitches. The use of optic microswitches for simple hand responses, combined with the availability of pleasant stimuli for the responses, proved successful with both students. (Contains 9 references.) (CR)

  7. Deming's System of Profound Knowledge: An Overview for International Educators.

    ERIC Educational Resources Information Center

    Evans, Thomas J.

    W. Edwards Deming called for the transformation to a new style of organizational management based on greater cooperation between managers and employees. This transformation could be achieved by introducing "profound knowledge" into the system. This paper is a presentation outline that was used to introduce the basics of Deming's theory of…

  8. 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…

  9. 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…

  10. 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;…

  11. Profound Hematuria in a Toddler Yields an Unusual Diagnosis

    PubMed Central

    Young, Ezekiel E.; Gandhi, Nilay; Stuhldreher, Peter; Bishop, Justin A.; Wang, Ming-Hsien

    2016-01-01

    Herein we present a rare case of profound recurrent gross hematuria in a young child with no known predisposing event. She was eventually diagnosed with a large lymphovascular malformation of the bladder. She underwent multiple unsuccessful attempts at embolization before eventual curative partial cystectomy. PMID:27175341

  12. Profound Hematuria in a Toddler Yields an Unusual Diagnosis.

    PubMed

    Young, Ezekiel E; Gandhi, Nilay; Stuhldreher, Peter; Bishop, Justin A; Wang, Ming-Hsien

    2016-05-01

    Herein we present a rare case of profound recurrent gross hematuria in a young child with no known predisposing event. She was eventually diagnosed with a large lymphovascular malformation of the bladder. She underwent multiple unsuccessful attempts at embolization before eventual curative partial cystectomy. PMID:27175341

  13. Teaching the Severely and Profoundly Handicapped: Some Basic Issues.

    ERIC Educational Resources Information Center

    Haring, Norris; Csapo, Marg

    1980-01-01

    Problems in the public school education of profoundly mentally handicapped students and findings of recent research on the teaching of this population are discussed. Early educational intervention is one key to reducing the effects of retardation. Basic daily living skills, such as communication and grooming, should be taught through systematic…

  14. 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…

  15. 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…

  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. Anorexia nervosa in an adolescent with early profound deafness.

    PubMed

    Touyz, S; O'Sullivan, B; Beumont, P J

    1994-12-01

    This paper reports a case of anorexia nervosa in a 15-year-old schoolgirl who had been profoundly deaf since birth. She was admitted to a specialized eating disorders unit following a dramatic reduction in her weight. Her deafness and limited communication skills posed significant problems with regard to her overall management on the unit. Her clinical presentation and difficulties in management are presented.

  18. Collagenous gastritis: an unusual association with profound weight loss.

    PubMed

    Wang, Hanlin L; Shah, Amit G; Yerian, Lisa M; Cohen, Russell D; Hart, John

    2004-02-01

    Collagenous gastritis is a distinctive disorder characterized by thickening of the subepithelial collagen layer in the gastric mucosa. Although this entity was recognized in 1989, its etiology, pathogenesis, and clinicopathologic features remain poorly understood because of its rarity. An unusual case of collagenous gastritis was observed in a 37-year-old man who presented with profound weight loss, a feature that has not previously been emphasized. PMID:14736276

  19. High incidence of profound deafness in an isolated community.

    PubMed

    Zlotogora, Joel; Barges, Saleh

    2003-01-01

    In a Muslim Israeli Arab village, different types of hearing loss affect some 2% of the inhabitants. Most cases of profound deafness are due to recessive mutations in the Connexin-26 gene. Since in this community, marriages are by preference within the family (consanguineous), for many of the couples from the village the risk for an affected child is high. There are 30 families living in the village in which both parents have normal hearing and at least one child has a profound hearing defect. In these families, the birth of a child with profound deafness did not change family planning. The rate of marriage was similar for the siblings of deaf children as for other individuals in the village. The major problems were encountered by the deaf individuals themselves; in particular, most of the women were not married. Because of the distinctive nature of this particular problem, different types of screening programs were envisaged. However, all of them are problematic. Therefore, as a first step it was decided to begin a program including individual genetic counseling together with education of the entire population on practical aspects of human genetics.

  20. The Mediterranean diet protects against waist circumference enlargement in 12Ala carriers for the PPARgamma gene: 2 years' follow-up of 774 subjects at high cardiovascular risk.

    PubMed

    Razquin, Cristina; Alfredo Martinez, J; Martinez-Gonzalez, Miguel A; Corella, Dolores; Santos, José Manuel; Marti, Amelia

    2009-09-01

    The PPARgamma gene regulates insulin sensitivity and adipogenesis. The Pro12Ala polymorphism of this gene has been related to fat accumulation. Our aim was to analyse the effects of a 2-year nutritional intervention with Mediterranean-style diets on adiposity in high-cardiovascular risk patients depending on the Pro12Ala polymorphism of the PPARgamma gene. The population consisted of a substudy (774 high-risk subjects aged 55-80 years) of the Prevención con Dieta Mediterránea (PREDIMED) randomised trial aimed at assessing the effect of the Mediterranean diet for CVD prevention. There were three nutritional intervention groups: two of them of a Mediterranean-style diet and the third was a control group advised to follow a conventional low-fat diet. All the participants were genotyped by PCR-restriction fragment length polymorphism (RFLP). The results showed that carriers of the 12Ala allele allocated to the control group had a statistically significant higher change in waist circumference (adjusted difference coefficient = 2.37 cm; P = 0.014) compared with wild-type subjects after 2 years of nutritional intervention. This adverse effect was not observed among 12Ala carriers allocated to both Mediterranean diet groups. In diabetic patients a statistically significant interaction between Mediterranean diet and the 12Ala allele regarding waist circumference change was observed ( - 5.85 cm; P = 0.003). In conclusion, the Mediterranean diet seems to be able to reduce waist circumference in a high-cardiovascular risk population, reversing the negative effect that the 12Ala allele carriers of the PPARgamma gene appeared to have. The beneficial effect of this dietary pattern seems to be higher among type 2 diabetic subjects. PMID:19267951

  1. 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.

  2. Curcumin promotes cholesterol efflux from adipocytes related to PPARgamma-LXRalpha-ABCA1 passway.

    PubMed

    Dong, Shao-zhuang; Zhao, Shui-ping; Wu, Zhi-hong; Yang, Jun; Xie, Xiang-zhu; Yu, Bi-lian; Nie, Sai

    2011-12-01

    Curcumin affects the functions of adipocytes. But it is not known whether curcumin has some effect on the cholesterol efflux process of adipocytes. Rabbit subcutaneous adipocytes were incubated with 5, 10 and 20 μg/ml curcumin for 24 h. The cholesterol efflux onto apoAI was assessed, and the peroxisome proliferators-activated receptor (PPAR) γ, liver X receptor (LXR) α and ATP-binding cassette transporter A1 (ABCA1) mRNA expression in adipocytes were quantified by reverse-transcription polymerase chain reaction (RT-PCR). Curcumin increased the cholesterol efflux from adipocytes in dose-dependent manner. The increased expression of PPARγ, LXRα and ABCA1 caused by curcumin were parallel. When the adipocytes were pre-treated by GW9662, the increased expression of PPARγ induced by curcumin was partially prevented, subsequent to the down-regulation of LXRα and ABCA1. Curcumin can affect the cholesterol efflux from adipocytes by regulating the PPARγ-LXR-ABCA1 passway.

  3. Enteral glutamine: a novel mediator of PPARgamma in the postischemic gut.

    PubMed

    Ban, Kechen; Kozar, Rosemary A

    2008-09-01

    Early enteral nutrition supplemented with glutamine, arginine, omega-3 fatty acids, and nucleotides has been shown to decrease infection complications in critically injured patients. Concern has been raised, however, that under conditions of hyperinflammation, these diets may be injurious through the induction of inducible NO synthase by enteral arginine. In a rodent model of gut ischemia/reperfusion, inflammation and injury are intensified by enteral arginine and abrogated by glutamine. These findings correlate with the degree of metabolic stress imposed upon the gut by hypoperfusion. Glutamine is metabolized by the gut and therefore, can contribute back energy in the form of ATP, whereas arginine is a nonmetabolizable nutrient, using but not contributing energy. Recent data suggest that one of the molecular mechanisms responsible for the gut-protective effects of enteral glutamine is the activation of peroxisome proliferator-activated receptor gamma. This anti-inflammatory transcription factor belongs to the family of nuclear receptors, plays a key role in adipocyte development and glucose homeostasis, and has been recognized as an endogenous regulator of intestinal inflammation. Preliminary clinical studies support the use of enteral glutamine in patients with gut hypoperfusion.

  4. Prevalence, aetiology, and care of severe and profound hearing loss.

    PubMed Central

    Baille, M F; Arnaud, C; Cans, C; Grandjean, H; du Mazaubrun, C; Rumeau-Rouquette, C

    1996-01-01

    Severe and profound hearing loss (> 70 dB) were analysed in a retrospective study of 226 children, born between 1976 and 1985, and recruited from three French administrative departments. The prevalence was 0.54 per 1000 children under 9 years old, with no decrease over the study period. A hereditary origin was identified in 20.8% of cases and an infectious origin in 11.5%. Perinatal risk factors were present in 11.5%, while the aetiology was undetermined in more than half the cases. In 85.8% of the children there was no other severe impairment. Marked learning difficulties were observed: 36% of the children were two years behind their age group and 28% were more than two years behind. The age of initial care decreased over the study period but is still too advanced. Systematic neonatal screening would enable earlier care, which should limit the social and educational impact of hearing loss. PMID:8869193

  5. 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. PMID:27555184

  6. Encoding voice pitch for profoundly hearing-impaired listeners.

    PubMed

    Grant, K W

    1987-08-01

    The ability of five profoundly hearing-impaired subjects to "track" connected speech and to make judgments about the intonation and stress in spoken sentences was evaluated under a variety of auditory-visual conditions. These included speechreading alone, speechreading plus speech (low-pass filtered at 4 kHz), and speechreading plus a tone whose frequency, intensity, and temporal characteristics were matched to the speaker's fundamental frequency (F0). In addition, several frequency transfer functions were applied to the normal F0 range resulting in new ranges that were both transposed and expanded with respect to the original F0 range. Three of the five subjects were able to use several of the tonal representations of F0 nearly as well as speech to improve their speechreading rates and to make appropriate judgments concerning sentence intonation and stress. The remaining two subjects greatly improved their identification performance for intonation and stress patterns when expanded F0 signals were presented alone (i.e., without speechreading), but had difficulty integrating visual and auditory information at the connected discourse level, despite intensive training in the connected discourse tracking procedure lasting from 27.8-33.8 h.

  7. Degree of oxidation of low density lipoprotein affects expression of CD36 and PPARgamma, but not cytokine production, by human monocyte-macrophages.

    PubMed

    Kavanagh, Ian C; Symes, Carole E; Renaudin, Pauline; Nova, Esther; Mesa, Maria Dolores; Boukouvalas, George; Leake, David S; Yaqoob, Parveen

    2003-06-01

    Oxidized low-density lipoprotein (oxLDL) exhibits many atherogenic effects, including the promotion of monocyte recruitment to the arterial endothelium and the induction of scavenger receptor expression. However, while atherosclerosis involves chronic inflammation within the arterial intima, it is unclear whether oxLDL alone provides a direct inflammatory stimulus for monocyte-macrophages. Furthermore, oxLDL is not a single, well-defined entity, but has structural and physical properties which vary according to the degree of oxidation. We tested the hypothesis that the biological effects of oxLDL will vary according to its degree of oxidation and that some species of oxLDL will have atherogenic properties, while other species may be responsible for its inflammatory activity. The atherogenic and inflammatory properties of LDL oxidized to predetermined degrees (mild, moderate and extensive oxidation) were investigated in a single system using human monocyte-derived macrophages. Expression of CD36 mRNA was up-regulated by mildly- and moderately-oxLDL, but not highly-oxLDL. The expression of the transcription factor, proliferator-activated receptor-gamma (PPARgamma), which has been proposed to positively regulate the expression of CD36, was increased to the greatest degree by highly-oxLDL. However, the DNA binding activity of PPARgamma was increased only by mildly- and moderately-oxLDL. None of the oxLDL species appeared to be pro-inflammatory towards monocytes, either directly or indirectly through mediators derived from lymphocytes, regardless of the degree of oxidation.

  8. Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice

    PubMed Central

    1985-01-01

    We have shown that a mixture of murine leukemia viruses (MuLV) causes the acute onset of lymphoproliferation and immunosuppression when injected into adult C57BL/6 mice. The ecotropic/MCF (mink cell focus- inducing) mixture of MuLV stimulates polyclonal B lymphocyte proliferation and differentiation to antibody-secreting cells. Serum Ig levels are elevated for all isotypes except IgA. The viral infection leads to a rapid decline in T lymphocyte responses to mitogens and alloantigens, as well as a decrease in helper cell activity. Specific antibody responses to both T-dependent and T-independent antigens are impaired, and the response of B lymphocytes to mitogens is abolished. The profound immunosuppression seems to be due to the MuLV-induced polyclonal activation of lymphocytes. No active suppression of normal lymphocyte responses by cells from virus-infected mice was observed. The disease induced by the LP-BM5 MuLV isolate thus seems a promising model for the study of lymphocyte activation and the mechanisms of retrovirus-induced immunosuppression. PMID:2984305

  9. 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.

  10. 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

  11. 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

  12. [Speech perception test in Italian language for profoundly deaf children].

    PubMed

    Genovese, E; Orzan, E; Turrini, M; Babighian, G; Arslan, E

    1995-10-01

    Speech perception tests are an important part of procedures for diagnosing pre-verbal hearing loss. Merely establishing a child's hearing threshold with and without a hearing aid is not sufficient to ensure an adequate evaluation with a view to selecting cases suitable for cochlear implants because it fails to indicate the real benefit obtained from using a conventional hearing aid reliably. Speech perception tests have proved useful not only for patient selection, but also for subsequent evaluation of the efficacy of new hearing aids, such as tactile devices and cochlear implants. In clinical practice, the tests most commonly adopted with small children are: The Auditory Comprehension Test (ACT), Discrimination after Training (DAT), Monosyllable, Trochee, Spondee tests (MTS), Glendonald Auditory Screening Priocedure (GASP), Early Speech Perception Test (ESP), Rather than considering specific results achieved in individual cases, reference is generally made to the four speech perception classes proposed by Moog and Geers of the CID of St. Louis. The purpose of this classification, made on the results obtained with suitably differentiated tests according to the child's age and language ability, is to detect differences in perception of a spoken message in ideal listening conditions. To date, no italian language speech perception test has been designed to establish the assessment of speech perception level in children with profound hearing impairment. We attempted, therefore, to adapt the existing English tests to the Italian language taking into consideration the differences between the two languages. Our attention focused on the ESP test since it can be applied to even very small children (2 years old). The ESP is proposed in a standard version for hearing-impaired children over the age of 6 years and in a simplified version for younger children. The rationale we used for selecting Italian words reflect the rationale established for the original version, but the

  13. [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

  14. [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

  15. Delayed profound thrombocytopenia presenting 7 days after use of abciximab (ReoPro).

    PubMed

    Sharma, Sanjiv; Bhambi, Brijesh; Nyitray, William; Sharma, Geetanjali; Shambaugh, Shawn; Antonescu, Adrian; Shukla, Pankaj; Denny, Eileen

    2002-01-01

    A case of a 65-year-old woman presenting with delayed profound thrombocytopenia 7 days after the use of abciximab (ReoPro) in the setting of percutaneous coronary intervention is described. The patient had normal platelet counts for the first 24 hours after the use of abciximab (ReoPro). She presented with petechiae and profound thrombocytopenia 1 week later. The patient was treated successfully with a platelet transfusion and recovered uneventfully. Profound thrombocytopenia occurs acutely within the first few hours after abciximab (ReoPro) use, so this case was unique in that the profound thrombocytopenia presented 1 week after use of abciximab (ReoPro).

  16. 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

  17. 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.…

  18. 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…

  19. An Acoustic and Perceptual Study of Final Stops Produced by Profoundly Hearing Impaired Adolescents

    ERIC Educational Resources Information Center

    Khouw, Edward; Ciocca, Valter

    2006-01-01

    Purpose: This study investigated formant frequencies for their role as acoustic and perceptual correlates to the place of articulation of Cantonese final stops produced by profoundly hearing impaired speakers. Method: Speakers were 10 Cantonese adolescents (mean age = 13;5 [years;months]) who were profoundly hearing impaired (HI). Control speakers…

  20. Happiness Indices among Persons with Profound and Severe Disabilities during Leisure and Work Activities: A Comparison.

    ERIC Educational Resources Information Center

    Yu, Dickie C. T.; Spevack, Sara; Hiebert, Rene; Martin, Toby L.; Goodman, Ryan; Martin, Todd G.; Harapiak, Shayla; Martin, Garry L.

    2002-01-01

    Happiness indices were observed during naturally occurring work and leisure activities for individuals with severe (n=12) and profound (n=7) disabilities. Both groups showed more happiness indices during leisure activities, although the difference for the profound group was smaller. There was also a significant difference between groups for…

  1. 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…

  2. 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…

  3. 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…

  4. 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…

  5. 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.…

  6. 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

  7. 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

  8. 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

  9. Connections that Count: Brain-Computer Interface Enables the Profoundly Paralyzed to Communicate

    MedlinePlus

    ... Current Issue Past Issues Connections that Count: Brain-Computer Interface Enables the Profoundly Paralyzed to Communicate Past ... this page please turn Javascript on. A brain-computer interface (BCI) system This brain-computer interface (BCI) ...

  10. 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).

  11. 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

  12. High fat-fed diabetic mice present with profound alterations of the osteocyte network.

    PubMed

    Mabilleau, Guillaume; Perrot, Rodolphe; Flatt, Peter R; Irwin, Nigel; Chappard, Daniel

    2016-09-01

    Diabetes mellitus is considered to be an independent risk factor for bone fragility fractures. Reductions in bone mass, observed only with type 1 diabetes mellitus, as well as modifications of bone microarchitectures and tissue material properties are landmarks of diabetes-related bone alterations. An interesting feature observed in type 2 diabetes mellitus (T2DM) is the augmented concentration in circulating sclerostin. This observation prompts us to hypothesize that modifications of osteocyte network and perilacunar mineralization occur in T2DM. As such, the aims of the present study were to ascertain by quantitative backscattered electron imaging, confocal microscopy and image analysis, modifications of perilacunar tissue mineral density, osteocyte morphology and osteocyte network topology in a mouse model of high fat-induced type 2 diabetes. As compared with lean control animals, diabetic mice exhibited a significant 48% decrease in perilacunar mineralization heterogeneity although mean perilacunar mineralization was unchanged. Furthermore, in diabetic animals, osteocyte volume was significantly augmented by 34% with no change in the overall number of dendrite processes. Finally, the network topology was profoundly modified in diabetic mice with increases in the mean node degree, mean node volume and hub numbers whilst the mean link length was reduced. Overall, it appeared that in diabetic animals, the dendritic network exhibited features of a scale-free network as opposed to the single-scale characteristic observed in lean controls. However, it is important to ascertain whether diabetic patients exhibit such modifications of the osteocyte network and whether anti-diabetic drugs could restore normal osteocyte and network parameters, thereby improving bone quality and protecting against fragility fractures. PMID:27312542

  13. 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. PMID:23850720

  14. 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.

  15. PPARgamma-dependent regulation of adenylate cyclase 6 amplifies the stimulatory effect of cAMP on renin gene expression.

    PubMed

    Desch, Michael; Schubert, Thomas; Schreiber, Andrea; Mayer, Sandra; Friedrich, Björn; Artunc, Ferruh; Todorov, Vladimir T

    2010-11-01

    The second messenger cAMP plays an important role in the regulation of renin gene expression. Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is known to stimulate renin gene transcription acting through PPARγ-binding sequences in renin promoter. We show now that activation of PPARγ by unsaturated fatty acids or thiazolidinediones drastically augments the cAMP-dependent increase of renin mRNA in the human renin-producing cell line Calu-6. The underlying mechanism involves potentiation of agonist-induced cAMP increase and up-regulation of adenylate cyclase 6 (AC6) gene expression. We identified a palindromic element with a 3-bp spacer (Pal3) in AC6 intron 1 (AC6Pal3). AC6Pal3 bound PPARγ and mediated trans-activation by PPARγ agonist. AC6 knockdown decreased basal renin mRNA level and attenuated the maximal PPARγ-dependent stimulation of the cAMP-induced renin gene expression. AC6Pal3 decoy oligonucleotide abrogated the PPARγ-dependent potentiation of cAMP-induced renin gene expression. Treatment of mice with PPARγ agonist increased AC6 mRNA kidney levels. Our data suggest that in addition to its direct effect on renin gene transcription, PPARγ "sensitizes" renin gene to cAMP via trans-activation of AC6 gene. AC6 has been identified as PPARγ target gene with a functional Pal3 sequence.

  16. Effect of BSA-induced ER stress on SGLT protein expression levels and alpha-MG uptake in renal proximal tubule cells.

    PubMed

    Lee, Yu Jin; Suh, Han Na; Han, Ho Jae

    2009-06-01

    Recent studies demonstrated that endoplasmic reticulum (ER) stress regulates glucose homeostasis and that ER stress preconditioning which induces an adaptive, protective unfolded protein response (UPR) offers cytoprotection against nephrotoxins. Thus the aim of the present study was to use renal proximal tubule cells (PTCs) to further elucidate the link between the BSA-induced ER stress and alpha-methyl-d-glucopyranoside (alpha-MG) uptake and to identify related signaling pathways. Among ER stress inducers such as high glucose, BSA, H2O2, or tumicamycin, BSA pretreatment ameliorated the reduction of Na(+)-glucose cotransporter (SGLT) expression and alpha-MG uptake by gentamicin or cyclosporine A. Immunofluorescence studies revealed that BSA (10 mg/ml) stimulated the expression of glucose-regulated protein 78 (GRP78), an ER stress biomarker. In addition, BSA increased levels of GRP78 protein expression and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation in a time-dependent manner. Furthermore, transfection with a GRP78-specific small interfering RNA (siRNA) inhibited BSA-stimulated SGLT expression and alpha-MG uptake. In experiments designed to unravel the mechanisms underlying BSA-induced ER stress, BSA stimulated the production of cellular reactive oxygen species (ROS), and antioxidants such as ascorbic acid or N-acetylcysteine (NAC) blocked BSA-induced increases in GRP78 activation, eIF2alpha phosphorylation, SGLT expression, and alpha-MG uptake. Moreover, the cells upregulated peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA levels in response to BSA or troglitazone (a PPARgamma agonist), but BSA was ineffective in the presence of GW9662 (a PPARgamma antagonist). In addition, both BSA and troglitazone stimulated GRP78 and eIF2alpha activation, SGLT expression, and alpha-MG uptake, whereas GW9662 inhibited the effects of BSA. BSA also stimulated phosphorylation of JNK and NF-kappaB, and GW9662 or GRP78 siRNA attenuated this

  17. Nonambulatory persons with profound mental retardation: physical, developmental, and behavioral characteristics.

    PubMed

    Kobe, F H; Mulick, J A; Rash, T A; Martin, J

    1994-01-01

    Although profound mental retardation is generally associated with various organic etiologies that result in substantial cognitive and behavioral deficits, little is known about specific subgroups of persons with profound mental retardation. This study presents data on the physical, developmental, and behavioral characteristics of a group of 203 nonambulatory persons with profound mental retardation residing within a specialized service setting. The results indicate that nonambulatory persons with profound mental retardation have a high prevalence of physical and medical problems along with high rates of self-injurious, stereotypic, and aggressive behavior. Assessment results from the Stanford-Binet (L-M), Bayley Scales of Infant Development-Mental Scale, and Vineland Adaptive Behavior Scale reveal a high degree of variability in cognitive and adaptive functioning. However, developmental age-equivalent scores of cognitive ability, communication, daily living, socialization, and motor skills for the group fell below the 1-year level. The data illustrate the complexity of needs in providing habilitative services to nonambulatory persons with profound mental retardation. PMID:7871230

  18. 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

  19. Parental adaptation to out-of-home placement of a child with severe or profound developmental disabilities.

    PubMed

    Jackson, Jeffrey B; Roper, Susanne Olsen

    2014-05-01

    Utilizing grounded theory qualitative research methods, a model was developed for describing parental adaptation after voluntary placement of a child with severe or profound developmental disabilities in out-of-home care. Interviews of parents from 20 families were analyzed. Parents' cognitive appraisals of placement outcomes were classified as either inducing emotional stress (i.e., guilt, sadness, fear and worry, anger and frustration, and uncertainty) or relief. Parental appraisals of responses to placement by children, extended family, and friends were identified as factors affecting the parents' adaptation to placement. The primary coping methods used by parents to decrease emotional stress and increase relief consisted of reappraisals regarding the necessity of placement, involvement in the child's life, psychotherapy, and the passage of time.

  20. 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.

  1. 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.

  2. 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…

  3. Liberating Silent Voices--Perspectives of Children with Profound & Complex Learning Needs on Inclusion

    ERIC Educational Resources Information Center

    Whitehurst, Teresa

    2007-01-01

    This paper describes the evaluation of a drama production which involved 6 young people with profound and complex learning needs and 23 pupils from a mainstream school. The young people worked together on the project for nearly 2 years. At the end of the project we wanted to find out what the young people with disabilities thought of the inclusion…

  4. Assessment of Depression in Adults with Severe or Profound Intellectual Disability.

    ERIC Educational Resources Information Center

    Evans, K. M.; Cotton, M. M.; Einfeld, S. L.; Florio, T.

    1999-01-01

    Nurses applied standard behavioral criteria for major depression to evaluate 89 institutionalized adults with severe or profound intellectual disability. Results suggested that several additional behaviors listed on the Aberrant Behavior Checklist and the Developmental Behavior Checklist may be associated with this disorder in this population.…

  5. Assessment of Computer-Based Preferences of Students with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Mechling, Linda C.; Bishop, Vanessa A.

    2011-01-01

    This article reports on two studies investigating the use of computer-based stimuli that may then be used to develop activities and programming for students with profound multiple disabilities (PMD). Both studies used an alternating treatments design and systematic assessment strategy to present stimuli sequentially and to measure student…

  6. 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…

  7. A Clinical Application of Applied Humanism for Young Adults with Severe and Profound Retardation.

    ERIC Educational Resources Information Center

    Mazzelli, AnnaMaria; Polirstok, Susan Rovet; Dana, Lawrence; Buono, Serafina; Mongelli, Vita; Trubia, Grazia; Ayala, Giovanni

    2000-01-01

    Describes an intensive habilitation program in Sicily for young adults with severe and profound retardation. Participants in the program showed significant improvement in functional skills and an accompanying reduction in maladaptive and stereotypic behaviors, without complex behavior plans; punishing contingencies; or high dose neuroleptic,…

  8. 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)

  9. 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…

  10. An Acoustic and Perceptual Study of Initial Stops Produced by Profoundly Hearing Impaired Adolescents

    ERIC Educational Resources Information Center

    Khouw, Edward; Ciocca, Valter

    2007-01-01

    This study investigated the role of Voice Onset Time (VOT) as perceptual cue to the aspiration contrast of Cantonese initial stops produced by adolescent profoundly hearing impaired speakers. Speakers with normal hearing signalled the aspiration contrast through VOT differences. Hearing impaired speakers produced initial stops with no significant…

  11. 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…

  12. 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…

  13. The Impact of Typical Peers on the Perceived Happiness of Students with Profound Multiple Disabilities.

    ERIC Educational Resources Information Center

    Logan, Kent R.; Jacobs, Heidi A.; Gast, David L.; Murray, Amy Streu; Daino, Kim; Skala, Chuck

    1998-01-01

    A study evaluated the effect of the type of peer group on behavior associated with the happiness of five elementary students with profound multiple disabilities. Results indicated higher levels of happiness behaviors (smiles, eyes open) with typical peers than with peers with disabilities across all five students. (Author/CR)

  14. 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…

  15. Multiple major cerebral artery thromboses with profound thrombocytopenia in acute leukaemia.

    PubMed

    Sims, D G; Scott, D J; Noble, T C

    1976-01-01

    A child with acute lymphoblastic leukaemia complicated by prolonged gastrointestinal and skin haemorrhages due to profound thrombocytopenia finally died of thrombotic occlusions of major cerebral arteries due to mucormycosis. Biopsy of any suspect lesion is needed urgently before prolonged therapy with amphotericin B is started. So far there have been no cures in childhood.

  16. 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)

  17. 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…

  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. 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…

  20. 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…

  1. 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)

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  6. Review of the Choice and Preference Assessment Literature for Individuals with Severe to Profound Disabilities

    ERIC Educational Resources Information Center

    Tullis, Christopher A.; Cannella-Malone, Helen I.; Basbigill, Abby R.; Yeager, Amanda; Fleming, Courtney V.; Payne, Daniel; Wu, Pei-Fang

    2011-01-01

    Since 2002, the body of literature examining choice interventions and preference assessments for individuals with severe to profound disabilities has grown substantially. This paper is an extension of the Lancioni, O'Reilly, & Emerson (1996) and Cannella, O'Reilly, & Lancioni (2005) papers and reviews 50 studies conducted between 2002 and 2010…

  7. 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…

  8. Facilitation of Communication Responses through Naturalized Sensory Reinforcement in Blind Mute/Profoundly Retarded Adults.

    ERIC Educational Resources Information Center

    Crawford, Michael E.

    The literature on symbolic forms of communication was reviewed, and an experimental program was designed to teach a single set of vocabulary to a group of four institutionalized profoundly retarded blind/mute adults through the use of gestures. Literature about deaf/blind persons suggested the use of coactive movement techniques and facilitation…

  9. Evaluating the Sensory-Motor Bases of Behavior in the Profoundly Retarded.

    ERIC Educational Resources Information Center

    Webb, Ruth C.; And Others

    Discussed are the theoretical background and evaluation procedures of the Glenwood Awareness, Manipulation, and Posture Index Number One, an instrument for measuring the sensory-motor bases of behavior in the profoundly retarded. The authors maintain that, by using the processes of recognition, interaction, and mobility as criteria for the…

  10. 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.…

  11. Involving Institutional Staff in the Development and Maintenance of Sign Language Skills with Profoundly Retarded Persons.

    ERIC Educational Resources Information Center

    Faw, Gerald D.; And Others

    1981-01-01

    A program to involve institutional staff in developing manual sign language skills with six profoundly retarded persons was evaluated. Results indicated that all participating residents learned to communicate with signing during structured interactions on their living unit and the skills maintained during follow-up assessments ranging from 39 to…

  12. 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…

  13. 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…

  14. A Task Force Approach to Serving Profoundly Retarded Children and Their Parents.

    ERIC Educational Resources Information Center

    Graf, Mercedes; Robbins, Pearl

    A task force approach to care of profoundly retarded children includes parent counseling services. Counseling is usually limited to initial interviews in which the psychologists must explain the diagnosis, teach parents to accept the child's maturity age as the best gauge of his ability, and make parents aware that their child will require…

  15. 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…

  16. 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…

  17. Teaching Subjects to Pupils with Profound and Multiple Learning Difficulties: Considerations for the New Framework.

    ERIC Educational Resources Information Center

    Peacey, Nick; Grove, Nicola

    1999-01-01

    Describes a framework for teaching British National Curriculum subjects to pupils with profound learning difficulties. Discussion focuses on curriculum adaptations, educational rationale for subject selection, insights from subject specialists, and integration of therapies, health care, and emotional support within education. (DB)

  18. Curriculum Guide for Teaching Physical Education to the Profoundly and Severely Retarded.

    ERIC Educational Resources Information Center

    Fait, Hollis F., Ed.

    For use with the profoundly and severely retarded, the guide to physical education curriculum describes methods and techniques, objectives, and core activities. The following are also considered: supplementary activities for the hyperactive and emotionally disturbed; suggestions for the teacher; and evaluation, including records, motor skills…

  19. 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…

  20. Extent, Duration, and Content of Day Services' Activities for Persons with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Vlaskamp, Carla; Hiemstra, Saskia J.; Wiersma, Linda A.; Zijlstra, Bonne J. H.

    2007-01-01

    In the Netherlands, the Dutch government instituted policies that enable persons with profound intellectual and multiple disabilities (PIMD) to attend day services. Over the past 15 years, surveys have indicated a progressive increase in the number of hours that such adults spend at day activities centers. However, information about how these…

  1. 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…

  2. 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…

  3. 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.…

  4. 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…

  5. 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…

  6. Recombinative Generalization of Action-Object Verbal Instruction Following by Profoundly Retarded Individuals.

    ERIC Educational Resources Information Center

    McCuller, William R.; Salzberg, Charles L.

    A study involving three profoundly retarded adults was designed to investigate the efficacy of a stair step diagonal training progression in promoting correct responses to untrained action-object verbal instructions. Procedures included pretraining assessment of action verbs and nouns, matrix training in which each S was physically put through the…

  7. Hey! Don't Forget About Me! Education's Investment in the Severely, Profoundly, and Multiply Handicapped.

    ERIC Educational Resources Information Center

    Thomas, M. Angele, Ed.

    Presented are 12 author contributed chapters which developed out of an invisible college of leaders concerned with providing services to the severely, profoundly, and multiply handicapped. Stressed throughout the book are such needs as the need to listen to parents, the need for new training programs for teachers of the severely handicapped, the…

  8. 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…

  9. 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…

  10. Ways to Communicate with Children Who Are Profoundly Mentally Retarded and Cannot Speak.

    ERIC Educational Resources Information Center

    Adam, Heidemarie

    Experiences working with nonverbal severely and profoundly retarded and multiply handicapped children are discussed in this paper. Alternative communication systems are reviewed, including use of manual signs, pictures and symbols, photographs, realistic drawings, pictograms, and Bliss Symbols. A model for teaching basic understanding of…

  11. 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.

  12. 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

  13. Aided speech recognition abilities of adults with a severe or severe-to-profound hearing loss.

    PubMed

    Flynn, M C; Dowell, R C; Clark, G M

    1998-04-01

    Adults with severe or severe-to-profound hearing losses constitute between 11% and 13.5% of the hearing-impaired population. A detailed investigation of the speech recognition of adults with severe (n = 20) or severe-to-profound (n = 14) hearing loss was conducted at The University of Melbourne. Each participant took part in a series of speech recognition tasks while wearing his or her currently fitted hearing aid(s). The assessments included closed-set tests of consonant recognition and vowel recognition, combined with open-set tests of monosyllabic word recognition and sentence recognition. Sentences were presented in quiet and in noise at +10 dB SNR to replicate an environment more typical of everyday listening conditions. Although the results demonstrated wide variability in performance, some general trends were observed. As expected vowels were generally well perceived compared with consonants. Monosyllabic word recognition scores for both the adults with a severe hearing impairment (M = 67.2%) and the adults with a severe-to-profound hearing impairment (M = 38.6%) could be predicted from the segmental tests, with an allowance for lexical effects. Scores for sentences presented in quiet showed additional linguistic effects and a significant decrease in performance with the addition of background noise (from 82.9% to 74.1% for adults with a severe hearing loss and from 55.8% to 34.2% for adults with a severe-to-profound hearing loss). Comparisons were made between the participants and a group of adults using a multiple-channel cochlear implant. This comparison indicated that some adults with a severe or severe-to-profound hearing loss may benefit from the use of a cochlear implant. The results of this study support the contention that cochlear implant candidacy should not rely solely on audiometric thresholds. PMID:9570583

  14. Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1.

    PubMed

    Yu, Xiaoyan; Li, Cai; Li, Xiaokun; Cai, Lu

    2007-04-01

    In the development of diabetic nephropathy, advanced glycation end products (AGEs) play a causative role via induction of extracellular matrix (ECM) accumulation. Plasminogen activator inhibitor-1 (PAI-1), as a major inhibitor of plasminogen activator that plays an important role in degrading ECM, was found to significantly increase in renal fibrotic diseases. Activation of peroxisome proliferator-activated receptor (PPAR)-gamma prevented diabetic nephropathy. The present study, therefore, was to define whether or not AGE-induced renal ECM accumulation and renal dysfunction are mediated by upregulation of PAI-1 expression and whether or not PPAR-gamma agonist can attenuate these AGE effects via suppressing PAI-1 expression. Rats were given AGEs alone by iv injection at 100 mg/kg daily with or without oral supplementation of PPAR-gamma agonist rosiglitazone (RGZ) at 2 mg/kg daily for 6 weeks. Results showed that AGEs induced a renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) contents in glomeruli, and a mild renal dysfunction, as shown by an increase in urinary proteins. AGEs also caused an increase in PAI-1 expression and a decrease in plasminogen activator bioactivity in the kidney. Treatment with RGZ significantly ameliorated AGE-induced renal ECM accumulation, proteinuria, and PAI-1 upregulation. Direct exposure of rat mesangial cells to AGEs in vitro induced increases in fibronectin and Col IV syntheses along with an increase in PAI-1 expression, effects significantly attenuated by RGZ. Preincubation of PAI-1 antibody to AGE-treated mesangial cells completely prevented AGE-induced fibronectin and Col IV production. These results suggest that upregulation of PAI-1 expression plays a critical role in AGE-induced renal ECM accumulation. Renal protection of RGZ from AGEs may be associated with the suppression of PAI-1 expression through PPAR-dependent and independent mechanisms.

  15. Rosiglitazone induces mitochondrial biogenesis in mouse brain.

    PubMed

    Strum, Jay C; Shehee, Ron; Virley, David; Richardson, Jill; Mattie, Michael; Selley, Paula; Ghosh, Sujoy; Nock, Christina; Saunders, Ann; Roses, Allen

    2007-03-01

    Rosiglitazone was found to simulate mitochondrial biogenesis in mouse brain in an apolipoprotein (Apo) E isozyme-independent manner. Rosiglitazone induced both mitochondrial DNA (mtDNA) and estrogen-stimulated related receptor alpha (ESRRA) mRNA, a key regulator of mitochondrial biogenesis. Transcriptomics and proteomics analysis suggested the mitochondria produced in the presence of human ApoE3 and E4 were not as metabolically efficient as those in the wild type or ApoE knockout mice. Thus, we propose that PPARgamma agonism induces neuronal mitochondrial biogenesis and improves glucose utilization leading to improved cellular function and provides mechanistic support for the improvement in cognition observed in treatment of Alzheimer's patients with rosiglitazone.

  16. 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

  17. Social skills training with institutionalized severely and profoundly mentally retarded persons.

    PubMed

    Singh, N N; Winton, A S

    1983-01-01

    This paper examines the literature on training severely and profoundly retarded individuals in social skills. Experimental studies have focused mainly on three areas: (1) cooperative responding during play, (2) non-verbal physical or close-proximity interactions, and (3) conversational skills. Training procedures varied but usually involved combinations of physical and verbal prompting, modeling, shaping, and social and edible reinforcement. These studies provide strong evidence that severely and profoundly retarded individuals can be taught useful interpersonal skills and can sometimes even assist the development of these skills in their peers. In general, the studies were methodologically sound in terms of basic design and interobserver reliabilities but weak with respect to maintenance and follow-up procedures. Only some studies tested for generalization of treatment effects and only a few specifically trained for such generalization. PMID:6670874

  18. A comprehensive evaluation of reinforcer identification processes for persons with profound multiple handicaps.

    PubMed Central

    Green, C W; Reid, D H; Canipe, V S; Gardner, S M

    1991-01-01

    We evaluated comprehensively a preference assessment for identifying reinforcers for persons with profound multiple handicaps. Four experiments were conducted involving 18 individuals. Results of Experiment 1 replicated previous findings in that the assessment identified student preferences for respective stimuli, and caregiver opinion of preferences did not coincide with the systematic assessment. Results of Experiment 2 indicated highly preferred stimuli were likely to function as reinforcers in training programs, whereas stimuli not highly preferred did not function as reinforcers. Results of Experiment 3 suggested the 12 stimuli used in the assessment represented a comprehensive stimulus set for identifying preferences, although the utility of the set sometimes could be enhanced by caregiver opinion. Results of Experiment 4 indicated the assessment identified preferences likely to be maintained over time. Overall, results are discussed in terms of identifying limits and alternatives to a behavioral teaching technology when applied to persons with profound multiple handicaps. PMID:1836459

  19. PPARgamma2 Pro12Ala polymorphism in relation to free fatty acids concentration and composition in lean healthy Czech individuals with and without family history of diabetes type 2.

    PubMed

    Bendlová, B; Vejrazková, D; Vcelák, J; Lukásová, P; Burkonová, D; Kunesová, M; Vrbíková, J; Dvoráková, K; Vondra, K; Vanková, M

    2008-01-01

    Free fatty acids (FFAs) are natural ligands of the PPARgamma2 receptor. FFA plasma concentration and composition may represent one of the factors accounting for high heterogeneity of conclusions concerning the effect of the Pro12Ala on BMI, insulin sensitivity or diabetes type 2 (DM2) susceptibility. Our objective was to investigate the relation and possible interactions between the Pro12Ala polymorphism and FFA status, metabolic markers, and body composition in 324 lean nondiabetic subjects (M/F: 99/225; age 32+/-11 years; BMI 23.9+/-4.0 kg/m(2)) with and without family history of DM2. Family history of DM2 was associated with lower % PUFA and slightly higher % MUFA. The presence of Pro12Ala polymorphism was not associated with fasting plasma FFA concentration or composition, anthropometric or metabolic markers of glucose and lipid metabolism in tested population. However, the interaction of carriership status with FFA levels influenced the basal glucose levels, insulin sensitivity and disposition indices, triglycerides, HDL-cholesterol and leptin levels, especially in women. The metabolic effects of 12Ala carriership were influenced by FFA levels - the beneficial role of 12Ala was seen only in the presence of low concentration of plasma FFA. Surprisingly, a high PUFA/SFA ratio was associated with lower insulin sensitivity, the protective effect of 12Ala allele was apparent in subjects with family history of DM2. On the basis of our findings and published data we recommend the genotyping of diabetic patients for Pro12Ala polymorphism of the PPARgamma2 gene before treatment with thiazolidinediones and education of subjects regarding diet and physical activity, which modulate metabolic outcomes.

  20. 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

  1. Speech pattern hearing aids for the profoundly hearing impaired: speech perception and auditory abilities.

    PubMed

    Faulkner, A; Ball, V; Rosen, S; Moore, B C; Fourcin, A

    1992-04-01

    A family of prototype speech pattern hearing aids for the profoundly hearing impaired has been compared to amplification. These aids are designed to extract acoustic speech patterns that convey essential phonetic contrasts, and to match this information to residual receptive abilities. In the first study, the presentation of voice fundamental frequency information from a wearable SiVo (sinusoidal voice) aid was compared to amplification in 11 profoundly deafened adults. Intonation reception was often better, and never worse, with fundamental frequency information. Four subjects scored more highly in audio-visual consonant identification with fundamental frequency information, five performed better with amplified speech, and two performed similarly under these two conditions. Five of the 11 subjects continued use of the SiVo aid after the tests were complete. A second study examined a laboratory prototype compound speech pattern aid, which encoded voice fundamental frequency, amplitude envelope, and the presence of voiceless excitation. In five profoundly deafened adults, performance was better in consonant identification when additional speech patterns were present than with fundamental frequency alone; the main advantage was derived from amplitude information. In both consonant identification and connected discourse tracking, performance with appropriately matched compound speech pattern signals was better than with amplified speech in three subjects, and similar to performance with amplified speech in the other two. In nine subjects, frequency discrimination, gap detection, and frequency selectivity were measured, and were compared to speech receptive abilities with both amplification and fundamental frequency presentation. The subjects who showed the greatest advantage from fundamental frequency presentation showed the greatest average hearing losses, and the least degree of frequency selectivity. Compound speech pattern aids appear to be more effective for some

  2. Assisted ambulation and activities for persons with profound multiple disabilities: assessing different ambulation levels.

    PubMed

    Lancioni, G E; Mantini, M; Groeneweg, J

    2001-06-01

    Two participants with profound multiple disabilities were exposed to two occupational situations, which included 1-min. and 3-min. robot-assisted ambulation prior to each activity, respectively. Analysis showed participants' mean percentages of engagement time (session time they spent ambulating or manipulating objects) were well above 90 in both situations. The amount of deviant behavior was somewhat higher in the latter occupational situation for one participant. Implications of the findings were discussed.

  3. Task variation versus task repetition for people with profound developmental disabilities: an assessment of preferences.

    PubMed

    Lancioni, G E; O'Reilly, M F; Campodonico, F; Mantini, M

    1998-01-01

    An assessment of preferences between task variation and task repetition with four adults with profound developmental disabilities was implemented. After participants were exposed to both task variation and task repetition conditions, they were allowed to choose between them. Results showed that all participants had strong preferences; three preferred task variation and one task repetition. Aspects of the assessment and use of assessment data for planning daily work conditions were discussed.

  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. 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.

  6. Audio-visual perception of compressed speech by profoundly hearing-impaired subjects.

    PubMed

    Drullman, R; Smoorenburg, G F

    1997-01-01

    For many people with profound hearing loss conventional hearing aids give only little support in speechreading. This study aims at optimizing the presentation of speech signals in the severely reduced dynamic range of the profoundly hearing impaired by means of multichannel compression and multichannel amplification. The speech signal in each of six 1-octave channels (125-4000 Hz) was compressed instantaneously, using compression ratios of 1, 2, 3, or 5, and a compression threshold of 35 dB below peak level. A total of eight conditions were composed in which the compression ratio varied per channel. Sentences were presented audio-visually to 16 profoundly hearing-impaired subjects and syllable intelligibility was measured. Results show that all auditory signals are valuable supplements to speechreading. No clear overall preference is found for any of the compression conditions, but relatively high compression ratios (> 3-5) have a significantly detrimental effect. Inspection of the individual results reveals that compression may be beneficial for one subject.

  7. Auditory cortical activation in severe-to-profound hearing-impaired patients monitored by SPET.

    PubMed

    Di Nardo, W; Di Giuda, D; Scarano, E; Picciotti, P M; Galla, S; De Rossi, G

    2006-08-01

    Single photon emission tomography was used to map blood flow increase in temporal and parietal cortex after auditory stimulation in 25 subjects: 10 normal-hearing, 10 severe-profound hearing-impaired and 5 totally deaf. After a 500 Hz pure tone stimulation, a marked perfusion increase was observed, particularly at the level of the contralateral auditory temporal cortex. Blood flow increase in temporal and parietal cortical areas of normal subjects was significantly higher than that observed in severe-to-profound hearing-impaired patients. In all cases, following 500 Hz pure tone acoustic stimulation, the most lateral sagittal slice tomograms (48.75 and 56.25 mm) showed the highest blood flow increase. Statistically significant differences were also observed between normal subjects and hearing-impaired patients in the 48.75 mm sagittal tomogram. In 2 hearing-impaired patients, the single photon emission tomography pattern showed activation of the intermediate sagittal tomogram, suggesting a possible new tonotopic cortical arrangement. No significant activation was present in totally deaf patients. In conclusion, Single Photon Emission Tomography appears to be a useful tool in the evaluation of auditory cortical activation and cortical plasticity, in severe-to-profound hearing-impaired patients. Moreover, it could be a useful test for the study of auditory central pathways.

  8. 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,…

  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. 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…

  11. The Prevalence, Incidence, and Factors Predictive of Mental Ill-Health in Adults with Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Cooper, Sally-Ann; Smiley, Elita; Finlayson, Janet; Jackson, Alison; Allan, Linda; Williamson, Andrew; Mantry, Dipali; Morrison, Jillian

    2007-01-01

    Background: There are no previous studies of the prevalence and incidence of mental ill-health in adults with profound intellectual disabilities. Method: In this population-based prospective cohort study, adults with profound intellectual disabilities underwent psychiatric assessment (n = 184), with further assessment after 2 years (n = 131).…

  12. 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); "'Where Do I Start?' Some…

  13. Petalonia improves glucose homeostasis in streptozotocin-induced diabetic mice

    SciTech Connect

    Kang, Seong-Il; Jin, Young-Jun; Ko, Hee-Chul; Choi, Soo-Youn; Hwang, Joon-Ho; Whang, Ilson; Kim, Moo-Han; Shin, Hye-Sun; Jeong, Hyung-Bok; Kim, Se-Jae

    2008-08-22

    The anti-diabetic potential of Petalonia binghamiae extract (PBE) was evaluated in vivo. Dietary administration of PBE to streptozotocin (STZ)-induced diabetic mice significantly lowered blood glucose levels and improved glucose tolerance. The mode of action by which PBE attenuated diabetes was investigated in vitro using 3T3-L1 cells. PBE treatment stimulated 3T3-L1 adipocyte differentiation as evidenced by increased triglyceride accumulation. At the molecular level, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and terminal marker protein aP2, as well as the mRNA of GLUT4 were up-regulated by PBE. In mature adipocytes, PBE significantly stimulated the uptake of glucose and the expression of insulin receptor substrate-1 (IRS-1). Furthermore, PBE increased PPAR{gamma} luciferase reporter gene activity in COS-1 cells. Taken together, these results suggest that the in vivo anti-diabetic effect of PBE is mediated by both insulin-like and insulin-sensitizing actions in adipocytes.

  14. 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. PMID:22587257

  15. Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis.

    PubMed

    Green, Thomas J; Bijlsma, Jan Jaap; Sweet, David D

    2010-09-01

    The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of “MUDPILES” (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen.

  16. 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.

  17. 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. PMID:17066778

  18. 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.

  19. Auditory feedback does not influence random number generation: Evidence from profoundly deaf adults with cochlear implant.

    PubMed

    Strenge, Hans; Müller-Deile, Joachim

    2007-08-01

    Oral random number generation is a widely used neuropsychological task engaging a number of overlapping neural systems of attention, number representation, response generation, and working memory. Although phonological processing is known to be essential for random number generation no information exists on the significance of the auditory feedback of hearing one's own voice on task performance. We therefore examined the influence of auditory feedback in 15 profoundly deaf adults with cochlear implants in a device-on/off experiment. No significant effects of occluding auditory feedback on random number generation were noted, thus supporting an internal response-monitoring model independent of auditory condition. PMID:17691037

  20. Developmental dysgraphia with profound hearing impairment: intervention by auditory methods enabled by cochlear implant.

    PubMed

    Fukushima, Kunihiro; Kawasaki, Akihiro; Nagayasu, Rie; Kunisue, Kazuya; Maeda, Yukihide; Kariya, Shin; Kataoka, Yuko; Nishizaki, Kazunori

    2008-06-01

    Learning disability combined with hearing impairment (LDHI) is a poor prognostic factor for the language development of hearing impaired children after educational intervention. A typical example of a child with LDHI and effective interventions provided by cochlear implants are presented in this report. A case of congenital cytomegaloviral infection that showed dysgraphia as well as profound deafness was reported and an underlying visual processing problem diagnosed in the present case caused the patient's dysgraphia. The dysgraphia could be circumvented by the use of auditory memory fairly established by a cochlear implant. PMID:18082987

  1. Crucial role of insulin in leptin maintenance: profound decrease in serum leptin by octreotide acetate in insulinoma subjects.

    PubMed

    Nakamura, T; Nagasaka, S; Ishikawa, S; Nonaka, M; Fujibayashi, K; Saito, T; Kusaka, I; Higashiyama, M; Saito, T

    2000-06-01

    To further clarify the relationship between insulin and leptin, time course changes in plasma glucose, serum insulin and leptin levels were analyzed after subcutaneous administration of 100 microg octreotide acetate in two insulinoma subjects. Octreotide acetate induced a prompt decrease in serum insulin level, accompanied with an increase in plasma glucose in both patients. Following the decrease in serum insulin level, serum leptin concentrations were profoundly decreased by 66% and 44%, 8-12 hrs after octreotide injection; that is, the concentrations decreased from 41.1 to 13.8 ng/ml in patient 1, and from 17.5 to 9.8 ng/ml in patient 2. Daily profiles of plasma glucose, serum insulin and leptin without octreotide administration did not show such alterations in these indexes in patient 1. These data show that circulating leptin may be susceptible to decline dependent on the decrease in serum insulin, suggesting that insulin plays a crucial role in the maintenance of leptin secretion in humans.

  2. 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. PMID:27507797

  3. 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

  4. 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.

  5. Nissen fundoplication in children with profound neurologic disability. High risks and unmet goals.

    PubMed

    Smith, C D; Othersen, H B; Gogan, N J; Walker, J D

    1992-06-01

    Anti-reflux procedures have been advocated in children with profound neurologic disability referred for feeding gastrostomy when gastroesophageal reflux is present. Facilitation of care, reduction in pneumonia and vomiting, and improvement in the general health and survival of these children have been major goals of fundoplication and gastrostomy. In large pediatric series, these procedures have been reported to have low risk and negligible mortality rates. Recent reports, however, document an increased incidence of sequelae of fundoplication in children with profound neurologic disability. This paper retrospectively reviews a series of 35 nonverbal, nonambulatory pediatric patients undergoing a total of 39 fundoplications (37 Nissen, 1 Thal, and 1 Belsey) over an 11-year period. Neurologic impairment of 17 (49%) patients was acquired, 13 (37%) congenital, and 5 (14%) due to a syndrome. Perioperative complications occurred in six (17%). Three additional complications led to early postoperative death. A fourth early death was unexplained. Fourteen (40%) had recurrent pneumonia, 11 (31%) recurrent vomiting, 8 (23%) choking-gagging-retching complex, and 3 (9%) bowel obstruction requiring laparotomy. Recurrent gastroesophageal reflux was documented in seven (20%) patients. A second ARP was performed in six (17%). There were 14 (40%) late deaths. Although the major goals of anti-reflux procedure are clearly achieved in many severely impaired children with gastroesophageal reflux, the use of Nissen fundoplication to resolve the complications of swallowing disorders and improve outcome with an acceptably low risk in this complex set of patients does not appear to be established.

  6. Whole Exome Sequencing Identifies Mutations in Usher Syndrome Genes in Profoundly Deaf Tunisian Patients

    PubMed Central

    Riahi, Zied; Bonnet, Crystel; Zainine, Rim; Lahbib, Saida; Bouyacoub, Yosra; Bechraoui, Rym; Marrakchi, Jihène; Hardelin, Jean-Pierre; Louha, Malek; Largueche, Leila; Ben Yahia, Salim; Kheirallah, Moncef; Elmatri, Leila; Besbes, Ghazi; Abdelhak, Sonia; Petit, Christine

    2015-01-01

    Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss. PMID:25798947

  7. Respiratory Function and Language Abilities of Profoundly Deaf Adolescents with and without Cochlear Implants.

    PubMed

    Żebrowska, A; Zwierzchowska, A; Manowska, B; Przybyła, K; Krużyńska, A; Jastrzębski, D

    2016-01-01

    The objective of the study was to investigate whether hearing loss has an effect on the ventilatory functional capability and whether possible deviations of ventilatory variables from the reference ranges could have to do with the language abilities of deaf adolescents. Spirometric evaluations were performed in 72 prelingually profoundly deaf adolescents with and without cochlear implants (CI) and compared with the results of a control group consisting of 48 participants with normal hearing (CG). The deaf adolescents showed a significantly lower vital capacity (VC), forced vital capacity (FVC), and expiratory flows (PEF and MEF) compared with their hearing peers. The adolescents with CI demonstrated predominantly the oral communication mode, which however did not affect the students' education achievements. Perseverance of oral communication was also associated with higher FVC and PEF, compared with deaf participants without CI. We conclude that sensory deprivation of prelingually deaf adolescents affects the respiratory system function. The use of oral communication seems to have beneficial effects on respiratory performance in profoundly deaf adolescents. PMID:26987322

  8. Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation.

    PubMed

    Jin, Song; Mathis, A Scott; Rosenblatt, Joseph; Minko, Tamara; Friedman, Gary S; Gioia, Kevin; Serur, David S; Knipp, Gregory T

    2004-02-27

    Clinical monitoring of organ-transplant recipients suggests that administration of cyclosporine (CsA) may increase the risk of atherosclerosis when compared with the general population. The purpose of this work is to demonstrate the utility of the in vitro Tamm-Horsfall protein (THP)-1 human monocyte cell culture model for determining drug-related atherosclerotic potential in macrophages. The effect of CsA on the mRNA expression of macrophage scavenger receptor genes including CD36, CD68, scavenger receptor (SR)-A, SR-BII, and lectin-like oxidized low-density lipoprotein receptor (LOX-1); the nuclear hormone receptors, including peroxisome-proliferator activated receptor (PPAR)gamma and liver-X-receptor (LXR)alpha; and the cholesterol efflux pump ABCA1 were investigated as markers of atherosclerotic progression. The THP-1 cells were cultured and differentiated into macrophages. The macrophages were then treated with CsA to assess gene expression. Time- (1, 2, 4, 8, and 24 hours) and dose- (concentrations [mg/L] corresponding to the trough [0.5], peak [1.25] and 4x peak [5]) dependency of CsA was assessed. The treated macrophage mRNA gene expression of CD36, CD68, and PPARgamma were up-regulated in the presence of CsA. Interestingly, SR-A, SR-BII, LOX-1, and LXRalpha expression appeared to be slightly down-regulated, and ABCA1 was relatively unchanged. Immunoblotting studies demonstrated that the protein expression of CD36 was unchanged or increased, PPARgamma was unchanged, and ABCA1 was unchanged or decreased at 4 and 8 hours. The results document CsA-induced mRNA and protein changes in receptors relevant to lipid-laden foam cell formation and demonstrate the utility of THP-1 macrophages for screening of atherosclerotic risk potential. PMID:15084924

  9. Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation.

    PubMed

    Jin, Song; Mathis, A Scott; Rosenblatt, Joseph; Minko, Tamara; Friedman, Gary S; Gioia, Kevin; Serur, David S; Knipp, Gregory T

    2004-02-27

    Clinical monitoring of organ-transplant recipients suggests that administration of cyclosporine (CsA) may increase the risk of atherosclerosis when compared with the general population. The purpose of this work is to demonstrate the utility of the in vitro Tamm-Horsfall protein (THP)-1 human monocyte cell culture model for determining drug-related atherosclerotic potential in macrophages. The effect of CsA on the mRNA expression of macrophage scavenger receptor genes including CD36, CD68, scavenger receptor (SR)-A, SR-BII, and lectin-like oxidized low-density lipoprotein receptor (LOX-1); the nuclear hormone receptors, including peroxisome-proliferator activated receptor (PPAR)gamma and liver-X-receptor (LXR)alpha; and the cholesterol efflux pump ABCA1 were investigated as markers of atherosclerotic progression. The THP-1 cells were cultured and differentiated into macrophages. The macrophages were then treated with CsA to assess gene expression. Time- (1, 2, 4, 8, and 24 hours) and dose- (concentrations [mg/L] corresponding to the trough [0.5], peak [1.25] and 4x peak [5]) dependency of CsA was assessed. The treated macrophage mRNA gene expression of CD36, CD68, and PPARgamma were up-regulated in the presence of CsA. Interestingly, SR-A, SR-BII, LOX-1, and LXRalpha expression appeared to be slightly down-regulated, and ABCA1 was relatively unchanged. Immunoblotting studies demonstrated that the protein expression of CD36 was unchanged or increased, PPARgamma was unchanged, and ABCA1 was unchanged or decreased at 4 and 8 hours. The results document CsA-induced mRNA and protein changes in receptors relevant to lipid-laden foam cell formation and demonstrate the utility of THP-1 macrophages for screening of atherosclerotic risk potential.

  10. Limitations of Mild, Moderate, and Profound Hypothermia in Protecting Developing Hippocampal Neurons After Simulated Ischemia

    PubMed Central

    Gregersen, Maren; Lee, Deok Hee; Gabatto, Pablo

    2013-01-01

    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. PMID:24380031

  11. 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)

  12. 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

  13. Assessment and treatment of multiple behavior problems exhibited by a profoundly retarded adolescent.

    PubMed

    Slifer, K J; Ivancic, M T; Parrish, J M; Page, T J; Burgio, L D

    1986-09-01

    The severe aggression and noncompliance of a profoundly retarded blind male were subjected to extensive behavioral assessment in order to identify controlling variables. The assessment, conducted across settings and therapists, suggested that these inappropriate behaviors functioned to avoid or terminate nonpreferred activities. Intervention consisted of manual guidance when there was noncompliance with instructions and edible reinforcement upon compliance; there were no direct contingencies for the inappropriate behaviors. Treatment procedures were implemented in a multiple baseline design across therapists and settings. Results show that the intervention consistently increased compliance, with concurrent decreases in inappropriate behaviors. Edible reinforcement and neuroleptic medication were withdrawn systematically with no loss of therapeutic gains. Family members and school personnel were trained to use the intervention procedures. Results are discussed in terms of functional assessment, response covariation, compliance training, parent and staff training, and behavioral assessment of the effects of neuroleptic medication. PMID:2876010

  14. Surface sensitivity of Mg 2NiH 4 leading to a profound color change

    NASA Astrophysics Data System (ADS)

    Rönnebro, Ewa; Noréus, Dag

    2004-04-01

    Very small amounts of air have been observed to oxidise the surface of the ternary hydride Mg 2NiH 4. This leads to a profound color change from orange to brown and to a sealing of the surface with respect to desorption, which can be mistaken for a stability increase of the bulk hydride. An unoxidised sample starts to desorb significant amounts of hydrogen when it is heated above 450 K, as is expected from the van't Hoff relation for the hydride. A sample with a slightly oxidised surface may need to be heated above 700 K before hydrogen is released. The subsequent hydrogen desorption is, on the other hand, very rapid at this elevated temperature.

  15. The journey to accepting support: how parents of profoundly disabled children experience support in their lives.

    PubMed

    Brett, Jane

    2004-10-01

    Advances in medical knowledge and care have extended the lives of children with profound and multiple disabilities. In most cases it is the parents who meet the often complex and continual needs of their child with disabilities in their own home. This study explored the experience of support in the lives of such parents. The interpretive, hermeneutic phenomenology of Heidegger was employed to create a detailed and authentic account of the parents' experiences of support. Five interrelated themes emerged from data from in-depth interviews with six parents randomly selected from a purposive sample in a special school setting. The themes were: parents' feelings about support, the journey to accepting support, support as a loss, disability and the parent and the supportive relationship. Understanding the experience of support from the parent's perspective may lead to a consideration of flexible systems that challenge practice to ensure that supporters listen, learn, develop and deliver support in ways that are helpful. PMID:15537108

  16. 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.

  17. Survival from profound metabolic acidosis due to hypovolaemic shock. A world record?

    PubMed Central

    Di Rollo, Nicola; Caesar, David; Ferenbach, David A; Dunn, Mark J G

    2013-01-01

    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. PMID:23370959

  18. Profound hypoglycemia-ınduced by vaccinium corymbosum juice and laurocerasus fruit

    PubMed Central

    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. PMID:25097289

  19. 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.

  20. [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. PMID:8721721

  1. Arogenate Dehydratase Isoenzymes Profoundly and Differentially Modulate Carbon Flux into Lignins*

    PubMed Central

    Corea, Oliver R. A.; Ki, Chanyoung; Cardenas, Claudia L.; Kim, Sung-Jin; Brewer, Sarah E.; Patten, Ann M.; Davin, Laurence B.; Lewis, Norman G.

    2012-01-01

    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. PMID:22311980

  2. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling.

    PubMed Central

    Peraldi, P; Xu, M; Spiegelman, B M

    1997-01-01

    TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man. Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPARgamma/ RXR complex is shown by the fact that similar effects are observed with other PPARgamma/RXR ligands such as 15 deoxy Delta12,14PGJ2 and LG268. The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions. PMID:9312188

  3. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma.

    PubMed

    Howell, Gareth R; MacNicoll, Katharine H; Braine, Catherine E; Soto, Ileana; Macalinao, Danilo G; Sousa, Gregory L; John, Simon W M

    2014-11-01

    The endothelin system is implicated in various human and animal glaucomas. Targeting the endothelin system has great promise as a treatment for human glaucoma, but the cell types involved and the exact mechanisms of action are not clearly elucidated. Here, we report a detailed characterization of the endothelin system in specific cell types of the optic nerve head (ONH) during glaucoma in DBA/2J mice. First, we show that key components of the endothelin system are expressed in multiple cell types. We discover that endothelin 2 (EDN2) is expressed in astrocytes as well as microglia/monocytes in the ONH. The endothelin receptor type A (Ednra) is expressed in vascular endothelial cells, while the endothelin receptor type B (Ednrb) receptor is expressed in ONH astrocytes. Second, we show that Macitentan treatment protects from glaucoma. Macitentan is a novel, orally administered, dual endothelin receptor antagonist with greater affinity, efficacy and safety than previous antagonists. Finally, we test the combinatorial effect of targeting both the endothelin and complement systems as a treatment for glaucoma. Similar to endothelin, the complement system is implicated in a variety of human and animal glaucomas, and has great promise as a treatment target. We discovered that combined targeting of the endothelin (Bosentan) and complement (C1qa mutation) systems is profoundly protective. Remarkably, 80% of DBA/2J eyes subjected to this combined inhibition developed no detectable glaucoma. This opens an exciting new avenue for neuroprotection in glaucoma.

  4. The profound impact of negative power law noise on statistical estimation.

    PubMed

    Reinhardt, Victor S

    2010-01-01

    This paper investigates the profound impact of negative power law (neg-p) noise - that is, noise with a power spectral density L(p)(f) proportional variant | f |(p) for p < 0 - on the ability of practical implementations of statistical estimation or fitting techniques, such as a least squares fit (LSQF) or a Kalman filter, to generate valid results. It demonstrates that such negp noise behaves more like systematic error than conventional noise, because neg-p noise is highly correlated, non-stationary, non-mean ergodic, and has an infinite correlation time tau(c). It is further demonstrated that stationary but correlated noise will also cause invalid estimation behavior when the condition T > tau(c) is not met, where T is the data collection interval for estimation. Thus, it is shown that neg-p noise, with its infinite Tau(c), can generate anomalous estimation results for all values of T, except in certain circumstances. A covariant theory is developed explaining much of this anomalous estimation behavior. However, simulations of the estimation behavior of neg-p noise demonstrate that the subject cannot be fully understood in terms of covariant theory or mean ergodicity. It is finally conjectured that one must investigate the variance ergodicity properties of neg-p noise through the use of 4th order correlation theory to fully explain such simulated behavior. PMID:20040429

  5. Profound desensitization by ambient GABA limits activation of δ-containing GABAA receptors during spillover.

    PubMed

    Bright, Damian P; Renzi, Massimiliano; Bartram, Julian; McGee, Thomas P; MacKenzie, Georgina; Hosie, Alastair M; Farrant, Mark; Brickley, Stephen G

    2011-01-12

    High-affinity extrasynaptic GABA(A) receptors (GABA(A)Rs) are a prominent feature of cerebellar granule neurons and thalamic relay neurons. In both cell types, the presence of synaptic glomeruli would be expected to promote activation of these GABA(A)Rs, contributing to phasic spillover-mediated currents and tonic inhibition. However, the precise role of different receptor subtypes in these two phenomena is unclear. To address this question, we made recordings from neurons in acute brain slices from mice, and from tsA201 cells expressing recombinant GABA(A)Rs. We found that δ subunit-containing GABA(A)Rs of both cerebellar granule neurons and thalamic relay neurons of the lateral geniculate nucleus contributed to tonic conductance caused by ambient GABA but not to spillover-mediated currents. In the presence of a low "ambient" GABA concentration, recombinant "extrasynaptic" δ subunit-containing GABA(A)Rs exhibited profound desensitization, rendering them insensitive to brief synaptic- or spillover-like GABA transients. Together, our results demonstrate that phasic spillover and tonic inhibition reflect the activation of distinct receptor populations.

  6. Profound Reversible Hypogammaglobulinemia Caused by Celiac Disease in the Absence of Protein Losing Enteropathy.

    PubMed

    Ameratunga, Rohan; Barker, Russell William; Steele, Richard Henderson; Deo, Maneka; Woon, See-Tarn; Yeong, Mee Ling; Koopmans, Wikke

    2015-08-01

    When patients with hypogammaglobulinemia are encountered, a vigorous search should be undertaken for secondary treatable causes. Here we describe the first case of a patient with severe asymptomatic hypogammaglobulinemia where the underlying cause was undiagnosed celiac disease. A strict gluten free diet resulted in resolution of her mild long-standing abdominal symptoms and correction of her hypogammaglobulinemia. There was corresponding improvement in her duodenal histology and normalisation of her celiac serology. Protein losing enteropathy was unlikely to have been the mechanism of her profound hypogammaglobulinemia, as her albumin was within the normal range and she had a normal fecal alpha 1 antitrypsin level. Application of the Ameratunga et al. (2013) diagnostic criteria was helpful in confirming this patient did not have Common Variable Immunodeficiency Disorder (CVID). Celiac disease must now be considered in the differential diagnosis of severe hypogammaglobulinemia. There should be a low threshold for undertaking celiac serology in patients with hypogammaglobulinemia, even if they have minimal symptoms attributable to gut disease.

  7. Envelope glycoproteins of human immunodeficiency virus type 1: profound influences on immune functions.

    PubMed Central

    Chirmule, N; Pahwa, S

    1996-01-01

    Infection by human immunodeficiency virus type 1 (HIV-1) leads to progressive destruction of the CD4+ T-cell subset, resulting in immune deficiency and AIDS. The specific binding of the viral external envelope glycoprotein of HIV-1, gp120, to the CD4 molecules initiates viral entry. In the past few years, several studies have indicated that the interaction of HIV-1 envelope glycoprotein with cells and molecules of the immune system leads to pleiotropic biological effects on immune functions, which include effects on differentiation of CD34+ lymphoid progenitor cells and thymocytes, aberrant activation and cytokine secretion patterns of mature T cells, induction of apoptosis, B-cell hyperactivity, inhibition of T-cell dependent B-cell differentiation, modulation of macrophage functions, interactions with components of complement, and effects on neuronal cells. The amino acid sequence homologies of the envelope glycoproteins with several cellular proteins have suggested that molecular mimicry may play a role in the pathogenesis of the disease. This review summarizes work done by several investigators demonstrating the profound biological effects of envelope glycoproteins of HIV-1 on immune system cells. Extensive studies have also been done on interactions of the viral envelope proteins with components of the immune system which may be important for eliciting a "protective immune response." Understanding the influences of HIV-1 envelope glycoproteins on the immune system may provide valuable insights into HIV-1 disease pathogenesis and carries implications for the trials of HIV-1 envelope protein vaccines and immunotherapeutics. PMID:8801439

  8. Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity.

    PubMed

    Lotze, Michael T; Buchser, William J; Liang, Xiaoyan

    2012-08-01

    Cancer is the leading cause of death in the United States in those dying under the age of 85. Although cancer is increasingly controlled as a chronic disease, true cures of patients with metastatic epithelial malignancies have rarely been obtained with currently available systemic therapies. For example, administration of high-dose recombinant interleukin 2 (IL2), enhancing cytolytic immune cell proliferation and delivery, promotes complete antitumor responses in < 10% of treated individuals. Means to reduce the toxicity, attributed to a cytokine storm and an associated "systemic autophagic syndrome" as well as enhance efficacy and increase the potential set of malignancies in which it is applied (currently patients with renal cancer and melanoma) would be of great interest. IL2 promotes both T-cell and NK cell induction of immune cell-mediated autophagy (iC-MA) in tumor targets. We have demonstrated that HMGB1 is detected at high levels in the serum of IL2-treated mice with translocation to the cytoplasm from the nucleus in the liver, consistent with HMGB1's release in response to stress, and ability to sustain autophagy. Limiting autophagy in mice with coadministration of chloroquine (CQ) diminishes serum levels of HMGB1, cytokines (IFNG and IL6 but not IL18), and autophagic flux, attenuating weight gain, enhancing DC, T-cell and NK cell numbers, and promoting long-term tumor control in a murine hepatic metastases model. Autophagy (programmed cell survival) is a metabolic process associated with promotion of late cancer growth. In tumor cell lines, CQ treatment limits ATP production through inhibition of oxidative phosphorylation and promotion of apoptosis. CQ increases autophagic vacuoles and LC3-II levels in tumor cells, associated with increased annexin V(+)/PI(-) cells, cleaved-PARP, cleaved-CASP3, and cytochrome c release from mitochondria. These observations, limiting toxicity and prolonging antitumor effects, with a combination of IL2 and autophagy inhibition in murine models are now being tested by the Cytokine Working Group in patients with advanced renal cell carcinoma. PMID:22660171

  9. Postural control in children with typical development and children with profound hearing loss

    PubMed Central

    de Sousa, Aneliza Maria Monteiro; de França Barros, Jônatas; de Sousa Neto, Brígido Martins

    2012-01-01

    Purpose To describe the behavior of the postural control in children with profound sensorineural hearing loss and compare the results of experimental tests with hearing children aged 7 to 10 years. Patients and methods This is a cross-sectional study where 100 children were divided into experimental and control groups. We used a force platform, AccuSway Plus, where the tests were conducted under the experimental conditions: open base, eyes open (OBEO); open base, eyes closed (OBEC); closed base, eyes open (CBEO); closed base, eyes closed (CBEC). The body sway velocity (V) of the center of pressure, the displacement in the anteroposterior direction (COPap) and mediolateral (COPml) of the center of pressure were the parameters to evaluate the postural control. For statistical analysis we used the nonparametric Mann–Whitney U test, with a significance level of 5%. Results In comparisons of variables between the groups, the experimental group outperformed by at least 75% of the control group values. In terms of global trends, the experimental group shows higher values of body oscillations in all experimental conditions and variables evaluated. Children with hearing loss had poorer balance performance compared to the group of hearing. The inferential analysis revealed a statistically significant difference in the balance between deaf and hearing children in the OBEC experimental condition in relation to the COPml parameter (P = 0.04). There were no statistically significant differences in comparisons between the sexes when the groups were analyzed separately. The prevalence of unknown etiology showed 58% of cases and congenital rubella in 16%. The discovery of deafness occurred in 70% of children before the age of 3 years. Conclusion In this study, children with hearing loss had poorer balance performance compared to the group of hearing children. This finding confirms the need to investigate postural control through longitudinal studies to identify the area of

  10. Achieving and sustaining profound institutional change in healthcare: case study using neo-institutional theory.

    PubMed

    Macfarlane, Fraser; Barton-Sweeney, Cathy; Woodard, Fran; Greenhalgh, Trisha

    2013-03-01

    Change efforts in healthcare sometimes have an ambitious, whole-system remit and seek to achieve fundamental changes in norms and organisational culture rather than (or as well as) restructuring the service. Long-term evaluation of such initiatives is rarely undertaken. We report a secondary analysis of data from an evaluation of a profound institutional change effort in London, England, using a mixed-method longitudinal case study design. The service had received £15 million modernisation funding in 2004, covering multiple organisations and sectors and overseen by a bespoke management and governance infrastructure that was dismantled in 2008. In 2010-11, we gathered data (activity statistics, documents, interviews, questionnaires, site visits) and compared these with data from 2003 to 2008. Data analysis was informed by neo-institutional theory, which considers organisational change as resulting from the material-resource environment and three 'institutional pillars' (regulative, normative and cultural-cognitive), enacted and reproduced via the identities, values and activities of human actors. Explaining the long-term fortunes of the different components of the original programme and their continuing adaptation to a changing context required attention to all three of Scott's pillars and to the interplay between macro institutional structures and embedded human agency. The paper illustrates how neo-institutional theory (which is typically used by academics to theorise macro-level changes in institutional structures over time) can also be applied at a more meso level to inform an empirical analysis of how healthcare organisations achieve change and what helps or hinders efforts to sustain those changes. PMID:23415586

  11. Profound systemic inflammatory response syndrome following non-emergent intestinal surgery in children☆

    PubMed Central

    Chawla, Bhani K.; Teitelbaum, Daniel H.

    2013-01-01

    Purpose Systemic inflammatory response syndrome (SIRS) is an uncommon but severe complication in surgical patients. While SIRS is well known, it is poorly described in the pediatric population. The goal of this study was to describe the incidence of profound SIRS following non-emergent intestinal surgery in children and to identify potential risk factors. Methods A retrospective review was conducted for patients 0–19 years of age following intestinal surgery and/or lysis of adhesions from 01/01/1999-02/28/2012. Children were excluded for preoperative instability or frank bowel perforation. Patients were then placed in a post-operative SIRS or non-SIRS group as defined by the 2005 International Pediatric Sepsis Consensus Conference Guidelines (6. B. Goldstein, B. Giroir, A. Randolph, and Sepsis International Consensus Conference on Pediatric, ‘International Pediatric Sepsis Consensus Conference: Definitions for Sepsis and Organ Dysfunction in Pediatrics’, Pediatr Crit Care Med, 6 (2005), 2–8.). Results SIRS was identified in 17 of the 381 patients. Logistic regression analysis was performed and showed heart disease, kidney disease, PN dependence, and intestinal obstruction to be predictive of post-operative SIRS. Conclusion This study represents one of the first reports to identify a previously poorly described process of significant SIRS after intestinal surgery in children. Both systemic organ failure and intestinal dysfunction are strong risk factors for post-operative SIRS in children. Potentially, these pre-existing conditions may lead to disruption of normal intestinal flora or barrier function, which in turn may predispose these children for dramatic SIRS after intestinal surgery. Understanding how these factors lead to SIRS will be critical to developing prevention strategies. PMID:24074671

  12. Transfer of Information between Parents and Teachers of Children with Profound Intellectual and Multiple Disabilities at Special Educational Centres

    ERIC Educational Resources Information Center

    Fonteine, H.; Zijlstra, H. P.; Vlaskamp, C.

    2008-01-01

    Background: Because of the complexity of the problems that affect children with profound intellectual and multiple disabilities (PIMD), communication between parents and teachers at special educational centres is indispensable. Logs are widely used in the Netherlands although only little is known about the effectiveness and efficiency of…

  13. Continuity and Change from Adolescence to Emerging Adulthood: Adolescence-Limited vs. Life-Course-Persistent Profound Ego Development Arrests

    ERIC Educational Resources Information Center

    Billings, Rebecca L.; Hauser, Stuart T.; Allen, Joseph P.

    2008-01-01

    Participants (n = 36) with consistent Pre-conformist ego development levels during multiple adolescent assessments were studied to determine whether and how their ego levels had changed at age 25. Those (n = 12) whose ego levels remained at the Pre-conformist level were assigned to a "life-course-persistent profound ego development arrest"…

  14. An Enriched Teaching Program for Reducing Resistance and Indices of Unhappiness among Individuals with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Green, Carolyn W.; Reid, Dennis H.; Rollyson, Jeannia H.; Passante, Susan C.

    2005-01-01

    We evaluated an enriched teaching program for reducing resistance and indices of unhappiness displayed by 3 individuals with profound multiple disabilities during teaching sessions. The program involved presentation of preferred activities before, during, and after each teaching session, discontinuation of identified nonpreferred activities, and a…

  15. The Relationship of Self-Injurious Behavior and Other Maladaptive Behaviors among Individuals with Severe and Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Cooper, Christopher; Malone, Carrie J.; Moskow, Sheree L.

    2008-01-01

    Participants were 101 individuals with self-injurious behavior (SIB) and severe or profound intellectual disability who were matched by gender, age, and level of intellectual disability to controls. Persons with SIB were more likely to exhibit the challenging behaviors of physical aggression, property destruction, sexually inappropriate behaviors…

  16. An Investigation into the Skill Set of Speech-Language Pathologists Working with Profoundly Deaf Children: A Study in Context

    ERIC Educational Resources Information Center

    Veyvoda, Michelle

    2013-01-01

    This study explored the skill sets possessed by speech-language pathologists working with profoundly deaf children in three types of settings (state-funded "4201" schools for the deaf, Board of Cooperative Educational Services programs, and local school districts) throughout New York State. The phenomenological method of inquiry was…

  17. Getting the Message: Intuition and Reflexivity in Professional Interpretations of Non-Verbal Behaviours in People with Profound Learning Disabilities

    ERIC Educational Resources Information Center

    Phelvin, Andrew

    2013-01-01

    This paper describes the current challenges facing nurses and other professionals who care for people with profound and multiple intellectual disabilities. This particularly vulnerable group of service users often rely on a repertoire of non-verbal behaviours to communicate their needs and wishes. These challenges include the requirements of…

  18. The Training of Parents of Profoundly and Severely Mentally Retarded Children in Handling Behavior at Home. Final Report.

    ERIC Educational Resources Information Center

    Blumberg, Allen

    Described is a project in which parents of profoundly and severely mentally retarded children were taught techniques of operant conditioning to be used in training their children in self help skills such as feeding, toileting, and dressing, with the end goal of reducing the anxiety level of parents. Involved were 25 parents whose children were on…

  19. Use of a Mouth-Wiping Response to Reduce Drooling by Two Persons with Profound Developmental Disabilities

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Pichierri, Sabrina; Iaffaldano, Daniela; Latrofa, Alessandra; Oliva, Doretta

    2008-01-01

    Two men with profound developmental disabilities used a mouth-wiping response instrumental to reduce drooling via a micro-switch-based program (i.e., a program in which the response was automatically monitored and followed by positive stimulation). The wiping response was performed via a napkin or a handkerchief placed inside a belt pocket. The…

  20. Speech and Language Therapists' Approaches to Communication Intervention with Children and Adults with Profound and Multiple Learning Disability

    ERIC Educational Resources Information Center

    Goldbart, Juliet; Chadwick, Darren; Buell, Susan

    2014-01-01

    Background: People with profound intellectual and multiple disabilities (PMLD) have communication impairments as one defining characteristic. Aims: To explore speech and language therapists' (SLTs) decision making in communication interventions for people with PMLD, in terms of the intervention approaches used, the factors informing the…

  1. The Documentation of Health Problems in Relation to Prescribed Medication in People with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    van der Heide, D. C.; van der Putten, A. A. J.; van den Berg, P. B.; Taxis, K.; Vlaskamp, C.

    2009-01-01

    Background: Persons with profound intellectual and multiple disabilities (PIMD) suffer from a wide range of health problems and use a wide range of different drugs. This study investigated for frequently used medication whether there was a health problem documented in the medical notes for the drug prescribed. Method: Persons with PIMD with an…

  2. The Locus Equation as an Index of Coarticulation in Syllables Produced by Speakers with Profound Hearing Loss

    ERIC Educational Resources Information Center

    McCaffrey Morrison, Helen

    2008-01-01

    Locus equations (LEs) were derived from consonant-vowel-consonant (CVC) syllables produced by four speakers with profound hearing loss. Group data indicated that LE functions obtained for the separate CVC productions initiated by /b/, /d/, and /g/ were less well-separated in acoustic space than those obtained from speakers with normal hearing. A…

  3. The Effect of Frequency Transposition on Speech Perception in Adolescents and Young Adults with Profound Hearing Loss

    ERIC Educational Resources Information Center

    Gou, J.; Smith, J.; Valero, J.; Rubio, I.

    2011-01-01

    This paper reports on a clinical trial evaluating outcomes of a frequency-lowering technique for adolescents and young adults with severe to profound hearing impairment. Outcomes were defined by changes in aided thresholds, speech perception, and acceptance. The participants comprised seven young people aged between 13 and 25 years. They were…

  4. Curriculum Guidelines for Teaching Profound and Severely Retarded Students (I.Q. Under 40) Including Those with Physical Handicaps.

    ERIC Educational Resources Information Center

    Bailey, Constance

    1975-01-01

    Presented are curriculum guidelines for teaching severely and profoundly retarded students, including students with physical handicaps. In addition to a listing of aims and objectives (such as that the student should analyze the need for space for himself and others), guidelines are provided for the following areas: awareness (of such stimuli as…

  5. What Makes Them Feel like They Do? Investigating the Subjective Well-Being in People with Severe and Profound Disabilities

    ERIC Educational Resources Information Center

    Vos, Pieter; De Cock, Paul; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2010-01-01

    Background: Because of the problems measuring subjective well-being in people with severe and profound intellectual disabilities, there are no studies to date which explore the factors contributing to the subjective well-being in these groups. We wanted to explore the client and service characteristics contributing to the subjective well-being of…

  6. Effects of Training on Naive Listeners' Judgments of the Speech Intelligibility of Children with Severe-to-Profound Hearing Loss

    ERIC Educational Resources Information Center

    Ellis, Lee W.; Beltyukova, Svetlana A.

    2008-01-01

    Purpose: This study examined the effects of feedback training, familiarization training, and no training on naive listeners' word identification (WI) and magnitude estimation scaling (MES) judgments of the speech intelligibility of children with severe-to-profound hearing impairments. Method: Depending on the training group, listeners received a…

  7. Self-Injurious Behavior in People with Profound Intellectual Disabilities: A Meta-Analysis of Single-Case Studies

    ERIC Educational Resources Information Center

    Denis, Jo; Van den Noortgate, Wim; Maes, Bea

    2011-01-01

    The limitations people with profound intellectual disabilities experience in functioning contribute to a vulnerability to self-injurious behavior. Since this problem behavior has important negative consequences for people concerned, examining the effectiveness of treatments is important. In the current meta-analysis, single-case studies…

  8. Prelinguistic Vocal Development in Infants with Typical Hearing and Infants with Severe-to-Profound Hearing Loss

    ERIC Educational Resources Information Center

    Iyer, Suneeti Nathani; Oller, D. Kimbrough

    2008-01-01

    Delays in the onset of canonical babbling with hearing loss are extensively documented. Relatively little is known about other aspects of prelinguistic vocal development and hearing loss. Eight infants with typical hearing and eight with severe-to-profound hearing loss were matched with regard to a significant vocal development milestone, the…

  9. Adapted Leisure Materials vs. Standard Leisure Materials: Evaluating Several Aspects of Programming for Persons Who Are Profoundly Handicapped.

    ERIC Educational Resources Information Center

    Realon, Rodney E.; And Others

    1989-01-01

    The study compared adapted leisure materials to standard leisure materials typically available in an institutional setting and evaluated their effects on profoundly retarded clients' (N=8) engagement, aberrant behaviors, staff interactions with clients, and client smiles. Among findings were higher staff interactions when standard leisure…

  10. Improving Social Skills in Adolescents and Adults with Autism and Severe to Profound Intellectual Disability: A Review of the Literature

    ERIC Educational Resources Information Center

    Walton, Katherine M.; Ingersoll, Brooke R.

    2013-01-01

    Social skills are important treatment targets for individuals with autism spectrum disorders (ASD) across the lifespan. However, few treatments are available for adolescents and adults with ASD who also have severe to profound intellectual disability (S/PID). Several social skill interventions have been described that may improve social skills in…

  11. The False-Friend Effect in Three Profoundly Deaf Learners of French: Disentangling Morphology, Phonology and Orthography

    ERIC Educational Resources Information Center

    Janke, Vikki; Kolokonte, Marina

    2015-01-01

    Three profoundly deaf individuals undertook a low-frequency backward lexical translation task (French/English), where morphological structure was manipulated and orthographic distance between test items was measured. Conditions included monomorphemic items (simplex), polymorphemic items (complex), items whose French morphological structure…

  12. Enhancing Literacy Skills of Students with Congenital and Profound Hearing Impairment in Nigeria Using Babudoh's Comprehension Therapy

    ERIC Educational Resources Information Center

    Babudoh, Gladys B.

    2014-01-01

    This study reports the effect of a treatment tool called "Babudoh's comprehension therapy" in enhancing the comprehension and writing skills of 10 junior secondary school students with congenital and profound hearing impairment in Plateau State, Nigeria. The study adopted the single group pretest-posttest quasi-experimental research…

  13. Pre-Linguistic Autism Diagnostic Observation Schedule Adapted for Older Individuals with Severe to Profound Mental Retardation: A Pilot Study

    ERIC Educational Resources Information Center

    Berument, Sibel Kazak; Starr, Elizabeth; Pickles, Andrew; Tomlins, Megan; Papanikolauou, Katerina; Lord, Catherine; Rutter, Michael

    2005-01-01

    The Autism Diagnostic Observational Schedule (ADOS) is a semi-structured observational scale developed to assess social interaction, communication and play in individuals who are suspected to have autism. Since the ADOS is not suitable to be used with severely or profoundly mentally retarded adolescents and adults with very limited language…

  14. Self-Management of Instruction Cues for Occupation: Review of Studies with People with Severe and Profound Developmental Disabilities.

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; O'Reilly, Mark F.

    2001-01-01

    This article reviews five self-management strategies used to help people with severe and profound developmental disabilities acquire and maintain constructive occupation: picture cues presented on sets of cards, picture cues stored in computer-aided systems, object cues attached to cards, verbal cues stored in audio recording devices, and…

  15. See Me, Feel Me. Using Physiology to Validate Behavioural Observations of Emotions of People with Severe or Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Vos, P.; De Cock, P.; Petry, K.; Van Den Noortgate, W.; Maes, B.

    2013-01-01

    Background: Behavioural observations are the most frequently used source of information about emotions of people with severe or profound intellectual disabilities but have not yet been validated against other measures of emotion. In this study we wanted to validate the behavioural observations of emotions using respiration (rib cage contribution,…

  16. Implications of Biobehavioral States for the Education and Treatment of Students with the Most Profoundly Handicapping Conditions.

    ERIC Educational Resources Information Center

    Guess, Doug; And Others

    1988-01-01

    Implications of biobehavioral state measures for the assessment of students with profoundly handicapping conditions are discussed in relation to similar behaviors observed in infants and among persons recovering from severe head trauma. Biobehavioral states assessed include: asleep-inactive, asleep-active, drowsy, awake-inactive-alert,…

  17. Choice and Preference Assessment Research with People with Severe to Profound Developmental Disabilities: A Review of the Literature

    ERIC Educational Resources Information Center

    Cannella, Helen I.; O'Reilly, Mark F.; Lancioni, Giulio E.

    2005-01-01

    Since the last major empirical review on choice interventions and preference assessments among people with severe to profound developmental disabilities (Lancioni, O'Reilly, & Emerson, 1996) the body of research in this area has grown extensively. This paper reviews thirty studies carried out between 1996 and 2002 that have been sorted into four…

  18. An Evaluation of Social and Adaptive Skills in Adults with Bipolar Disorder and Severe/Profound Intellectual Disability

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Terlonge, Cindy; Gonzalez, Melissa L.; Rivet, Tessa

    2006-01-01

    The purpose of this study was to explore the interrelationship of social and adaptive skills in adults with bipolar disorder and severe or profound intellectual disability. A bipolar group (N=14), a severe psychopathology group without bipolar disorder (N=14), and a control group with no DSM-IV Axis I diagnosis (N=14) were compared on the…

  19. The Gender Mix among Staff in Schools for Pupils with Severe and Profound Multiple Learning Difficulties and Its Impact.

    ERIC Educational Resources Information Center

    Goss, Phil

    2003-01-01

    This paper reports on several studies of gender mix among staff in ten schools for students with severe, profound and/or multiple disabilities. Headteachers' perceptions of the impact of women's dominance in these positions are explored, and a series of proposals for future recruitment and staff development is put forth. (Contains seven…

  20. Analysis and Discourse. Response to An Analysis of the Forum: Issues in Education of the Severely and Profoundly Retarded.

    ERIC Educational Resources Information Center

    Burton, Thomas A.; Hirshoren, Alfred

    1981-01-01

    In another response to criticism regarding state of the art analysis in the education of severely and profoundly retarded students, the article states that the criticism is a red herring, and that the differences cited are ones of style rather than interpretation. For related information, see EC 133 831-832. (CL)

  1. Informal Social Networks of People with Profound Intellectual and Multiple Disabilities: Relationship with Age, Communicative Abilities and Current Living Arrangements

    ERIC Educational Resources Information Center

    Kamstra, A.; van der Putten, A. A. J.; Post, W. J.; Vlaskamp, C.

    2015-01-01

    Background: People with profound intellectual and multiple disabilities (PIMD) have limited informal social contacts. Research to determine the factors which can positively influence establishing sound informal social contacts is required. Materials and Methods: Regression analysis for 200 people with PIMD was used to analyse how age,…

  2. Carer-Reported Contemporary Health Problems in People with Severe and Profound Intellectual Disability and Genetic Syndromes

    ERIC Educational Resources Information Center

    Berg, Katy; Arron, Kate; Burbidge, Cheryl; Moss, Joanna; Oliver, Chris

    2007-01-01

    Identifying health problems in people with severe and profound disabilities and genetic syndromes can be problematic, and unidentified or unmanaged health problems may adversely impact an individual's quality of life. The authors studied carer-reported contemporary health problems in three genetic syndromes (Angelman, Cornelia de Lange, and Cri du…

  3. Policy, Service Pathways and Mortality: A 10-Year Longitudinal Study of People with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Hogg, James; Juhlberg, K.; Lambe, L.

    2007-01-01

    Background: One hundred and forty-two children and adults with profound intellectual and multiple disabilities were identified in 1993 in a single Scottish region on whom detailed information was collected via a postal questionnaire survey. Methods: They were followed up in 2003. The time spanned represented a period of significant policy change…

  4. From Individualism to Co-Construction and Back Again: Rethinking Research Methodology for Children with Profound and Multiple Learning Disabilities

    ERIC Educational Resources Information Center

    Simmons, Ben; Watson, Debbie

    2015-01-01

    Children with profound and multiple learning disabilities (PMLD) are said to experience severe congenital impairments to consciousness and cognition stemming from neurological damage. Such children are understood as operating at the pre-verbal stages of development, and research in the field typically draws conceptual resources from psychology to…

  5. Camera-Based Microswitch Technology to Monitor Mouth, Eyebrow, and Eyelid Responses of Children with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Bellini, Domenico; Oliva, Doretta; Singh, Nirbhay N.; O'Reilly, Mark F.; Lang, Russell; Didden, Robert

    2011-01-01

    A camera-based microswitch technology was recently used to successfully monitor small eyelid and mouth responses of two adults with profound multiple disabilities (Lancioni et al., Res Dev Disab 31:1509-1514, 2010a). This technology, in contrast with the traditional optic microswitches used for those responses, did not require support frames on…

  6. Profound Expressive Language Impairment in Low Functioning Children with Autism: An Investigation of Syntactic Awareness Using a Computerised Learning Task

    ERIC Educational Resources Information Center

    McGonigle-Chalmers, Maggie; Alderson-Day, Ben; Fleming, Joanna; Monsen, Karl

    2013-01-01

    Nine low-functioning children with profound expressive language impairment and autism were studied in terms of their responsiveness to a computer-based learning program designed to assess syntactic awareness. The children learned to touch words on a screen in the correct sequence in order to see a corresponding animation, such as "monkey…

  7. A Psychodynamic Psychotherapy Approach to the Emotional Problems of Exceptionally and Profoundly Gifted Adolescents and Adults: A Psychiatrist's Experience

    ERIC Educational Resources Information Center

    Grobman, Jerald

    2009-01-01

    An eclectic form of psychodynamic psychotherapy is presented to address the emotional problems of exceptionally and profoundly gifted adolescents and adults. The approach includes cognitive/behavioral techniques as well as psychologically informed mentoring, coaching, and advising. Once a psychodynamic formulation was established, it was used to…

  8. Therapeutic Interventions in the Netherlands and Belgium in Support of People with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Vlaskamp, Carla; Nakken, Han

    2008-01-01

    For several reasons, people with profound and multiple disabilities may be offered a variety of therapeutic interventions. Thus far, researchers have shown a limited interest in providing an empirical base for these interventions. Research is needed on the theoretical rationale (if any), the supposed "modus operandi" and the claimed benefits of…

  9. Parental Adaptation to Out-of-Home Placement of a Child with Severe or Profound Developmental Disabilities

    ERIC Educational Resources Information Center

    Jackson, Jeffrey B.; Roper, Susanne Olsen

    2014-01-01

    Utilizing grounded theory qualitative research methods, a model was developed for describing parental adaptation after voluntary placement of a child with severe or profound developmental disabilities in out-of-home care. Interviews of parents from 20 families were analyzed. Parents' cognitive appraisals of placement outcomes were classified…

  10. People with Profound and Multiple Intellectual Disabilities Using Symbols to Control a Computer: Exploration of User Engagement and Supporter Facilitation

    ERIC Educational Resources Information Center

    Bunning, Karen; Kwiatkowska, Gosia; Weldin, Nick

    2012-01-01

    Computer usage features in everyday life for the majority of people in developed countries. Access is a problem for many users with intellectual disability. Action-research was conducted to develop and explore the potential of specially adapted, computer readable symbols for choosing and accessing media on a computer. Five people with profound and…

  11. Camera-Based Microswitch Technology for Eyelid and Mouth Responses of Persons with Profound Multiple Disabilities: Two Case Studies

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Bellini, Domenico; Oliva, Doretta; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff

    2010-01-01

    These two studies assessed camera-based microswitch technology for eyelid and mouth responses of two persons with profound multiple disabilities and minimal motor behavior. This technology, in contrast with the traditional optic microswitches used for those responses, did not require support frames on the participants' face but only small color…

  12. A Guide for the Instruction and Training of the Profoundly Retarded and Severely Multi-Handicapped Child.

    ERIC Educational Resources Information Center

    Ball, Thomas, Ed.

    The guide is intended for teachers of profoundly retarded and severely multiply handicapped children in California. It suggests relevant methodologies and media for such children as well as sample curricula for use in Development Centers for Handicapped Minors and state and private institutions. The major portion of the document consists of…

  13. Parental Attitudes toward the Inclusion of Children with Profound Intellectual and Multiple Disabilities in General Primary Education in the Netherlands

    ERIC Educational Resources Information Center

    de Boer, Anke A.; Munde, Vera S.

    2015-01-01

    Despite the growing introduction of inclusive education, children with profound intellectual and multiple disabilities (PIMD) are barely included. Because an underlying factor here may be the attitudes of those directly involved, the present study focuses on the attitude of parents and relating variables concerning experience with individuals with…

  14. Effects of rosiglitazone on global ischemia-induced hippocampal injury and expression of mitochondrial uncoupling protein 2

    SciTech Connect

    Chen, S.-D.; Wu, H.-Y.; Yang, D.-I; Lee, S.-Y.; Shaw, F.-Z.; Lin, T.-K.; Liou, C.-W.; Chuang, Y.-C. . E-mail: ycchuang@adm.cgmh.org.tw

    2006-12-08

    We investigate the effect of rosiglitazone, a ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) with anti-inflammatory and anti-oxidative actions, on hippocampal injury and its roles in mitochondrial uncoupling protein 2 (UCP2) expression caused by transient global ischemia (TGI) in rats. Increased UCP2 expression was observed in mitochondria of hippocampal CA1 2-24 h after TGI/reperfusion, with maximal expression levels at 6-18 h. Administration of rosiglitazone to hippocampus 30 min prior to the onset of TGI further enhanced mitochondrial UCP2 expression 2-6 h following TGI/reperfusion. Rats subjected to TGI/reperfusion displayed a significant increase in lipid peroxidation, based on increased malondialdehyde (MDA) levels, in hippocampal CA1 mitochondria 2-6 h after reperfusion. Rosiglitazone significantly attenuated TGI/reperfusion-induced lipid peroxidation and suppressed hippocampal CA1 neuronal death based on the surviving neuronal counts. In conclusion, our results provide correlative evidence for the 'PPAR{gamma} {sup {yields}} UCP2 {sup {yields}} neuroprotection' cascade in ischemic brain injury.

  15. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2}-induced down-regulation of endothelial nitric oxide synthase in association with HSP70 induction

    SciTech Connect

    Hwang, Jinah; Lee, Hyun-Il; Chang, Young-Sun; Lee, Soo Jae; Kim, Kwang Pyo; Park, Sang Ick . E-mail: parksi@nih.go.kr

    2007-05-25

    A natural ligand of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), 15-deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), decreases endothelial nitric oxide synthase (eNOS) expression by an unknown mechanism. Here we found that 15d-PGJ{sub 2}-induced eNOS reduction is inversely associated with heat shock protein 70 (HSP70) induction in endothelial cells. Treatment of cells with 15d-PGJ{sub 2} decreased eNOS protein expression in a concentration- and time-dependent manner, but independently of PPAR{gamma} with no effect on mRNA levels. Although 15d-PGJ{sub 2} elicited endothelial apoptosis, inhibition of both pan-caspases and cathepsins failed to reverse reduction of eNOS protein. Interestingly, we observed that 15d-PGJ{sub 2} induced HSP70 in a dose-dependent manner. Immunoprecipitation and heat shock treatment demonstrated that eNOS reduction was strongly related to HSP70 induction. Cellular fractionation revealed that treatment with 15d-PGJ{sub 2} increased eNOS distribution 2.5-fold from soluble to insoluble fractions. These findings provide new insights into mechanisms whereby eNOS regulation by 15d-PGJ{sub 2} is related to HSP70 induction.

  16. A Study of the Combined Use of a Hearing Aid and Tactual Aid in an Adult with Profound Hearing Loss

    ERIC Educational Resources Information Center

    Reed, Charlotte M.; Delhorne, Lorraine A.

    2006-01-01

    This study examined the benefits of the combined used of a hearing aid and tactual aid to supplement lip-reading in the reception of speech and for the recognition of environmental sounds in an adult with profound hearing loss. Speech conditions included lip-reading alone (L), lip-reading + tactual aid (L+TA) lip-reading + hearing aid (L+HA) and…

  17. Synthesis of new lipid-inspired ionic liquids by thiol-ene chemistry: profound solvent effect on reaction pathway.

    PubMed

    Mirjafari, Arsalan; O'Brien, Richard A; West, Kevin N; Davis, James H

    2014-06-16

    The synthesis of a series of new lipid-inspired ionic liquids through thiol-ene "click" reaction with a single-step process. This synthesis offers considerable promise as an efficient and orthogonal method to construct structurally diverse imidazolium-type ionic liquids with linear and branched cationic tails, as well as versatility in the placement of the sulfur heteroatom. Profound solvent effect in this ene reaction regioselectivity has been observed.

  18. Dosing profile profoundly influences nicotinic acid’s ability to improve metabolic control in rats

    PubMed Central

    Kroon, Tobias; Kjellstedt, Ann; Thalén, Pia; Gabrielsson, Johan; Oakes, Nicholas D.

    2015-01-01

    Acute nicotinic acid (NiAc) administration results in rapid reduction of plasma FFA concentrations. However, sustained NiAc exposure is associated with tolerance development resulting in return of FFA to pretreatment levels. The aim of this study was to determine whether a 12 h rectangular exposure profile (intermittent dose group) could avoid tolerance development and thereby reverse insulin resistance induced by lipid overload. FFA lowering was assessed in male Sprague Dawley (lean) and obese Zucker rats (obese) in response to a 5 h NiAc infusion, in either NiAc-naïve animals or after 5 days of continuous (24 h/day) or intermittent (12 h/day) NiAc dosing (via implantable, programmable minipump). We found that intermittent dosing over 5 days preserved NiAc-induced FFA lowering, comparable to dosing in NiAc-naïve animals. By contrast, following 5 days continuous administration, NiAc-induced FFA lowering was lost. The effect of intermittent NiAc infusion on insulin sensitivity was assessed in obese Zucker rats using hyperinsulinemic-isoglycemic clamps. The acute effect of NiAc to elevate glucose infusion rate (vs. saline control) was indeed preserved with intermittent dosing, while being lost upon continuous infusion. In conclusion, an intermittent but not continuous NiAc dosing strategy succeeded in retaining NiAc’s ability to lower FFA and improve insulin sensitivity in obese Zucker rats.—Kroon, T., A. Kjellstedt, P. Thalén, J. Gabrielsson, and N. D. Oakes. PMID:26168997

  19. Non-accidental chlorpyrifos poisoning-an unusual cause of profound unconsciousness.

    PubMed

    Lee, Jiun-Chang; Lin, Kuang-Lin; Lin, Jainn-Jim; Hsia, Shao-Hsuan; Wu, Chang-Teng

    2010-04-01

    Chlorpyrifos is an organophosphorus anticholinesterase insecticide, and organophosphate intoxication can induce symptoms such as miosis, urination, diarrhea, diaphoresis, lacrimation, excitation of central nervous system, salivation, and consciousness disturbance (MUDDLES). Although accidental poisoning of children with drugs and chemicals is a common cause for consciousness disturbance in children, the possibility of deliberate poisoning is rarely considered. We report on a healthy 5-year 6-month-old boy with recurrent organophosphate intoxication. Reports of chlorpyrifos intoxication in children are quite rare. This case report demonstrates decision-making process and how to disclose deliberate chlorpyrifos poisoning of the toddler by the stepmother, another example of Munchausen syndrome by proxy.

  20. Chronic ethanol consumption profoundly alters regional brain ceramide and sphingomyelin content in rodents.

    PubMed

    Roux, Aurelie; Muller, Ludovic; Jackson, Shelley N; Baldwin, Katherine; Womack, Virginia; Pagiazitis, John G; O'Rourke, Joseph R; Thanos, Panayotis K; Balaban, Carey; Schultz, J Albert; Volkow, Nora D; Woods, Amina S

    2015-02-18

    Ceramides (CER) are involved in alcohol-induced neuroinflammation. In a mouse model of chronic alcohol exposure, 16 CER and 18 sphingomyelin (SM) concentrations from whole brain lipid extracts were measured using electrospray mass spectrometry. All 18 CER concentrations in alcohol exposed adults increased significantly (range: 25-607%); in juveniles, 6 CER decreased (range: -9 to -37%). In contrast, only three SM decreased in adult and one increased significantly in juvenile. Next, regional identification at 50 μm spatial resolution from coronal sections was obtained with matrix implanted laser desorption/ionization mass spectrometry imaging (MILDI-MSI) by implanting silver nanoparticulate matrices followed by focused laser desorption. Most of the CER and SM quantified in whole brain extracts were detected in MILDI images. Coronal sections from three brain levels show qualitative regional changes in CER-SM ion intensities, as a function of group and brain region, in cortex, striatum, accumbens, habenula, and hippocampus. Highly correlated changes in certain white matter CER-SM pairs occur in regions across all groups, including the hippocampus and the lateral (but not medial) cerebellar cortex of adult mice. Our data provide the first microscale MS evidence of regional lipid intensity variations induced by alcohol.

  1. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.

    PubMed

    Wong, G William; Krawczyk, Sarah A; Kitidis-Mitrokostas, Claire; Revett, Tracy; Gimeno, Ruth; Lodish, Harvey F

    2008-12-01

    The insulin-sensitizing hormone, adiponectin, belongs to the expanding C1q/TNF (tumour necrosis factor) family of proteins. We recently identified a family of adiponectin paralogues designated as CTRP (C1q/TNF-related protein) 1-7, and in the present study describe CTRP10. In the present study, we show that CTRP1, CTRP2, CTRP3, CTRP5 and CTRP7 transcripts are expressed predominantly by adipose tissue. In contrast, placenta and eye expressed the highest levels of CTRP6 and CTRP10 transcripts respectively. Expression levels of CTRP1, CTRP2, CTRP3, CTRP6 and CTRP7 transcripts are up-regulated in 8-week-old obese (ob/ob) mice relative to lean controls. Treatment of mice with a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, rosiglitazone, increased the expression of CTRP1 and decreased CTRP6 transcript levels. All CTRPs are secreted glycoproteins when expressed in mammalian cells. CTRP1, CTRP2, CTRP3, CTRP5 and CTRP6 circulate in the blood and are potential endocrine hormones; their serum levels vary according to the sex and genetic background of mice. Importantly, serum levels of CTRP1 and CTRP6 are increased in adiponectin-null mice. Like adiponectin, all secreted CTRP proteins form trimers as their basic structural units. CTRP3, CTRP5, CTRP6 and CTRP10 trimers are further assembled into higher-order oligomeric complexes via disulfide bonding mediated by their N-terminal cysteine residues. Besides forming homo-oligomers, CTRP1/CTRP6, CTRP2/CTRP7 and adiponectin/CTRP2 are secreted as heterotrimers, thus providing a mechanism to potentially generate functionally distinct ligands. Functional characterization of one such family member, CTRP1, showed that it specifically activates Akt and p44/42-MAPK (mitogen-activated protein kinase) signalling pathways in differentiated mouse myotubes. Moreover, injection of recombinant CTRP1 into mice significantly reduced their serum glucose levels. Thus at least CTRP1 may be considered a novel adipokine. In

  2. Pain Assessment in People with Profound Intellectual and Multiple Disabilities; a Pilot Study into the Use of the Pain Behaviour Checklist in Everyday Practice

    ERIC Educational Resources Information Center

    van der Putten, Annette; Vlaskamp, Carla

    2011-01-01

    Because of their physical and general health problems, people with a combination of profound intellectual and severe or profound motor disabilities (PIMD) are at risk of pain-related medical conditions. They are fully dependent on support professionals for the detection and accurate interpretation of nonverbal pain behaviour. These professionals…

  3. Stimulation of Toll-Like Receptors profoundly influences the titer of polyreactive antibodies in the circulation.

    PubMed

    Gunti, Sreenivasulu; Messer, Ronald J; Xu, Chengfu; Yan, Ming; Coleman, William G; Peterson, Karin E; Hasenkrug, Kim J; Notkins, Abner L

    2015-01-01

    Polyreactive antibodies are a major component of the natural antibody repertoire and bind to a variety of structurally unrelated molecules. These antibodies are thought to provide a first line of defense against bacterial infections and play a major role in the clearance of apoptotic cells. What triggers the secretion of these antibodies has remained an enigma. Using a surrogate assay for measuring polyreactive antibodies, we found that about 50% of serum IgM is polyreactive and that stimulation of TLR4(+/+), but not TLR4(-/-), mice resulted in a 40 fold increase in polyreactive antibodies. Stimulation of TLRs 3, 7, 9 also increased the secretion of polyreactive antibodies. Infection with a virus or tissue damage induced by a toxin similarly led to an increase in polyreactive antibodies in MyD88(+/+), but not MyD88(-/-) mice. We conclude that stimulation of TLRs is a key link in the mechanism of polyreactive antibody secretion into the circulation. PMID:26463758

  4. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.

    PubMed

    Ogasawara, Daisuke; Deng, Hui; Viader, Andreu; Baggelaar, Marc P; Breman, Arjen; den Dulk, Hans; van den Nieuwendijk, Adrianus M C H; van den Nieuwendijk, Adriann M C H; Soethoudt, Marjolein; van der Wel, Tom; Zhou, Juan; Overkleeft, Herman S; Sanchez-Alavez, Manuel; Mori, Simone; Mo, Simone; Nguyen, William; Conti, Bruno; Liu, Xiaojie; Chen, Yao; Liu, Qing-Song; Cravatt, Benjamin F; van der Stelt, Mario

    2016-01-01

    Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.

  5. Better Visuospatial Working Memory in Adults Who Report Profound Deafness Compared to Those With Normal or Poor Hearing: Data From the UK Biobank Resource.

    PubMed

    Rudner, Mary; Keidser, Gitte; Hygge, Staffan; Rönnberg, Jerker

    2016-01-01

    Experimental work has shown better visuospatial working memory (VSWM) in profoundly deaf individuals compared to those with normal hearing. Other data, including the UK Biobank resource shows poorer VSWM in individuals with poorer hearing. Using the same database, the authors investigated VSWM in individuals who reported profound deafness. Included in this study were 112 participants who were profoundly deaf, 1310 with poor hearing and 74,635 with normal hearing. All participants performed a card-pair matching task as a test of VSWM. Although variance in VSWM performance was large among profoundly deaf participants, at group level it was superior to that of participants with both normal and poor hearing. VSWM in adults is related to hearing status but the association is not linear. Future study should investigate the mechanism behind enhanced VSWM in profoundly deaf adults. PMID:27232076

  6. A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4

    SciTech Connect

    Min, Kyung-Won; Zhang, Xiaobo; Imchen, Temjenmongla; Baek, Seung Joon

    2012-09-01

    MCC-555 is a novel PPARα/γ dual ligand of the thiazolidinedione class and was recently developed as an anti-diabetic drug with unique properties. MCC-555 also has anti-proliferative activity through growth inhibition and apoptosis induction in several cancer cell types. Our group has shown that MCC-555 targets several proteins in colorectal tumorigenesis including nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) which plays an important role in chemoprevention responsible for chemopreventive compounds. NAG-1 is a member of the TGF-β superfamily and is involved in tumor progression and development; however, NAG-1's roles in pancreatic cancer have not been studied. In this report, we found that MCC-555 alters not only NAG-1 expression, but also p21 and cyclin D1 expression. NAG-1 and p21 expression was not blocked by PPARγ-specific antagonist GW9662, suggesting that MCC-555-induced NAG-1 and p21 expression is independent of PPARγ activation. However, decreasing cyclin D1 by MCC-555 seems to be affected by PPARγ activation. Further, we found that the GC box located in the NAG-1 promoter play an important role in NAG-1 transactivation by MCC-555. Subsequently, we screened several transcription factors that may bind to the GC box region in the NAG-1 promoter and found that KLF4 potentially binds to this region. Expression of KLF4 precedes NAG-1 and p21 expression in the presence of MCC-555, whereas blocking KLF4 expression using specific KLF4 siRNA showed that both NAG-1 and p21 expression by MCC-555 was blocked. In conclusion, MCC-555's actions on anti-proliferation involve both PPARγ-dependent and -independent pathways, thereby enhancing anti-tumorigenesis in pancreatic cancer cells. -- Highlights: ► PPARα/γ ligand MCC-555 exhibits anti-proliferative activity in pancreatic cancer cells. ► MCC-555 affects KLF4 expression following by NAG-1 and p21 expression in a PPARγ independent manner. ► MCC-555 also affects cyclin D1 down

  7. Immune history profoundly affects broadly protective B cell responses to influenza.

    PubMed

    Andrews, Sarah F; Huang, Yunping; Kaur, Kaval; Popova, Lyubov I; Ho, Irvin Y; Pauli, Noel T; Henry Dunand, Carole J; Taylor, William M; Lim, Samuel; Huang, Min; Qu, Xinyan; Lee, Jane-Hwei; Salgado-Ferrer, Marlene; Krammer, Florian; Palese, Peter; Wrammert, Jens; Ahmed, Rafi; Wilson, Patrick C

    2015-12-01

    Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk-biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies. PMID:26631631

  8. Cryptoblemes: A New Discovery with Major Economic Implications and Profound Changes to the Geologic Paradigm

    NASA Technical Reports Server (NTRS)

    Windolph, J., Jr.; Sutton, J.

    1997-01-01

    Cryptoblemes are subtle impact shock signatures imprinted by cosmic debris on the crustal surfaces of lunar planetary bodes. These signatures constitute a complex cumulative overprinting of topographic, structural geophysical, and tectonic patterns that have a conspicuous radial centric multiringed symmetry. The geometry and distribution of cryptoblemes on Earth is comparable to the size and density of impact features on lunar planetary surfaces. Analysis of satellite imagery, sea-floor sonar, side-looking radar and aerial photographs of specific sites reveals new criteria for the identification and confirmation of impact-shock signatures. These criteria include joint and foliation patterns with asbestiform minerals, ribbon-quartz, spheroidal weathering, domal exfoliation, pencil shale, and shock spheres, which may originate from hydrocavitation of water-saturated sedimentary rocks. Cryptoblemes may also be associated with breccia pipes, sinkholes, buttes, mesas, and bogs, high-Rn anomalies, nodular concentrations, and earthquake epicenters. Major implications of cryptobleme identification include exploratory targeting of hydrocarbon and mineral deposits and the explanation of their origins. Analysis of known mineral deposits, structural traps and sedimentary basins show a direct correlation with cryptobleme patterns. Significant geologic paradigm shifts related to cryptoblemes include mountain building processes, structural orogenies, induced volcanism, earthquake origins, hydrocarbon diagenesis, formation mineral deposits, continental rifting, and plate movements, magnetic overprinting and local regional, and global geologic extinction and speciation patterns. Two figures provide a comparison between a multiring impact overprint in water and multiring cryptobleme in the U.S. basin range. (Additional information is contained in the original document).

  9. Immune history profoundly affects broadly protective B cell responses to influenza

    PubMed Central

    Andrews, Sarah F.; Huang, Yunping; Kaur, Kaval; Popova, Lyubov I.; Ho, Irvin Y.; Pauli, Noel T.; Dunand, Carole J. Henry; Taylor, William M; Lim, Samuel; Huang, Min; Qu, Xinyan; Lee, Jane-Hwei; Salgado-Ferrer, Marlene; Krammer, Florian; Palese, Peter; Wrammert, Jens; Ahmed, Rafi; Wilson, Patrick C.

    2016-01-01

    Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal Abs generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, HA stalk-biased, response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies. PMID:26631631

  10. Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches

    PubMed Central

    Page, Karen M.

    2016-01-01

    During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules—morphogens—guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively

  11. Absence of Neuroplastin-65 Affects Synaptogenesis in Mouse Inner Hair Cells and Causes Profound Hearing Loss

    PubMed Central

    Carrott, Leanne; Aguilar, Carlos; Johnson, Stuart L.; Chessum, Lauren; West, Melissa; Morse, Susan; Dorning, Joanne; Smart, Elizabeth; Hardisty-Hughes, Rachel; Ball, Greg; Parker, Andrew; Barnard, Alun R.; MacLaren, Robert E.; Wells, Sara; Marcotti, Walter

    2016-01-01

    The Neuroplastin gene encodes two synapse-enriched protein isoforms, Np55 and Np65, which are transmembrane glycoproteins that regulate several cellular processes, including the genesis, maintenance, and plasticity of synapses. We found that an absence of Np65 causes early-onset sensorineural hearing loss and prevented the normal synaptogenesis in inner hair cells (IHCs) in the newly identified mouse mutant pitch. In wild-type mice, Np65 is strongly upregulated in the cochlea from around postnatal day 12 (P12), which corresponds to the onset of hearing. Np65 was specifically localized at the presynaptic region of IHCs. We found that the colocalization of presynaptic IHC ribbons and postsynaptic afferent terminals is greatly reduced in pitch mutants. Moreover, IHC exocytosis is also reduced with mutant mice showing lower rates of vesicle release. Np65 appears to have a nonessential role in vision. We propose that Np65, by regulating IHC synaptogenesis, is critical for auditory function in mammals. SIGNIFICANCE STATEMENT In the mammalian cochlea, the sensory inner hair cells (IHCs) encode auditory information. They do this by converting sound wave-induced mechanical motion of their hair bundles into an electrical current. This current generates a receptor potential that controls release of glutamate neurotransmitter from their ribbon synapses onto the auditory afferent fiber. We show that the synapse-enriched protein Np65, encoded by the Neuroplastin gene, is localized at the IHC presynaptic region. In mutant mice, absence of Np65 causes early-onset sensorineural hearing loss and prevents normal neurotransmitter release in IHCs and colocalization of presynaptic ribbons with postsynaptic afferents. We identified Neuroplastin as a novel deafness gene required for ribbon synapse formation and function, which is critical for sound perception in mammals. PMID:26740663

  12. Cortical activation in profoundly deaf patients during cochlear implant stimulation demonstrated by H sub 2 (15)O PET

    SciTech Connect

    Herzog, H.; Lamprecht, A.; Kuehn, A.R.; Roden, W.; Vosteen, K.H.; Feinendegen, L.E. )

    1991-05-01

    Cochlear implants (CIs) are used to provide sensations of sound to profoundly deaf patients. The performance of the CI is assessed mainly by the subjective reports of patients. The aim of this study was to look for objective cortical responses to the stimulation of the CI. Two postlingually and two prelingually deaf patients were investigated by positron emission tomography (PET) using {sup 15}O-labeled water (H{sub 2}{sup 15}O) to determine the regional cerebral blood flow (rCBF). Instead of quantifying rCBF in absolute terms, it was estimated by referring the regional tissue concentration of H{sub 2}{sup 15}O to the mean whole brain concentration. CI stimulation encoded from white noise and sequential words led to an increased rCBF in the primary and secondary (Wernicke) auditory cortex. Relative elevations of up to 33% were observed bilaterally, although they were higher contralateral to the CI. These results were obtained not only in the postlingually deaf patients but also in two patients who had never been able to hear. Thus, it could be demonstrated that PET measurements of cerebral H{sub 2}{sup 15}O distribution yield objective responses of the central auditory system during electrical stimulation by CIs in profoundly deaf patients.

  13. Asystolic Cardiac Arrest of Unknown Duration in Profound Hypothermia and Polysubstance Overdose: A Case Report of Complete Recovery

    PubMed Central

    Lubana, Sandeep Singh; Genin, Dennis Iilya; Singh, Navdeep; De La Cruz, Angel

    2015-01-01

    Patient: Male, 20 Final Diagnosis: Asystolic cardiac arrest in profound hypothermia and poly-substance overdose Symptoms: Cardiac arrest • cardiac arrhythmia Medication: — Clinical Procedure: Endotracheal intubation • hemodialysis Specialty: Critical Care Medicine Objective: Unusual clinical course Background: Opioid addiction and overdose is a serious problem worldwide. Fatal overdoses from opioids are responsible for numerous deaths and are increasing, especially if taken in combination with other psychoactive substances. Combined with environmental exposure, opioid overdose can cause profound hypothermia. Opioid abuse and other drugs of abuse impair thermoregulation, leading to severe hypothermia. Both drug overdose and severe hypothermia can cause cardiac arrest. Case Report: We report a case of 20-year-old man with history of polysubstance abuse presenting with severe hypothermia and asystole of unknown duration with return of spontaneous circulation (ROSC) achieved after 28 minutes of cardiopulmonary resuscitation (CPR). Urine toxicology was positive for cocaine, heroin, and benzodiazepine, along with positive blood alcohol level. The patient was rewarmed using non-invasive techniques. Hospital course was complicated by acute renal failure (ARF), severe rhabdomyolysis, severe hyperkalemia, ST-elevation myocardial infarction (STEMI), shock liver, coagulopathy, and aspiration pneumonia. Conclusions: Survival with full cardiovascular and neurologic recovery after a cardiac arrest caused by drug overdose in the setting of severe hypothermia is still possible, even if the cardiac arrest is of unknown or prolonged duration. Patients with severe hypothermia experiencing cardiac arrest/hemodynamic instability can be rewarmed using non-invasive methods and may not necessarily need invasive rewarming techniques. PMID:26054008

  14. Transient blood-brain barrier permeability following profound temporary global ischemia: an experimental study using /sup 14/C-AIB

    SciTech Connect

    Dobbin, J.; Crockard, H.A.; Ross-Russell, R.

    1989-02-01

    The influence of reperfusion after profound incomplete forebrain ischemia on blood-brain barrier (BBB) permeability to a small protein tracer was studied in male Sprague-Dawley rats. The mean cortical blood to brain transfer constant (Ki) for /sup 14/C-amino isobutyric acid (AIB) was significantly greater at 3 and 6 h of reperfusion, 2.5 times the mean values of controls (p less than 0.05) (2.5 microliter g-1 min-1 and 1.0 microliters g-1 min-1 respectively), but had returned to control values after reperfusion for 24 h. Analysis of distribution of Ki values showed that following 15 min and 30 min of profound ischemia, there was a significant increase in transfer of AIB across the blood-brain barrier (BBB) after recirculation for up to 6 h, though there was no evidence of protein extravasation as assessed by Evans Blue (EB) dye. After 24 h of reperfusion, the BBB to AIB was restored, and Ki values had returned to control values. It is concluded that following transient global ischemia, the BBB may recover rapidly.

  15. Prelinguistic Vocal Development in Infants with Typical Hearing and Infants with Severe-to-Profound Hearing Loss

    PubMed Central

    Iyer, Suneeti Nathani; Oller, D. Kimbrough

    2010-01-01

    Delays in the onset of canonical babbling with hearing loss are extensively documented. Relatively little is known about other aspects of prelinguistic vocal development and hearing loss. Eight infants with typical hearing and eight with severe-to-profound hearing loss were matched with regard to a significant vocal development milestone, the onset of canonical babbling, and were examined at three points in time: before, at, and after the onset of canonical babbling. No differences in volubility were noted between the two infant groups. Growth in canonical babbling appeared to be slower for infants with hearing loss than infants with typical hearing. Glottal and glide production was similar in both groups. The results add to a body of information delineating aspects of prelinguistic vocal development that seem to differ or to be similar in infants with hearing loss compared to infants with typical hearing. PMID:21499444

  16. Silent Endurance and Profound Loneliness: Socioemotional Suffering in African Americans Living With HIV in the Rural South

    PubMed Central

    Miles, Margaret Shandor; Isler, Malika Roman; Banks, Bahby B.; Sengupta, Sohini; Corbie-Smith, Giselle

    2011-01-01

    We explored how community responses to HIV contribute to distress in African Americans living with HIV in the rural South of the United States. We listened to the voices of community members through focus groups and African Americans with HIV through interviews. Community avoidance of HIV, negative views of HIV, and discriminatory behavior powerfully affected the distress of people living with HIV (PLWH). Ongoing distress, coupled with limited support, led to a life in which many PLWH endured their pain in silence and experienced profound loneliness. We conceptualized their experiences as socioemotional suffering—the hidden emotional burden and inner distress of not only living with HIV, a complex serious illness, but also with the societal attitudes and behaviors that are imposed on the illness and on PLWH. To improve the quality of life and health of PLWH, we cannot focus solely on the individual, but must also focus on the local community and society as a whole. PMID:21041516

  17. A gene responsible for profound congenital nonsyndromal recessive deafness maps to the pericentromeric region of chromosome 17

    SciTech Connect

    Friedman, T.B.; Liang, Y.; Asher, J.H. Jr.

    1994-09-01

    Autosomal recessive deafness is the most common form of human hereditary hearing loss. Two percent of the 2,185 residents of Bengkala, Bali, Indonesia have profound congenital neurosensory nonsyndromal hereditary deafness due to a fully penetrant autosomal recessive mutation (NARD1). Families, identified through children with profound congenital deafness having hearing parents, give the expected 25% deaf progeny when corrected for ascertainment bias. Congenitally deaf individuals from Bengkala show no response to pure tone audiological examination. Obligate heterozygotes for autosomal recessive deafness in Bengkala have normal or borderline normal hearing. A chromosomal location for NARD1 was assigned directly using a linkage strategy that combines allele-frequency dependent homozygosity mapping (AHM) followed by an analysis of historical recombinants to position NARD1 relative to flanking markers. Thirteen deaf Bengkala villagers of hearing parents were typed initially for 148 STRPs distributed across the human genome and a cluster of tightly linked 17p markers with a significantly higher number of homozygotes than expected under Hardy-Weinberg and linkage equilibrium were identified. NARD1 maps closest to STRPs for D17S261 (Mfd41) and D17S805 (AFM234ta1) that are 3.2 cM apart. Recombinant genotypes for the flanking markers, D17S122 (VAW409) and D17S783 (AFM026vh7), in individuals homozygous for NARD1 place NARD1 in a 5.3 cM interval of the pericentromeric region of chromosome 17 on a refined 17p-17q12 genetic map.

  18. The aporphine alkaloid boldine induces adiponectin expression and regulation in 3T3-L1 cells.

    PubMed

    Yu, Bangning; Cook, Carla; Santanam, Nalini

    2009-10-01

    Adiponectin is an adipokine secreted by differentiated adipocytes. Clinical studies suggest a negative correlation between oxidative stress and adiponectin levels in patients with metabolic syndrome or cardiovascular disease. Natural compounds that can prevent oxidative stress mediated inhibition of adiponectin may be potentially therapeutic. Boldine, an aporphine alkaloid abundant in the medicinal plant Peumus boldus, is a powerful antioxidant. The current study demonstrates the effects of boldine on the expression of adiponectin and its regulators, CCAAT/enhancer binding protein-alpha (C/EBPalpha) and peroxisome proliferator-activated receptor (PPAR)-gamma, in 3T3-L1 cells. Differentiated 3T3-L1 adipocytes were exposed to either hydrogen peroxide (H(2)O(2)) (100 microM) or tumor necrosis factor-alpha (TNFalpha) (1 ng/mL) for 24 hours in the presence or absence of increasing concentrations of boldine (5-100 microM). Quantitative polymerase chain reaction showed that both the oxidants decreased the mRNA levels of adiponectin, PPARgamma, and C/EBPalpha to half of the control levels. Boldine, at all concentrations, counteracted the inhibitory effect of H(2)O(2) or TNFalpha and increased the expression of adiponectin and its regulators. The effect of boldine on adiponectin expression was biphasic, with the lower concentrations (5-25 microM) having a larger inductive effect compared to higher concentrations (50-100 microM). Boldine treatment alone in the absence of H(2)O(2) or TNFalpha was also able to induce adiponectin at the inductive phase of adipogenesis. Peroxisome proliferator response element-luciferase promoter transactivity analysis showed that boldine interacts with the PPAR response element and could potentially modulate PPAR responsive genes. Our results indicate that boldine is able to modulate the expression of adiponectin and its regulators in 3T3-L1 cells and has the potential to be beneficial in obesity-related cardiovascular disease. PMID:19857072

  19. Hearing Instruments for Unilateral Severe-to-Profound Sensorineural Hearing Loss in Adults: A Systematic Review and Meta-Analysis

    PubMed Central

    Smith, Sandra Nelson; Lucas, Laura

    2016-01-01

    Objectives: A systematic review of the literature and meta-analysis was conducted to assess the nature and quality of the evidence for the use of hearing instruments in adults with a unilateral severe to profound sensorineural hearing loss. Design: The PubMed, EMBASE, MEDLINE, Cochrane, CINAHL, and DARE databases were searched with no restrictions on language. The search included articles from the start of each database until February 11, 2015. Studies were included that (a) assessed the impact of any form of hearing instrument, including devices that reroute signals between the ears or restore aspects of hearing to a deaf ear, in adults with a sensorineural severe to profound loss in one ear and normal or near-normal hearing in the other ear; (b) compared different devices or compared a device with placebo or the unaided condition; (c) measured outcomes in terms of speech perception, spatial listening, or quality of life; (d) were prospective controlled or observational studies. Studies that met prospectively defined criteria were subjected to random effects meta-analyses. Results: Twenty-seven studies reported in 30 articles were included. The evidence was graded as low-to-moderate quality having been obtained primarily from observational before-after comparisons. The meta-analysis identified statistically significant benefits to speech perception in noise for devices that rerouted the speech signals of interest from the worse ear to the better ear using either air or bone conduction (mean benefit, 2.5 dB). However, these devices also degraded speech understanding significantly and to a similar extent (mean deficit, 3.1 dB) when noise was rerouted to the better ear. Data on the effects of cochlear implantation on speech perception could not be pooled as the prospectively defined criteria for meta-analysis were not met. Inconsistency in the assessment of outcomes relating to sound localization also precluded the synthesis of evidence across studies. Evidence for

  20. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} induces renal epithelial cell death through NF-{kappa}B-dependent and MAPK-independent mechanism

    SciTech Connect

    Kang, Dae Sik; Kwon, Chae Hwa; Park, Ji Yeon; Kim, Jae Ho; Woo, Jae Suk; Jung, Jin Sup; Kim, Yong Keun . E-mail: kim430@pusan.ac.kr

    2006-11-01

    The peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) ligand 15d-PGJ{sub 2} induces cell death in renal proximal tubular cells. However, the underlying molecular mechanism(s) remains unidentified. The present study was undertaken to examine the roles of reactive oxygen species (ROS), mitogen-activated protein kinase, and NF-{kappa}B in opossum kidney (OK) cell death induced by 15d-PGJ{sub 2}. Treatment of OK cells with 15d-PGJ{sub 2} resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. 15d-PGJ{sub 2} increased ROS production and the effect was inhibited by catalase and N-acetylcysteine. The 15d-PGJ{sub 2}-induced cell death was also prevented by these antioxidants, suggesting that the cell death was associated with ROS generation. The PPAR{gamma} antagonist GW9662 did not prevent the 15d-PGJ{sub 2}-induced cell death. 15d-PGJ{sub 2} caused a transient activation of extracellular signal-regulated kinase (ERK). However, inhibitors (PD98059 and U0126) of MEK, an ERK upstream kinase, did not alter the 15d-PGJ{sub 2}-induced cell death. Transfection with constitutively active MEK and dominant-negative MEK had no effect on the cell death. 15d-PGJ{sub 2} inhibited the NF-{kappa}B transcriptional activity, which was accompanied by an inhibition of nuclear translocation of the NF-{kappa}B subunit p65 and impairment in DNA binding. Inhibition of NF-{kappa}B with a NF-{kappa}B specific inhibitor pyrrolidinecarbodithioate and transfection with I{kappa}B{alpha} (S32A/36A) caused cell death. These results suggest that the 5d-PGJ{sub 2}-induced OK cell death was associated with ROS production and NF-{kappa}B inhibition, but not with MAPK activation.

  1. Macroevolutionary consequences of profound climate change on niche evolution in marine molluscs over the past three million years

    PubMed Central

    Saupe, E. E.; Hendricks, J. R.; Portell, R. W.; Dowsett, H. J.; Haywood, A.; Hunter, S. J.; Lieberman, B. S.

    2014-01-01

    In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks. PMID:25297868

  2. Plasmacytoid, conventional, and monocyte-derived dendritic cells undergo a profound and convergent genetic reprogramming during their maturation

    PubMed Central

    Vu Manh, Thien-Phong; Alexandre, Yannick; Baranek, Thomas; Crozat, Karine; Dalod, Marc

    2013-01-01

    DCs express receptors sensing microbial, danger or cytokine signals, which when triggered in combination drive DC maturation and functional polarization. Maturation was proposed to result from a discrete number of modifications in conventional DCs (cDCs), in contrast to a cell-fate conversion in plasmacytoid DCs (pDCs). cDC maturation is generally assessed by measuring cytokine production and membrane expression of MHC class II and co-stimulation molecules. pDC maturation complexity was demonstrated by functional genomics. Here, pDCs and cDCs were shown to undergo profound and convergent changes in their gene expression programs in vivo during viral infection. This observation was generalized to other stimulation conditions and DC subsets, by public microarray data analyses, PCR confirmation of selected gene expression profiles, and gene regulatory sequence bioinformatics analyses. Thus, maturation is a complex process similarly reshaping all DC subsets, including through the induction of a core set of NF-κB- or IFN-stimulated genes irrespective of stimuli. PMID:23553052

  3. B-less: a strain of profoundly B cell-deficient mice expressing a human lambda transgene

    PubMed Central

    1992-01-01

    We have created several transgenic mouse strains that bear the human lambda light chain gene driven by its own promoter and a mouse immunoglobulin heavy chain enhancer. The transgene is expressed in many tissues, with particularly high levels of expression in the bone marrow, thymus, spleen, and lymph nodes. One of these transgenic lines, B-less, displays a dramatic phenotype characterized by an acute susceptibility to bacterial and viral infections. Analysis of this strain shows it to be profoundly deficient in both immature (pre-B) and mature B cells, as well as in circulating immunoglobulin. The pre-B and B cell defects are cell autonomous, as judged by cell culture and bone marrow graft chimeras. Despite this B cell deficiency, the T cell lineage appears grossly normal as assessed by flow cytometric analysis and by its response to mitogen stimulation. Since an independently derived transgenic strain bearing the same human lambda construct displays a partial B-less phenotype, it is likely that the B lineage deficiency is due to a dominant effect of transgene expression rather than to the insertional perturbation of an endogenous mouse gene. It is interesting that the deficiency phenotype is fully expressed in the FVB/N genetic background, but is suppressed in F1 hybrids formed between the FVB/N and C57BL/6 inbred strains. Evidently, there are one or more dominant genetic suppressors of B-less in the C57BL/6 genome. PMID:1314882

  4. Macroevolutionary consequences of profound climate change on niche evolution in marine molluscs over the past three million years

    USGS Publications Warehouse

    Saupe, E.E.; Hendricks, J.R.; Portell, R.W.; Dowsett, Harry J.; Haywood, A. M.; Hunter, S.J.; Lieberman, B.S.

    2014-01-01

    In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks.

  5. Macroevolutionary consequences of profound climate change on niche evolution in marine molluscs over the past three million years.

    PubMed

    Saupe, E E; Hendricks, J R; Portell, R W; Dowsett, H J; Haywood, A; Hunter, S J; Lieberman, B S

    2014-11-22

    In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks.

  6. Effects of the age of cochlear implantation on the quality of the speech produced by profoundly HOH speakers

    NASA Astrophysics Data System (ADS)

    Lake, Samantha; Kollia, Betty

    2003-04-01

    Four hearing-impaired children with prelingual, bilateral, severe-to-profound hearing loss were grouped by age, gender, and age at implantation; the younger group consisted of females approximately 6 years old and implanted between 1-2 years of age and the older group consisted of males approximately 14 years old and implanted at 9 years of age. Each child was diagnosed with prelingual hearing loss, was implanted with the Nucleus 24® cochlear implant in 1998, and has approximately 4 years of experience using the implant consistently. All subjects receive 8 h of direct instruction with the implant per week, in a school for the deaf that utilizes total communication. Each subject also receives speech therapy in 30-min sessions four times per week and exhibits intelligible speech. Coarticulation in the children's speech was studied using five consonant-diphthong-consonant pseudowords, in the carrier sentence ``it's a -- again.'' The recordings were digitized and analyzed acoustically. The results are discussed with reference to the age of cochlear implantation of the children and its role in the quality of their speech.

  7. Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function

    PubMed Central

    Jara, Javier H.; Genç, Barış; Cox, Gregory A.; Bohn, Martha C.; Roos, Raymond P.; Macklis, Jeffrey D.; Ulupınar, Emel; Özdinler, P. Hande

    2015-01-01

    Corticospinal motor neurons (CSMN) receive, integrate, and relay cerebral cortex's input toward spinal targets to initiate and modulate voluntary movement. CSMN degeneration is central for numerous motor neuron disorders and neurodegenerative diseases. Previously, 5 patients with mutations in the ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) gene were reported to have neurodegeneration and motor neuron dysfunction with upper motor neuron involvement. To investigate the role of UCHL1 on CSMN health and stability, we used both in vivo and in vitro approaches, and took advantage of the Uchl1nm3419 (UCHL1−/−) mice, which lack all UCHL1 function. We report a unique role of UCHL1 in maintaining CSMN viability and cellular integrity. CSMN show early, selective, progressive, and profound cell loss in the absence of UCHL1. CSMN degeneration, evident even at pre-symptomatic stages by disintegration of the apical dendrite and spine loss, is mediated via increased ER stress. These findings bring a novel understanding to the basis of CSMN vulnerability, and suggest UCHL1−/− mice as a tool to study CSMN pathology. PMID:25596590

  8. Effects of Unilateral Cochlear Implantation on Balance Control and Sensory Organization in Adult Patients with Profound Hearing Loss

    PubMed Central

    Parietti-Winkler, Cécile; Lion, Alexis; Montaut-Verient, Bettina; Grosjean, Rémy; Gauchard, Gérome C.

    2015-01-01

    Many studies were interested in the consequence of vestibular dysfunction related to cochlear implantation on balance control. This pilot study aimed to assess the effects of unilateral cochlear implantation on the modalities of balance control and sensorimotor strategies. Posturographic and vestibular evaluations were performed in 10 patients (55 ± 20 years) with profound hearing loss who were candidates to undergo unilateral multichannel cochlear implantation. The evaluation was carried out shortly before and one year after surgery. Posturographic tests were also performed in 10 age-matched healthy participants (63 ± 16 years). Vestibular compensation was observed within one year. In addition, postural performances of the patients increased within one year after cochlear implantation, especially in the more complex situations, in which sensory information is either unavailable or conflicting. Before surgery, postural performances were higher in the control group compared to the patients' group. One year after cochlear implantation, postural control was close to normalize. The improvement of postural performance could be explained by a mechanism of vestibular compensation. In addition, the recovery of auditory information which is the consequence of cochlear implantation could lead to an extended exploration of the environment possibly favoring the development of new balance strategies. PMID:26583121

  9. Effects of subject- versus experimenter-selected reinforcers on the behavior of individuals with profound developmental disabilities.

    PubMed Central

    Smith, R G; Iwata, B A; Shore, B A

    1995-01-01

    Results from a number of studies have shown that individuals with profound developmental disabilities often show differential approach behavior to stimuli presented in a variety of formats, and that such behavior is a reasonably good predictor of reinforcement effects when these "preferred" stimuli are used subsequently in a contingent arrangement. Recent data suggest that reinforcement effects may be enhanced further by allowing individuals to select, just prior to training sessions, which (of several) preferred stimuli would be used as reinforcers, but whether this method is superior to one based on selection by a teacher or therapist has not been adequately addressed. We compared the effects of these two methods of reinforcer selection on rates of responding on a free-operant task, using stimuli previously identified as potential reinforcers. Results obtained with 4 subjects indicated little or no difference in reinforcement effects when stimuli were selected by subjects rather than experimenters. Implications of these results with respect to choice and its relation to reinforcement are discussed. PMID:7706151

  10. Effects of subject- versus experimenter-selected reinforcers on the behavior of individuals with profound developmental disabilities.

    PubMed

    Smith, R G; Iwata, B A; Shore, B A

    1995-01-01

    Results from a number of studies have shown that individuals with profound developmental disabilities often show differential approach behavior to stimuli presented in a variety of formats, and that such behavior is a reasonably good predictor of reinforcement effects when these "preferred" stimuli are used subsequently in a contingent arrangement. Recent data suggest that reinforcement effects may be enhanced further by allowing individuals to select, just prior to training sessions, which (of several) preferred stimuli would be used as reinforcers, but whether this method is superior to one based on selection by a teacher or therapist has not been adequately addressed. We compared the effects of these two methods of reinforcer selection on rates of responding on a free-operant task, using stimuli previously identified as potential reinforcers. Results obtained with 4 subjects indicated little or no difference in reinforcement effects when stimuli were selected by subjects rather than experimenters. Implications of these results with respect to choice and its relation to reinforcement are discussed.

  11. Ligand-independent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity.

    PubMed

    Al-Rasheed, Nawal M; Chana, Ravinder S; Baines, Richard J; Willars, Gary B; Brunskill, Nigel J

    2004-11-26

    Peroxisome proliferator-activated receptor gamma (PPARgamma) has key roles in the regulation of adipogenesis, inflammation, and lipid and glucose metabolism. C-peptide is believed to be inert and without appreciable biological functions. Recent studies suggest that C-peptide possesses multiple functions. The present study investigated the effects of insulin and C-peptide on PPARgamma transcriptional activity in opossum kidney proximal tubular cells. Both insulin and C-peptide induced a concentration-dependent stimulation of PPARgamma transcriptional activity. Both agents substantially augmented thiazolidinedione-stimulated PPARgamma transcriptional activity. Neither insulin nor C-peptide had any effect on the expression levels of PPARgamma. GW9662, a PPARgamma antagonist, blocked PPARgamma activation by thiazolidinediones but had no effect on either insulin- or C-peptide-stimulated PPARgamma transcriptional activity. Co-transfection of opossum kidney cells with dominant negative mitogen-activated protein kinase kinase significantly depressed basal PPARgamma transcriptional activity but had no effect on that induced by either insulin or C-peptide. Both insulin- and C-peptide-stimulated PPARgamma transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol (PI) 3-kinase p85 regulatory subunit. In addition PI 3-kinase-dependent phosphorylation of PPARgamma was observed after stimulation by C-peptide or insulin. C-peptide effects but not insulin on PPARgamma transcriptional activity were abolished by pertussis toxin pretreatment. Finally both C-peptide and insulin positively control the expression of the PPARgamma-regulated CD36 scavenger receptor in human THP-1 monocytes. We concluded that insulin and C-peptide can stimulate PPARgamma activity in a ligand-independent fashion and that this effect is mediated by PI 3-kinase. These results support a new and potentially important physiological role for C-peptide in

  12. ¹H-MRS before and after resuscitation following selective cerebral ultra-profound hypothermic blood flow occlusion in monkeys.

    PubMed

    Niu, X-Q; Zhao, X-X; Li, B-C; Gao, Y-J; Xu, W; Fan, Y-D; Fu, G-P; Wang, K; Pu, J

    2015-01-01

    We investigated the effect of selective cerebral ultra-profound hypothermic blood flow occlusion on brain tissue and cell metabolism to ascertain the efficacy and safety of selective deep hypothermic technologies using proton magnetic resonance spectroscopy ((1)H-MRS). The bilateral carotid artery was blocked at room temperature for 10 min. Other neck vessels were then blocked through cold perfusion of the internal carotid artery and reflux of the ipsilateral jugular vein. Thus, selective cerebral extracorporeal circulation was established. Brain temperature was reduced to 15.1° ± 0.9°C. After 60 min, cerebral blood flow recovered naturally. Routine magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and (1)H-MRS examination of the bilateral frontal cortex and basal ganglia were performed prior to surgery and 4, 24, 72 h, 21 days after recovery. The formants and areas under the curve (AUC) of N-acetyl aspartate (NAA), choline (Cho), creatine/phosphocreatine (Cr/Cr2) were analyzed using 1H-MRS. The pre- and postoperative AUC of NAA and Cho at different time points were compared. Conventional MRI and DWI showed no abnormal signal changes in the brain parenchyma or right basal ganglia before and after surgery (P > 0.05). There was no significant difference in the ratio between NAA/(Cr+Cr2) and Cho/(Cr+Cr2) before and after surgery in the bilateral basal ganglia and frontoparietal regions of the cortex (P > 0.05). Quantitative (1)H-MRS showed that selective deep cerebral hypothermia significantly improved the brain's tolerance to ischemia and hypoxia. Our results could provide a better understanding of the efficacy and safety of selective deep hypothermia and blood flow occlusion. PMID:26505410

  13. Staff attributions of the causes of challenging behaviour in children and adults with profound intellectual and multiple disabilities.

    PubMed

    Poppes, P; van der Putten, A A J; ten Brug, A; Vlaskamp, C

    2016-01-01

    A study has shown that staff do not generally perceive challenging behaviour in people with profound intellectual and multiple disabilities (PIMD) as being of serious consequence. In this study we aimed to gain a better understanding of the causal explanations that direct care and support staff give for challenging behaviour in this group. The purpose of this study was twofold: (1) to determine the way staff attribute challenging behaviour in children and adults with PIMD; and (2) to analyse whether more experienced staff attribute challenging behaviour in children and adults with PIMD differently than less experienced staff. In total, 195 direct support staff and an equal number of children and adults with PIMD participated in the study. Direct support staff filled out the Challenging behaviour Attribution Scale (five causal explanatory models of challenging behaviour) to explain challenging behaviour in one individual that they supported. The results show that direct support staff as a whole report the biomedical model as the most plausible explanation for challenging behaviour in children and adults with PIMD. However, in the present study the mean scores on all models are low. This might indicate that a large number of staff found none of the models particularly useful as possible explanations of challenging behaviour in people with PIMD. This could mean that staff have difficulties stating the cause of challenging behaviour in this group. Another possible explanation could be that there is little scientific knowledge about causing and maintaining factors of challenging behaviour in people with PIMD. It could also mean that staff have additional explanations for challenging behaviour in this target group that are not mentioned in the instrument used. Future research should address these issues. No differences were found between more experienced and less experienced direct support staff.

  14. Method Designed to Respect Molecular Heterogeneity Can Profoundly Correct Present Data Interpretations for Genome-Wide Expression Analysis

    PubMed Central

    Chen, Chih-Hao; Hsu, Chueh-Lin; Huang, Shih-Hao; Chen, Shih-Yuan; Hung, Yi-Lin; Chen, Hsiao-Rong; Wu, Yu-Chung

    2015-01-01

    Although genome-wide expression analysis has become a routine tool for gaining insight into molecular mechanisms, extraction of information remains a major challenge. It has been unclear why standard statistical methods, such as the t-test and ANOVA, often lead to low levels of reproducibility, how likely applying fold-change cutoffs to enhance reproducibility is to miss key signals, and how adversely using such methods has affected data interpretations. We broadly examined expression data to investigate the reproducibility problem and discovered that molecular heterogeneity, a biological property of genetically different samples, has been improperly handled by the statistical methods. Here we give a mathematical description of the discovery and report the development of a statistical method, named HTA, for better handling molecular heterogeneity. We broadly demonstrate the improved sensitivity and specificity of HTA over the conventional methods and show that using fold-change cutoffs has lost much information. We illustrate the especial usefulness of HTA for heterogeneous diseases, by applying it to existing data sets of schizophrenia, bipolar disorder and Parkinson’s disease, and show it can abundantly and reproducibly uncover disease signatures not previously detectable. Based on 156 biological data sets, we estimate that the methodological issue has affected over 96% of expression studies and that HTA can profoundly correct 86% of the affected data interpretations. The methodological advancement can better facilitate systems understandings of biological processes, render biological inferences that are more reliable than they have hitherto been and engender translational medical applications, such as identifying diagnostic biomarkers and drug prediction, which are more robust. PMID:25793610

  15. Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

    PubMed Central

    Sassa, Shigeru; Kappas, Attallah

    1983-01-01

    Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase. It is known that patients with this hereditary disease excrete excessive amounts of δ-aminolevulinic acid (ALA) in urine and that certain patients have an accompanying clinical syndrome resembling that of acute intermittent porphyria (AIP). In order to elucidate the relation of succinylacetone to the heme biosynthetic pathway, we have examined the effects of this metabolite on the cellular heme content of cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse and bovine liver. Our data indicate that succinylacetone is an extremely potent competitive inhibitor of ALA dehydratase in human as well as in animal tissues. By using purified preparations of the enzyme from human erythrocytes and mouse and bovine liver, an inhibitor constant ranging from 2 × 10-7 M to 3 × 10-7 M was obtained. In cultured hepatocytes, succinylacetone also inhibited ALA dehydratase activity, decreased the cellular content of heme and cytochrome P-450, and greatly potentiated the induction response of ALA synthase to drugs such as phenobarbital, chemicals such as allylisopropylacetamide and 3,5-dicarbethoxy-1,4-dihydrocollidine, and natural steroids such as etiocholanolone. Four patients with hereditary tyrosinemia have been studied and all were found to have greatly depressed levels of erythrocyte ALA dehydratase activity and elevated concentrations of this inhibitor in urine. These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway, resulting from the primary gene defect of the disease, profoundly inhibits heme biosynthesis in normal cells through a blockade at the ALA dehydratase level, leading to clinical and metabolic

  16. Effects of chronic cochlear electrical stimulation after an extended period of profound deafness on primary auditory cortex organization in cats.

    PubMed

    Fallon, James B; Shepherd, Robert K; Irvine, Dexter R F

    2014-03-01

    Extended periods of deafness have profound effects on central auditory system function and organization. Neonatal deafening results in loss of the normal cochleotopic organization of the primary auditory cortex (AI), but environmentally-derived intracochlear electrical stimulation, via a cochlear implant, initiated shortly after deafening, can prevent this loss. We investigated whether such stimulation initiated after an extended period of deafness can restore cochleotopy. In two groups of neonatally-deafened cats, a multi-channel intracochlear electrode array was implanted at 8 weeks of age. One group received only minimal stimulation, associated with brief recordings at 4-6-week intervals, over the following 6 months to check the efficacy of the implant. In the other group, this 6-month period was followed by 6 months of near-continuous intracochlear electrical stimulation from a modified clinical cochlear implant system. We recorded multi-unit clusters in the auditory cortex and used two different methods to define the region of interest in the putative AI. There was no evidence of cochleotopy in any of the minimally stimulated animals, confirming our earlier finding. In three of six chronically stimulated cats there was clear evidence of AI cochleotopy, and in a fourth cat in which the majority of penetrations were in the anterior auditory field there was clear evidence of cochleotopy in that field. The finding that chronic intracochlear electrical stimulation after an extended period of deafness is able to restore cochleotopy in some (but not all) cases has implications for the performance of patients implanted after an extended period of deafness.

  17. Antiobesity effects of yerba maté extract (Ilex paraguariensis) in high-fat diet-induced obese mice.

    PubMed

    Arçari, Demétrius P; Bartchewsky, Waldemar; dos Santos, Tanila W; Oliveira, Karim A; Funck, Alexandre; Pedrazzoli, José; de Souza, Marina F F; Saad, Mario J; Bastos, Deborah H M; Gambero, Alessandra; Carvalho, Patricia de O; Ribeiro, Marcelo L

    2009-12-01

    Because the potential of yerba maté (Ilex paraguariensis) has been suggested in the management of obesity, the aim of the present study was to evaluate the effects of yerba maté extract on weight loss, obesity-related biochemical parameters, and the regulation of adipose tissue gene expression in high-fat diet-induced obesity in mice. Thirty animals were randomly assigned to three groups. The mice were introduced to standard or high-fat diets. After 12 weeks on a high-fat diet, mice were randomly assigned according to the treatment (water or yerba maté extract 1.0 g/kg). After treatment intervention, plasma concentrations of total cholesterol, high-density lipoprotein cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and glucose were evaluated. Adipose tissue was examined to determine the mRNA levels of several genes such as tumor necrosis factor-alpha (TNF-alpha), leptin, interleukin-6 (IL-6), C-C motif chemokine ligand-2 (CCL2), CCL receptor-2 (CCR2), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), adiponectin, resistin, peroxisome proliferator-activated receptor-gamma(2) (PPAR-gamma(2)), uncoupling protein-1 (UCP1), and PPAR-gamma coactivator-1 alpha (PGC-1 alpha). The F4/80 levels were determined by immunoblotting. We found that obese mice treated with yerba maté exhibited marked attenuation of weight gain, adiposity, a decrease in epididymal fat-pad weight, and restoration of the serum levels of cholesterol, triglycerides, LDL cholesterol, and glucose. The gene and protein expression levels were directly regulated by the high-fat diet. After treatment with yerba maté extract, we observed a recovery of the expression levels. In conclusion, our data show that yerba maté extract has potent antiobesity activity in vivo. Additionally, we observed that the treatment had a modulatory effect on the expression of several genes related to obesity.

  18. Flexible Arm Splints in the Control of a Lesch-Nyhan Victim's Finger Biting and a Profoundly Retarded Client's Finger Sucking.

    ERIC Educational Resources Information Center

    Ball, Thomas S.; And Others

    1985-01-01

    Flexible arm splints permitting the control of hand-to-mouth contacts without restricting range of motion effectively suppressed the self-injurious finger biting of a child with Lesch-Nyhan disease and a profoundly retarded adult's stereotypic finger sucking. They offered an easily applied and much less restrictive alternative to soft-tie and…

  19. The Content of Support of Persons with Profound Intellectual and Multiple Disabilities: An Analysis of the Number and Content of Goals in the Educational Programmes

    ERIC Educational Resources Information Center

    van der Putten, Annette; Vlaskamp, Carla; Poppes, Petra

    2009-01-01

    Background: This study focuses on the support of persons with profound intellectual and multiple disabilities (PIMD) by analysing the number and content of formulated goals in the educational programmes. Methods: The programmes of 145 persons with PIMD were analysed. The number of long- and short-term goals as well as the number of goals reached…

  20. An Introduction to Selecting Appropriate Goals and Activities for the Severely/Profoundly Impaired That Are Appropriate for Their Age. (Using Curricular Domains).

    ERIC Educational Resources Information Center

    Arnold, Yvonne

    Two introductory manuals, written as part of a practicum to meet the staff needs in the Philadelphia, Pennsylvania School District's severely/profoundly impaired (SPI) programs, focus on selecting goals and activities that are age appropriate for SPI students. Introductory materials review judicial rulings regarding Philadelphia's services for SPI…

  1. Effects of Inservice Teacher Training on Correct Implementation of Assessment and Instructional Procedures for Teachers of Students with Profound Multiple Disabilities

    ERIC Educational Resources Information Center

    Horrocks, Erin L.; Morgan, Robert L.

    2011-01-01

    A multicomponent training package (live training, video modeling, role playing, and feedback) was used to train teachers to conduct assessment and to instruct students with profound multiple disabilities. Phase 1 of the study involved training seven teachers to conduct assessment in three areas: (a) preference assessment (i.e., identification of…

  2. Health Status, Social Support, and Quality of Life among Family Carers of Adults with Profound Intellectual and Multiple Disabilities (PIMD) in Taiwan

    ERIC Educational Resources Information Center

    Chou, Yueh-Ching; Chiao, Chi; Fu, Li-Yeh

    2011-01-01

    Background: Primary family carers of adults with profound intellectual and multiple disabilities (PIMD) experience a range of considerable demands. Method: A census survey was conducted in a city of Taiwan; 796 family carers of adults (aged 18 or older) diagnosed with intellectual disability and/or with multiple disabilities living with the family…

  3. Program Planning Guidelines: A Review of Research with Implications for the Education and Training of the Severely to Profoundly Mentally Retarded.

    ERIC Educational Resources Information Center

    Perlman, Joseph; Stober, Marvin

    Provided is a selected review of research on the education and training of the severely to profoundly mentally retarded which was reported in academic and professional publications in the years 1969 - 1975. Sections present bibliographic information and annotations for approximately 164 citations in the following eight research categories (sample…

  4. Feasibility, Test-Retest Reliability, and Interrater Reliability of the Modified Ashworth Scale and Modified Tardieu Scale in Persons with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Waninge, A.; Rook, R. A.; Dijkhuizen, A.; Gielen, E.; van der Schans, C. P.

    2011-01-01

    Caregivers of persons with profound intellectual and multiple disabilities (PIMD) often describe the quality of the daily movements of these persons in terms of flexibility or stiffness. Objective outcome measures for flexibility and stiffness are muscle tone or level of spasticity. Two instruments used to grade muscle tone and spasticity are the…

  5. The Tell-Tale: What Do Heart Rate; Skin Temperature and Skin Conductance Reveal about Emotions of People with Severe and Profound Intellectual Disabilities?

    ERIC Educational Resources Information Center

    Vos, Pieter; De Cock, Paul; Munde, Vera; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2012-01-01

    Identifying emotions in people with severe and profound intellectual disabilities is a difficult challenge. Since self-reports are not available, behaviour is the most used source of information. Given the limitations and caveats associated with using behaviour as the sole source of information about their emotions, it is important to supplement…

  6. Transferring Young People with Profound Intellectual and Multiple Disabilities from Pediatric to Adult Medical Care: Parents' Experiences and Recommendations

    ERIC Educational Resources Information Center

    Bindels-de Heus, Karen G. C. B.; van Staa, AnneLoes; van Vliet, Ingeborg; Ewals, Frans V. P. M.; Hilberink, Sander R.

    2013-01-01

    Many children with profound intellectual and multiple disabilities (PIMD) now reach adulthood. The aim of this study was to elicit parents' experiences with the transfer from pediatric to adult medical care. A convenience sample of 131 Dutch parents of young people with PIMD (16--26 years) completed a web-based questionnaire. Twenty-two…

  7. Automatic Prompting and Positive Attention to Reduce Tongue Protrusion and Head Tilting by Two Adults with Severe to Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Didden, Robert; Pichierri, Sabrina

    2010-01-01

    This study assessed a simple behavioral strategy for reducing stereotypic tongue protrusion and forward head tilting displayed by a woman and a man with severe to profound intellectual disabilities. The strategy involved (a) auditory prompting (i.e., verbal encouragements to keep the tongue in the mouth or the head upright) delivered automatically…

  8. Look Closer: The Alertness of People with Profound Intellectual and Multiple Disabilities during Multi-Sensory Storytelling, a Time Sequential Analysis

    ERIC Educational Resources Information Center

    Ten Brug, Annet; Munde, Vera S.; van der Putten, Annette A.J.; Vlaskamp, Carla

    2015-01-01

    Introduction: Multi-sensory storytelling (MSST) is a storytelling method designed for individuals with profound intellectual and multiple disabilities (PIMD). It is essential that listeners be alert during MSST, so that they become familiar with their personalised stories. Repetition and the presentation of stimuli are likely to affect the…

  9. Do Theory of Mind and Executive Function Deficits Underlie the Adverse Outcomes Associated with Profound Early Deprivation?: Findings from the English and Romanian Adoptees Study

    ERIC Educational Resources Information Center

    Colvert, Emma; Rutter, Michael; Kreppner, Jana; Beckett, Celia; Castle, Jenny; Groothues, Christine; Hawkins, Amanda; Stevens, Suzanne; Sonuga-Barke, Edmund J. S.

    2008-01-01

    Theory of Mind (ToM) and Executive Function (EF) have been associated with autism and with attention-deficit hyperactivity disorder (ADHD), and hence might play a role in similar syndromes found following profound early institutional deprivation. In order to examine this possibility the current study included a group of 165 Romanian adoptees, of…

  10. Do You Know What I Feel? A First Step towards a Physiological Measure of the Subjective Well-Being of Persons with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Vos, Pieter; De Cock, Paul; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2010-01-01

    Background: Because of limited communicative skills, it is not self-evident to measure subjective well-being in people with profound intellectual and multiple disabilities. As a first step towards a non-interpretive measure of subjective well-being, we explored how the respiratory, cardiovascular and electro dermal response systems were associated…

  11. Utilizing Individual Inservice Training Packets for Staff Development with Community-Based Instruction for Severely and Profoundly Handicapped Students (K-12).

    ERIC Educational Resources Information Center

    Kissire, Pat

    This practicum was designed to: improve the skills of personnel working with students with severe and/or profound handicaps in junior high school; to improve staff development; and to increase the consistency of services offered in a community-based instruction program for K-12. A needs assessment survey of 10 staff members determined the level of…

  12. A Pilot Study of SPINE Test Scores and Measures of Tongue Deviancy in Speakers with Severe-to Profound Hearing Loss.

    ERIC Educational Resources Information Center

    Wold, Donald C.; And Others

    1994-01-01

    This study found that clinician-generated SPINE (Speech Intelligibility Evaluation) test scores were correlated with objective computer-generated measures of tongue deviancy during vowel production in 28 persons (ages 14-20) with severe/profound hearing loss. Data suggest that subjects were more deviant in their production of front vowels than…

  13. An Overview of Behavioral Strategies for Reducing Hand-Related Stereotypies of Persons with Severe to Profound Intellectual and Multiple Disabilities: 1995-2007

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff

    2009-01-01

    This paper provides an overview of behavioral strategies used for reducing hand-related stereotypies (i.e., hand/finger mouthing, eye poking, self-slapping, and other hand-to-head/body responses) of persons with severe to profound intellectual and multiple disabilities. Computerized and manual searches were conducted to identify the studies…

  14. Teaching Methods and Curriculum Models Used in Finland in the Education of Students Diagnosed with Having Severe/Profound Intellectual Disabilities

    ERIC Educational Resources Information Center

    Kontu, Elina K.; Pirttimaa, Raija A.

    2010-01-01

    Ten years ago children diagnosed as having severe/profound intellectual disabilities were allowed to attend and study in Finnish comprehensive schools. The nationwide intensive developmental work for creating a curriculum for this group of students began earlier, in the 1980s. The aim of this study was to discover what types of models of…

  15. An Audit of Adults with Profound and Multiple Learning Disabilities within a West Midlands Community Health Trust--Implications for Service Development

    ERIC Educational Resources Information Center

    Gittins, Deborah; Rose, Nikki

    2008-01-01

    An audit was carried out to gain an overview of the profound and multiple learning disabilities (PMLD) population in a local health trust to inform current and future service provision. An overview of the issues faced in developing clear defining criteria is presented. Published definitions of PMLD were used to identify clients from data held on…

  16. Att Tolka Barns Signaler: Gravt utvecklingsstorda flerhandikappade barns lek och kommunikation (To Interpret Childrens' Signals: Play and Communication in Profoundly Mentally Retarded and Multiply Handicapped Children).

    ERIC Educational Resources Information Center

    Brodin, Jane

    Written in Swedish with an English-language summary, this report describes a study which examined the interaction between mothers or caregivers and their children with profound mental retardation and multiple disabilities, particularly looking at the function of play in communicative interaction. The six children all had five or six handicaps in…

  17. The Time and Effort in Taking Care for Children with Profound Intellectual and Multiple Disabilities: A Study on Care Load and Support

    ERIC Educational Resources Information Center

    Tadema, Annemarie C.; Vlaskamp, Carla

    2010-01-01

    Raising children with profound intellectual and multiple disabilities is considered to be extremely difficult for parents, but figures on the content and amount of time needed for the caring task of parents is lacking. Data on what the caring task actually means (in terms of amount of time and type of task) is needed to be able to understand the…

  18. Multi-Sensory Storytelling as an Aid to Assisting People with Profound Intellectual Disabilities to Cope with Sensitive Issues: A Multiple Research Methods Analysis of Engagement and Outcomes

    ERIC Educational Resources Information Center

    Young, Hannah; Fenwick, Maggi; Lambe, Loretto; Hogg, James

    2011-01-01

    The importance of storytelling in social, cultural and educational contexts is well established and documented. The extension of storytelling to people with profound intellectual and multiple disabilities (PIMD) has in recent years been undertaken with an emphasis on the value of sensory experience and the context storytelling provides for social…

  19. Supporting Children with Severe-to-Profound Learning Difficulties and Complex Communication Needs to Make Their Views Known: Observation Tools and Methods

    ERIC Educational Resources Information Center

    Greathead, Scot; Yates, Rhiannon; Hill, Vivian; Kenny, Lorcan; Croydon, Abigail; Pellicano, Elizabeth

    2016-01-01

    All children have the right to shape decisions that influence their lives. Yet, children with severe-to-profound intellectual disabilities and complex communication needs are often marginalized from this process. Here, we examined the utility of a set of tools incorporating ethnographic and structured observational methods with three such…

  20. Absence of Intervention Training Programs: Effects Upon the Severely and Profoundly Retarded, Part I: Selected Cases of Emotional and Behavioral Disturbances.

    ERIC Educational Resources Information Center

    Balthazar, Earl E.; And Others

    Fifteen institutionalized profoundly retarded Ss, median age 7 years, who received no intervention training program, were assessed on the Balthazar Scales of Adaptive Behavior (BSAB), Sections I and II to determine whether social coping behavior would improve spontaneous maturation during a 6-month period. The Ss were recommended by nursing…

  1. Not Fit for Purpose: A Call for Separate and Distinct Pedagogies as Part of a National Framework for Those with Severe and Profound Learning Difficulties

    ERIC Educational Resources Information Center

    Imray, Peter; Hinchcliffe, Viv

    2012-01-01

    The introduction of the National Curriculum in 1988 caused much discussion (some of it angst-ridden) among both academics and practitioners working with pupils with severe and profound learning difficulties, and much of the meat (and the angst) of these discussions is still going on today. We argue that 24 years is a long experiment; that despite…

  2. Stability and Change in Sustainability of Daily Routines and Social Networks in Families of Children with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Wilder, Jenny; Granlund, Mats

    2015-01-01

    Background: Children with profound intellectual and multiple disabilities (PIMD) demand intense family accommodations from birth and onwards. This study used an exploratory and qualitative study design to investigate stability and change in sustainability of daily routines and social networks of Swedish families of children with PIMD. Materials…

  3. The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle.

    PubMed

    Chinsomboon, Jessica; Ruas, Jorge; Gupta, Rana K; Thom, Robyn; Shoag, Jonathan; Rowe, Glenn C; Sawada, Naoki; Raghuram, Srilatha; Arany, Zoltan

    2009-12-15

    Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1alpha from an alternate promoter. The induction of PGC-1alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1alpha. The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.

  4. Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma.

    PubMed

    Lassaletta, Alvaro; Guerreiro Stucklin, Ana; Ramaswamy, Vijay; Zapotocky, Michal; McKeown, Tara; Hawkins, Cynthia; Bouffet, Eric; Tabori, Uri

    2016-11-01

    Infants with low-grade glioma (LGG) have a poor survival. BRAFV600E mutation has been identified in pediatric LGG; however, the use of BRAF inhibitors in infants has never been reported. A 2-month-old with V600E mutant hypothalamic/chiasmatic glioma progressed on chemotherapy resulting in profound visual loss, massive ascites, and diencephalic syndrome. Initiation of dabrafenib resulted in rapid and sustained disappearance of clinical symptoms and a profound sustained cytoreduction. BRAF inhibition was safely tolerated with dramatic clinicoradiological response, suggesting early targeted therapy is a viable option in infants with LGG. A re-evaluation of current management paradigms in this population is warranted to leverage the potential benefit of upfront-targeted therapies.

  5. How musical engagement promotes well-being in education contexts: The case of a young man with profound and multiple disabilities

    PubMed Central

    McFerran, Katrina S.; Shoemark, Helen

    2013-01-01

    Students with profound intellectual disabilities disorders (IDDs) have the right to participate in educational opportunities that recognize their unique resources and needs, as do all children. Because of their specific communication challenges, positive relationships with attentive communication partners are critical for success. In fact, the power of positive relationships in schools is recognized to be connected to student well-being more broadly. This article examines the case of one young man with profound IDD and his relationship with his music therapist using a duo-ethnographic informed paradigmatic case study. Video analysis based on multi-voice perspectives is used to generate hermeneutic phenomenological findings to closely examine the relationship between a young man with profound IDD and a music therapist. The voices of four allied health researchers were also gathered to inform the authors’ construction of an informed commentary on the phenomenon. The results suggest that the essence lay in a combination of attentive, responsive and creative being with the other person over time. Four principles of musical engagement were identified in the video footage as critical to the meaningful relationships through music: the music therapist listens; the music therapist takes responsibility for structure; spontaneous initiation is sought from the young person; and the relationship is built over time. These concepts are contextualized within a discussion of student well-being that is underpinned by positive relationships and leads to students achieving their full potential within diverse school contexts. PMID:23930986

  6. Multi-sensory rooms: comparing effects of the Snoezelen and the Stimulus Preference environment on the behavior of adults with profound mental retardation.

    PubMed

    Fava, Leonardo; Strauss, Kristin

    2010-01-01

    The present study examined whether Snoezelen and Stimulus Preference environments have differential effects on disruptive and pro-social behaviors in adults with profound mental retardation and autism. In N=27 adults these target behaviors were recorded for a total of 20 sessions using both multi-sensory rooms. Three comparison groups were created by diagnosis and motor respective linguistic abilities. Each client was exposed to only one multi-sensory room. Results showed that Snoezelen intervention decreased disruptive behaviors only in individuals with autism, while Stimulus Preference increased pro-social behaviors only in participants with profound mental retardation with co-occurring poor motor and linguistic abilities. Furthermore, several trend analyses of the improved behaviors were conducted throughout all sessions toward short and mid term effects of the multi-sensory room applications. These findings support both the prudence of using the Snoezelen room in individuals with developmental disabilities and the importance of using a Stimulus Preference assessment in multi-sensory environments in clients with profound mental retardation.

  7. Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs.

    PubMed

    Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Richardson, Rachael T

    2014-01-01

    The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.

  8. Hair Cell Regeneration after ATOH1 Gene Therapy in the Cochlea of Profoundly Deaf Adult Guinea Pigs

    PubMed Central

    Atkinson, Patrick J.; Wise, Andrew K.; Flynn, Brianna O.; Nayagam, Bryony A.; Richardson, Rachael T.

    2014-01-01

    The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness. PMID:25036727

  9. The Rapid Exchange of Zinc(2+) Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu(2+)/Zn(2+) Mixtures.

    PubMed

    Matheou, Christian J; Younan, Nadine D; Viles, John H

    2016-07-17

    The misfolding and self-assembly of amyloid-β (Aβ) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn(2+) homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models. Here, we investigate how the kinetics of Aβ fibre growth are affected at a range of Zn(2+) concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for Aβ(1-40), and Aβ(1-42), as little as 0.01mol equivalent of Zn(2+) (100nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, Aβ(1-40) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas Aβ(1-42) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn(2+) ions are able to influence a great many Aβ molecules through the rapid exchange of Zn(2+) between Aβ peptides. Surprisingly, although Cu(2+) binds to Aβ 10,000 times tighter than Zn(2+), the effect of Zn(2+) on Aβ assembly dominates in Cu(2+)/Zn(2+) mixtures, suggesting that trace levels of Zn(2+) must have a profound effect on extracellular Aβ accumulation. Trace Zn(2+) levels profoundly influence Aβ assembly even at concentrations weaker than its affinity for Aβ. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact. PMID:27320389

  10. Early natural auditory-verbal education of children with profound hearing impairments in the Federal Republic of Germany: results of a 4 year study.

    PubMed

    Diller, G; Graser, P; Schmalbrock, C

    2001-09-28

    Early education of children with hearing impairments has been carried out in the FRG for the past ca. 40 years using a variety of different educational concepts. One of these concepts is the natural auditory-verbal approach. By supporting the development of hearing, even amongst children with profound hearing impairments, it stakes the claim of being capable of initiating the children's development of natural auditory-verbal skills, which are then comparable to those of children with normal hearing. Nevertheless, to this date, no empirical study of the approach and its measure of success had ever been undertaken. During the course of this study, the measures involved in a hearing-oriented system of early education were comprehensively examined. The analysis was performed on the advancements made in the natural auditory-verbal skills of infants suffering a loss of hearing of 90 dB or more and who were educated in such a way. The study comprised 103 children with profound hearing impairments, who were younger than 24 months old at the time the study began. Their respective developments were followed in three separate surveys between 1996 and 1998. The results were analysed using bivariate as well as statistical correlation methods. The children's development is impeded by such factors as late initial diagnosis; delayed supply of hearing aids and late commencement of early education; poorly-adjusted hearing aids and short periods of wearing them. A system of early education that is only to a very limited degree hearing-oriented, and a family environment where little is spoken and where the child's auditory disability receives only scant attention, may also play a part. On the other hand, under favourable circumstances, even children with profound hearing-impairments may attain a development level of natural auditory-verbal skills which corresponds to that of children who can hear well-perhaps with a certain time-delay, and certainly involving a greater effort on the

  11. Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior

    PubMed Central

    Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif; Hossain, Shakhawat; Ilnytskyy, Yaroslav; Ghose, Abhijit; Kirkby, Charles; Ghasroddashti, Esmaeel; Kolb, Bryan; Kovalchuk, Olga

    2016-01-01

    Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way. PMID:27375442

  12. Physical disturbance shapes vascular plant diversity more profoundly than fire in the sagebrush steppe of southeastern Idaho, U.S.A.

    PubMed

    Lavin, Matt; Brummer, Tyler J; Quire, Ryan; Maxwell, Bruce D; Rew, Lisa J

    2013-06-01

    Fire is thought to profoundly change the ecology of the sagebrush steppe. The Idaho National Laboratory provides an ideal setting to compare the effects of fire and physical disturbance on plant diversity in high-native-cover sagebrush steppe. Seventy-eight 1-hectare transects were established along paved, green-striped, gravel, and two-track roads, in overgrazed rangeland, and within sagebrush steppe involving different fire histories. Transects were sampled for the diversity and abundance of all vascular plants. Alpha, beta, and phylogenetic beta diversity were analyzed as a response to fire and physical disturbance. Postfire vegetation readily rebounds to prefire levels of alpha plant diversity. Physical disturbance, in contrast, strongly shapes patterns of alpha, beta, and especially phylogenetic beta diversity much more profoundly than fire disturbance. If fire is a concern in the sagebrush steppe then the degree of physical-disturbance should be more so. This finding is probably not specific to the study area but applicable to the northern and eastern portions of the sagebrush biome, which is characterized by a pulse of spring moisture and cold mean minimum winter temperatures. The distinction of sagebrush steppe from Great Basin sagebrush should be revised especially with regard to reseeding efforts and the control of annual grasses.

  13. Physical disturbance shapes vascular plant diversity more profoundly than fire in the sagebrush steppe of southeastern Idaho, U.S.A

    PubMed Central

    Lavin, Matt; Brummer, Tyler J; Quire, Ryan; Maxwell, Bruce D; Rew, Lisa J

    2013-01-01

    Fire is thought to profoundly change the ecology of the sagebrush steppe. The Idaho National Laboratory provides an ideal setting to compare the effects of fire and physical disturbance on plant diversity in high-native-cover sagebrush steppe. Seventy-eight 1-hectare transects were established along paved, green-striped, gravel, and two-track roads, in overgrazed rangeland, and within sagebrush steppe involving different fire histories. Transects were sampled for the diversity and abundance of all vascular plants. Alpha, beta, and phylogenetic beta diversity were analyzed as a response to fire and physical disturbance. Postfire vegetation readily rebounds to prefire levels of alpha plant diversity. Physical disturbance, in contrast, strongly shapes patterns of alpha, beta, and especially phylogenetic beta diversity much more profoundly than fire disturbance. If fire is a concern in the sagebrush steppe then the degree of physical-disturbance should be more so. This finding is probably not specific to the study area but applicable to the northern and eastern portions of the sagebrush biome, which is characterized by a pulse of spring moisture and cold mean minimum winter temperatures. The distinction of sagebrush steppe from Great Basin sagebrush should be revised especially with regard to reseeding efforts and the control of annual grasses. PMID:23789073

  14. What moral status should be accorded to those human beings who have profound intellectual disabilities? A reply to Curtis and Vehmas.

    PubMed

    McLachlan, Hugh V

    2016-08-01

    Curtis and Vehmas present an argument in support of full moral status for those with profound intellectual disabilities based on Moore's famous defence of a common-sense view of the nature and existence of the external world. According to them, the need for such an argument arises from the disturbing inferences that can, supposedly, be drawn from the standard Lockean philosophical theory of personhood. This paper develops and supports Curtis and Vehmas's central claim concerning this equality of moral status by suggesting a basis for rejecting Locke's position, based on reflections upon Wittgenstein's remarks about games and family resemblances. It also questions the validity of the disturbing inferences. It asserts that our moral duties towards and concerning people who have and people who do not have profound intellectual disability, human and non-human animals, do not derive solely from their moral status. The existence, content and strength of our moral duties towards particular people can be grounded in conditions and circumstances that pertain to us rather than to them.

  15. Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness.

    PubMed

    Delmaghani, Sedigheh; Aghaie, Asadollah; Bouyacoub, Yosra; El Hachmi, Hala; Bonnet, Crystel; Riahi, Zied; Chardenoux, Sebastien; Perfettini, Isabelle; Hardelin, Jean-Pierre; Houmeida, Ahmed; Herbomel, Philippe; Petit, Christine

    2016-06-01

    By genetic linkage analysis in a large consanguineous Iranian family with eleven individuals affected by severe to profound congenital deafness, we were able to define a 2.8 Mb critical interval (at chromosome 1p21.2-1p21.1) for an autosomal-recessive nonsyndromic deafness locus (DFNB). Whole-exome sequencing allowed us to identify a CDC14A biallelic nonsense mutation, c.1126C>T (p.Arg376(∗)), which was present in the eight clinically affected individuals still alive. Subsequent screening of 115 unrelated individuals affected by severe or profound congenital deafness of unknown genetic cause led us to identify another CDC14A biallelic nonsense mutation, c.1015C>T (p.Arg339(∗)), in an individual originating from Mauritania. CDC14A encodes a protein tyrosine phosphatase. Immunofluorescence analysis of the protein distribution in the mouse inner ear showed a strong labeling of the hair cells' kinocilia. By using a morpholino strategy to knockdown cdc14a in zebrafish larvae, we found that the length of the kinocilia was reduced in inner-ear hair cells. Therefore, deafness caused by loss-of-function mutations in CDC14A probably arises from a morphogenetic defect of the auditory sensory cells' hair bundles, whose differentiation critically depends on the proper growth of their kinocilium.

  16. Simultaneous Labyrinthectomy and Cochlear Implantation for Patients with Single-Sided Ménière's Disease and Profound Sensorineural Hearing Loss

    PubMed Central

    Doobe, G.; Ernst, A.; Ramalingam, R.; Mittmann, P.; Todt, I.

    2015-01-01

    Objective. To investigate the treatment outcome of a simultaneous labyrinthectomy and cochlear implantation in patients with single-sided Ménière's disease and profound sensorineural hearing loss. Study Design. Prospective study. Method. Five patients with single-sided Ménière's disease with active vertigo and functional deafness were included. In all cases, simultaneous cochlear implantation combined with labyrinthectomy surgery was performed. The outcome has been evaluated by the Dizziness Handicap Inventory (DHI) and speech recognition. Results. The combined labyrinthectomy and cochlear implantation led in all patients to a highly significant reduction of dizziness up to a restitutio ad integrum. After activation of the cochlear implant and rehabilitation, a mean monosyllabic speech understanding of 69% at 65 dB was observed. Conclusion. For patients with single-sided Ménière's disease and profound sensorineural hearing loss the simultaneous labyrinthectomy and cochlear implantation are efficient method for the treatment of vertigo as well as the rehabilitation of the auditory system. PMID:26380275

  17. Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats.

    PubMed

    Ilic, S; Brcic, I; Mester, M; Filipovic, M; Sever, M; Klicek, R; Barisic, I; Radic, B; Zoricic, Z; Bilic, V; Berkopic, L; Brcic, L; Kolenc, D; Romic, Z; Pazanin, L; Seiwerth, S; Sikiric, P

    2009-12-01

    We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application. PMID:20388953

  18. A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.

    PubMed

    Schupp, Michael; Curtin, Joshua C; Kim, Roy J; Billin, Andrew N; Lazar, Mitchell A

    2007-05-01

    Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.

  19. Revisiting the Cause of Focal Neurological Deficits and Profound Dyspnea at High Altitude-The Potential Role of Patent Foramen Ovale.

    PubMed

    Murdoch, David R

    2015-12-01

    A 49-year-old man developed weakness due to acute infarction of the left precentral gyrus. Subsequent investigation revealed a large patent foramen ovale (PFO), and it was concluded that the cerebral infarction was likely caused by a paradoxical embolus in association with the PFO. In hindsight, the PFO may explain several previous transient focal neurological deficits, some of which had occurred at high altitude and had been attributed to migraine. Furthermore, the large PFO may explain several episodes of profound shortness of breath that had occurred while exercising at high altitude during his lifetime, typically above 5000 m. Arterial hypoxemia due to hypobaric hypoxia may be exacerbated in individuals with PFO and affect physical performance at high altitude.

  20. Comparison of severely and profoundly hearing-impaired children's amplification preferences with the NAL-RP and the DSL 3.0 prescriptions.

    PubMed

    Ching, T Y; Newall, P; Wigney, D

    1997-01-01

    Prompted by a recent paper in this journal (Snik et al., 1995), this communication compares the gain and frequency response preferred by a group of 21 severely and profoundly hearing-impaired children (37 test ears) to the NAL-RP and the DSL 3.0 hearing aid prescriptions. The results support the findings of Snik et al. (1995) that the NAL-RP procedure provides an adequate prescription of amplification on average. The individual discrepancies between prescribed and preferred characteristics imply that fine-tuning with an evaluation tool is necessary for some children. It is uncertain whether previous listening experience affects listeners' preferences, and it is suggested that further studies be carried out to address this issue.

  1. Development of Bone-Conducted Ultrasonic Hearing Aid for the Profoundly Deaf: Assessments of the Modulation Type with Regard to Intelligibility and Sound Quality

    NASA Astrophysics Data System (ADS)

    Nakagawa, Seiji; Fujiyuki, Chika; Kagomiya, Takayuki

    2012-07-01

    Bone-conducted ultrasound (BCU) is perceived even by the profoundly sensorineural deaf. A novel hearing aid using the perception of amplitude-modulated BCU (BCU hearing aid: BCUHA) has been developed; however, further improvements are needed, especially in terms of articulation and sound quality. In this study, the intelligibility and sound quality of BCU speech with several types of amplitude modulation [double-sideband with transmitted carrier (DSB-TC), double-sideband with suppressed carrier (DSB-SC), and transposed modulation] were evaluated. The results showed that DSB-TC and transposed speech were more intelligible than DSB-SC speech, and transposed speech was closer than the other types of BCU speech to air-conducted speech in terms of sound quality. These results provide useful information for further development of the BCUHA.

  2. Profound inhibition of the PCR step of CF V3 multiplex PCR/OLA assay by the use of UV-irradiated plastic reaction tubes.

    PubMed

    Fox, David H; Huang, Chih-Kang; Du, Juan; Chang, Tylis Y; Pan, Qiulu

    2007-06-01

    Supplies, such as bags of plastic reaction tubes, are sometimes left in the laminar flow hoods unintentionally while the ultraviolet (UV) lamp is illuminated overnight. In addition, UV irradiation is used for sterilization and amplicon inactivation to avoid contamination. The oligonucleotide ligation assay (OLA) is a unique approach to mutation detection of point mutations, small deletions, and small insertions. Recently, we encountered problems with this assay and peak heights were much lower or disappeared. After going through systemic trouble-shooting, we found that profound inhibition of the polymerase chain reaction (PCR) step of CF V3 multiplex PCR/OLA assay by the use of UV-irradiated plastic reaction tubes. When UV-irradiated tubes used throughout the assay, tubes exposed for 8 weeks at 0.7 m from the UV source gave a reduction of 60% and 67% in the assay products on the basis of sum of peak heights. Tubes exposed for 3 weeks at 0.1 m from the UV source totally eliminated assay product yielding no peaks. Further experiments showed that the inhibition happened mostly in the PCR step. Burgess and Hall had reported that inhibition of PCR of human glyceraldehydes-3-phosphate dehydrogenase transcripts after UV irradiating the tubes. This showed that the inhibition was not assay-specific. The reason that the inhibition of PCR was more profound could be due to a multiplex PCR assay and small reaction volume. The mechanism of PCR inhibition by UV irradiation is not clear. In conclusion, plastic reaction tubes intended for PCR/OLA assays should not be exposed to UV.

  3. The Profound Power of Groups

    ERIC Educational Resources Information Center

    Brendtro, Larry K.; Mitchell, Martin L.

    2010-01-01

    Decades of studies show that children's behavior is shaped by relationships in the "social ecology" of family, peers, school, and community. But in recent decades the prevailing scientific dogma was that genes determine destiny. Now it is clear that experience changes genes. For better or worse, environmental experiences including nutrition,…

  4. A Profound Development in Education.

    ERIC Educational Resources Information Center

    American School Board Journal, 1983

    1983-01-01

    In February 1983, Mountain View-Los Altos Union High School District in California's Silicon Valley will link its school computer to privately owned microcomputers in students' homes. Funded by a $75,000 grant from the Atari Foundation, the link will initially help students to match their school records with college admissions requirements. (RW)

  5. Nutrition-/diet-induced changes in gene expression in white adipose tissue.

    PubMed

    Al-Hasani, Hadi; Joost, Hans-Georg

    2005-12-01

    Nutrients regulate metabolic fluxes and homeostasis through transcriptional and translational control of enzyme concentrations and allosteric modulation of enzyme activity. Dietary omega-3 polyunsaturated fatty acids (PUFAs) have been shown to exert a variety of beneficial health effects such as reducing adiposity and increasing insulin sensitivity in rodents. It is now clear that PUFAs regulate fundamental adipose cell and liver functions through modulation of activity and abundance of key transcription factors that act as nutrient sensors, including peroxisome proliferator-activated receptors (PPARalpha/delta/gamma), sterol regulatory element binding proteins (SREBP-1/2), and liver X receptors (LXRalpha/beta). However, in the state of obesity, where adipose tissue shows elevated storage of triglycerides, many lipogenic genes that are essential for adipose cell function including PPARgamma, SREBP-1c, CCAAT-enhancer binding protein alpha and stearoyl-CoA desaturase-1 are downregulated, apparently due to desensitization of the very same crucial nutrient sensors. This chapter will summarize recent studies of PUFA- and obesity-induced changes in gene expression in white adipose tissue.

  6. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.

    PubMed

    Gaidhu, Mandeep P; Fediuc, Sergiu; Anthony, Nicole M; So, Mandy; Mirpourian, Mani; Perry, Robert L S; Ceddia, Rolando B

    2009-04-01

    This study was designed to investigate the effects of prolonged activation of AMP-activated protein kinase (AMPK) on lipid partitioning and the potential molecular mechanisms involved in these processes in white adipose tissue (WAT). Rat epididymal adipocytes were incubated with 5'-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside (AICAR;0.5 mM) for 15 h. Also, epididymal adipocytes were isolated 15 h after AICAR was injected (i.p. 0.7 g/kg body weight) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma NEFA concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, and PPARgamma-coactivator-1alpha (PGC-1alpha) mRNA levels. Lipolysis was first suppressed, but then increased, both in vitro and in vivo, with prolonged AICAR treatment. Exposure to AICAR increased adipose triglyceride lipase (ATGL) content and FA release, despite inhibition of basal and epinephrine-stimulated hormone-sensitive lipase (HSL) activity. Here, we provide evidence that prolonged AICAR-induced AMPK activation can remodel adipocyte metabolism by upregulating pathways that favor energy dissipation versus lipid storage in WAT. Additionally, we show novel time-dependent effects of AICAR-induced AMPK activation on lipolysis, which involves antagonistic modulation of HSL and ATGL.

  7. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

    PubMed

    Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John

    2009-09-01

    Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.

  8. Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

    SciTech Connect

    Zhao Weiling; Payne, Valerie; Tommasi, Ellen; Diz, Debra I.; Hsu, F.-C.; Robbins, Mike E. . E-mail: mrobbins@wfubmc.edu

    2007-01-01

    Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

  9. Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-{gamma}

    SciTech Connect

    Ghosh, Asish K Wei, Jun; Wu, Minghua; Varga, John

    2008-09-19

    Transforming growth factor-{beta} (TGF-{beta}), a potent inducer of collagen synthesis, is implicated in pathological fibrosis. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is a nuclear hormone receptor that regulates adipogenesis and numerous other biological processes. Here, we demonstrate that collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-{gamma} compared to heterozygous control MEFs. Treatment with the PPAR-{gamma} ligand 15d-PGJ{sub 2} failed to down-regulate collagen gene expression in PPAR-{gamma} null MEFs, whereas reconstitution of these cells with ectopic PPAR-{gamma} resulted in their normalization. Compared to control MEFs, PPAR-{gamma} null MEFs displayed elevated levels of the Type I TGF-{beta} receptor (T{beta}RI), and secreted more TGF-{beta}1 into the media. Furthermore, PPAR-{gamma} null MEFs showed constitutive phosphorylation of cellular Smad2 and Smad3, even in the absence of exogenous TGF-{beta}, which was abrogated by the ALK5 inhibitor SB431542. Constitutive Smad2/3 phosphorylation in PPAR-{gamma} null MEFs was associated with Smad3 binding to its cognate DNA recognition sequences, and interaction with coactivator p300 previously implicated in TGF-{beta} responses. Taken together, these results indicate that loss of PPAR-{gamma} in MEFs is associated with upregulation of collagen synthesis, and activation of intracellular Smad signal transduction, due, at least in part, to autocrine TGF-{beta} stimulation.

  10. p-Hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock.

    PubMed

    Cotoia, Antonella; Scrima, Rosella; Gefter, Julia V; Piccoli, Claudia; Cinnella, Gilda; Dambrosio, Michele; Fink, Mitchell P; Capitanio, Nazzareno

    2014-01-01

    The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2-4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent.

  11. Work preferences, life values, and personal views of top math/science graduate students and the profoundly gifted: Developmental changes and gender differences during emerging adulthood and parenthood.

    PubMed

    Ferriman, Kimberley; Lubinski, David; Benbow, Camilla P

    2009-09-01

    Work preferences, life values, and personal views of top math/science graduate students (275 men, 255 women) were assessed at ages 25 and 35 years. In Study 1, analyses of work preferences revealed developmental changes and gender differences in priorities: Some gender differences increased over time and increased more among parents than among childless participants, seemingly because the mothers' priorities changed. In Study 2, gender differences in the graduate students' life values and personal views at age 35 were compared with those of profoundly gifted participants (top 1 in 10,000, identified by age 13 and tracked for 20 years: 265 men, 84 women). Again, gender differences were larger among parents. Across both cohorts, men appeared to assume a more agentic, career-focused perspective than women did, placing more importance on creating high-impact products, receiving compensation, taking risks, and gaining recognition as the best in their fields. Women appeared to favor a more communal, holistic perspective, emphasizing community, family, friendships, and less time devoted to career. Gender differences in life priorities, which intensify during parenthood, anticipated differential male-female representation in high-level and time-intensive careers, even among talented men and women with similar profiles of abilities, vocational interests, and educational experiences.

  12. Development of a Bone-Conducted Ultrasonic Hearing Aid for the Profoundly Deaf: Evaluation of Sound Quality Using a Semantic Differential Method

    NASA Astrophysics Data System (ADS)

    Nakagawa, Seiji; Fujiyuki, Chika; Kagomiya, Takayuki

    2013-07-01

    Bone-conducted ultrasound (BCU) is perceived even by the profoundly sensorineural deaf. A novel hearing aid using the perception of amplitude-modulated BCU (BCU hearing aid: BCUHA) has been developed. However, there is room for improvement particularly in terms of sound quality. BCU speech is accompanied by a strong high-pitched tone and contain some distortion. In this study, the sound quality of BCU speech with several types of amplitude modulation [double-sideband with transmitted carrier (DSB-TC), double-sideband with suppressed carrier (DSB-SC), and transposed modulations] and air-conducted (AC) speech was quantitatively evaluated using semantic differential and factor analysis. The results showed that all the types of BCU speech had higher metallic and lower esthetic factor scores than AC speech. On the other hand, transposed speech was closer than the other types of BCU speech to AC speech generally; the transposed speech showed a higher powerfulness factor score than the other types of BCU speech and a higher esthetic factor score than DSB-SC speech. These results provide useful information for further development of the BCUHA.

  13. Work preferences, life values, and personal views of top math/science graduate students and the profoundly gifted: Developmental changes and gender differences during emerging adulthood and parenthood.

    PubMed

    Ferriman, Kimberley; Lubinski, David; Benbow, Camilla P

    2009-09-01

    Work preferences, life values, and personal views of top math/science graduate students (275 men, 255 women) were assessed at ages 25 and 35 years. In Study 1, analyses of work preferences revealed developmental changes and gender differences in priorities: Some gender differences increased over time and increased more among parents than among childless participants, seemingly because the mothers' priorities changed. In Study 2, gender differences in the graduate students' life values and personal views at age 35 were compared with those of profoundly gifted participants (top 1 in 10,000, identified by age 13 and tracked for 20 years: 265 men, 84 women). Again, gender differences were larger among parents. Across both cohorts, men appeared to assume a more agentic, career-focused perspective than women did, placing more importance on creating high-impact products, receiving compensation, taking risks, and gaining recognition as the best in their fields. Women appeared to favor a more communal, holistic perspective, emphasizing community, family, friendships, and less time devoted to career. Gender differences in life priorities, which intensify during parenthood, anticipated differential male-female representation in high-level and time-intensive careers, even among talented men and women with similar profiles of abilities, vocational interests, and educational experiences. PMID:19686005

  14. Clinically relevant deoxycytidine levels are high enough to profoundly alter 9-beta-D-arabinofuranosylguanine cytotoxicity for human T-cell acute leukemia cells in vitro.

    PubMed

    Cohen, J D; Strock, D J; Teik, J E; LaGuardia, E A; Katz, T B

    1999-01-01

    Plasma deoxycytidine levels can vary markedly during chemotherapy, from < 0.05 microM to at least 10.3 microM in T-cell acute lymphoblastic leukemia (T-ALL). This study demonstrates that clinically relevant deoxycytidine levels can dramatically protect human T-ALL cells against 9-beta-D-arabinofuranosylguanine (araG), a promising drug in this leukemia. At 0.4, 1.2, 3.6, and 10.8 microM deoxycytidine, the dose of araG required to kill 50% of MOLT3 T-ALL cells increased 4.23 +/- 1.95-(mean +/- SEM), 23.1 +/- 5.42-, 39.3 +/- 19.3-, and 67.0 +/- 11.5-fold compared to araG without deoxycytidine. Such deoxycytidine concentrations sharply reduced intracellular araG levels and blocked inhibition of DNA synthesis even in the presence of 160 and 640 microM araG. These data offer the first evidence that clinically relevant deoxycytidine levels could profoundly modulate araG toxicity in T-ALL.

  15. Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects*

    PubMed Central

    Swisa, Avital; Granot, Zvi; Tamarina, Natalia; Sayers, Sophie; Bardeesy, Nabeel; Philipson, Louis; Hodson, David J.; Wikstrom, Jakob D.; Rutter, Guy A.; Leibowitz, Gil; Glaser, Benjamin; Dor, Yuval

    2015-01-01

    The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucose-stimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months. PMID:26139601

  16. Profound Lack of Interleukin (IL)-12/IL-23p40 in Neonates Born Early in Gestation Is Associated with an Increased Risk of Sepsis

    PubMed Central

    Lavoie, Pascal M.; Huang, Qing; Jolette, Elyse; Whalen, Mihoko; Nuyt, Anne Monique; Audibert, Francois; Speert, David P.; Lacaze-Masmonteil, Thierry; Soudeyns, Hugo; Kollmann, Tobias R.

    2010-01-01

    Background. Infants born prematurely are highly vulnerable to infections and also exhibit a high susceptibility to organ damage due to inflammation. Methods. To investigate homeostatic immune control early in life, we used advanced multiparameter flow cytometry to compare responses to multiple Toll-like receptor (TLR) ligands in single cells and mononuclear cell populations in term neonates versus preterm neonates born before 29 weeks of gestation. Results. Preterm neonates had globally attenuated TLR-stimulated interleukin (IL)-6, interferon-α, and, to a lesser extent, tumor necrosis factor-α responses but demonstrated relative preservation of anti-inflammatory IL10 responses in monocytes and dendritic cell subtypes. Remarkably, preterm neonates were also profoundly deficient in the common IL-12 and IL-23 cytokines' p40 subunit, which is critical for immunity against a wide variety of microbial pathogens in mice. Consistent with the increased susceptibility to infections resulting from the lack of IL-12/IL-23 in human newborns, significantly lower serum p40 concentrations were observed at birth in infants who developed early-onset sepsis. Conclusion. To our knowledge, this study is the first detailed analysis of multiple TLR function in neonates born extremely premature. Although attenuation of proinflammatory pathways may protect against tissue-damaging immunity early in life, this previously unrecognized p40 immune deficiency appears to result in considerably increased susceptibility to infection in human preterm newborns. PMID:20977341

  17. Perfluorooctanesulfonate Mediates Renal Tubular Cell Apoptosis through PPARgamma Inactivation.

    PubMed

    Wen, Li-Li; Lin, Chien-Yu; Chou, Hsiu-Chu; Chang, Chih-Cheng; Lo, Hau-Yin; Juan, Shu-Hui

    2016-01-01

    Perfluorinated chemicals (PFCs) are ubiquitously distributed in the environments including stainless pan-coating, raincoat, fire extinguisher, and semiconductor products. The PPAR family has been shown to contribute to the toxic effects of PFCs in thymus, immune and excretory systems. Herein, we demonstrated that perfluorooctanesulfonate (PFOS) caused cell apoptosis through increasing ratio of Bcl-xS/xL, cytosolic cytochrome C, and caspase 3 activation in renal tubular cells (RTCs). In addition, PFOS increased transcription of inflammatory cytokines (i.e., TNFα, ICAM1, and MCP1) by NFκB activation. Conversely, PFOS reduced the mRNA levels of antioxidative enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, as a result of reduced PPARγ transactivational activity by using reporter and chromatin immuoprecipitation (ChIP) assays. PFOS reduced the protein interaction between PPARγ and PPARγ coactivator-1 alpha (PGC1α) by PPARγ deacetylation through Sirt1 upregulation, of which the binding of PPARγ and PGC1α to a peroxisome proliferator response element (PPRE) in the promoter regions of these antioxidative enzymes was alleviated in the ChIP assay. Furthermore, Sirt1 also deacetylated p53 and then increased the binding of p53 to Bax, resulting in increased cytosolic cytochrome C. The effect of PPARγ inactivation by PFOS was validated using the PPARγ antagonist GW9662, whereas the adverse effects of PFOS were prevented by PPARγ overexpression and activators, rosiglitozone and L-carnitine, in RTCs. The in vitro finding of protective effect of L-carnitine was substantiated in vivo using Balb/c mice model subjected to PFOS challenge. Altogether, we provide in vivo and in vitro evidence for the protective mechanism of L-carnitine in eliminating PFOS-mediated renal injury, at least partially, through PPARγ activation. PMID:27171144

  18. Perfluorooctanesulfonate Mediates Renal Tubular Cell Apoptosis through PPARgamma Inactivation

    PubMed Central

    Chou, Hsiu-Chu; Chang, Chih-Cheng; Lo, Hau-Yin; Juan, Shu-Hui

    2016-01-01

    Perfluorinated chemicals (PFCs) are ubiquitously distributed in the environments including stainless pan-coating, raincoat, fire extinguisher, and semiconductor products. The PPAR family has been shown to contribute to the toxic effects of PFCs in thymus, immune and excretory systems. Herein, we demonstrated that perfluorooctanesulfonate (PFOS) caused cell apoptosis through increasing ratio of Bcl-xS/xL, cytosolic cytochrome C, and caspase 3 activation in renal tubular cells (RTCs). In addition, PFOS increased transcription of inflammatory cytokines (i.e., TNFα, ICAM1, and MCP1) by NFκB activation. Conversely, PFOS reduced the mRNA levels of antioxidative enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, as a result of reduced PPARγ transactivational activity by using reporter and chromatin immuoprecipitation (ChIP) assays. PFOS reduced the protein interaction between PPARγ and PPARγ coactivator-1 alpha (PGC1α) by PPARγ deacetylation through Sirt1 upregulation, of which the binding of PPARγ and PGC1α to a peroxisome proliferator response element (PPRE) in the promoter regions of these antioxidative enzymes was alleviated in the ChIP assay. Furthermore, Sirt1 also deacetylated p53 and then increased the binding of p53 to Bax, resulting in increased cytosolic cytochrome C. The effect of PPARγ inactivation by PFOS was validated using the PPARγ antagonist GW9662, whereas the adverse effects of PFOS were prevented by PPARγ overexpression and activators, rosiglitozone and L-carnitine, in RTCs. The in vitro finding of protective effect of L-carnitine was substantiated in vivo using Balb/c mice model subjected to PFOS challenge. Altogether, we provide in vivo and in vitro evidence for the protective mechanism of L-carnitine in eliminating PFOS-mediated renal injury, at least partially, through PPARγ activation. PMID:27171144

  19. Clustered Charge-to-Alanine Mutagenesis of the Vaccinia Virus H5 Gene: Isolation of a Dominant, Temperature-Sensitive Mutant with a Profound Defect in Morphogenesis

    PubMed Central

    DeMasi, Joseph; Traktman, Paula

    2000-01-01

    The vaccinia virus H5 gene encodes a 22.3-kDa phosphoprotein that is expressed during both the early and late phases of viral gene expression. It is a major component of virosomes and has been implicated in viral transcription and, as a substrate of the B1 kinase, may participate in genome replication. To enable a genetic analysis of the role of H5 during the viral life cycle, we used clustered charge-to-alanine mutagenesis in an attempt to create a temperature-sensitive (ts) virus with a lesion in the H5 gene. Five mutant viruses were isolated, with one of them, tsH5-4, having a strong ts phenotype as assayed by plaque formation and measurements of 24-h viral yield. Surprisingly, no defects in genome replication or viral gene expression were detected at the nonpermissive temperature. By electron microscopy, we observed a profound defect in the early stages of virion morphogenesis, with arrest occurring prior to the formation of crescent membranes or immature particles. Nonfunctional, “curdled” virosomes were detected in tsH5-4 infections at the nonpermissive temperature. These structures appeared to revert to functional virosomes after a temperature shift to permissive conditions. We suggest an essential role for H5 in normal virosome formation and the initiation of virion morphogenesis. By constructing recombinant genomes containing two H5 alleles, wild type and H5-4, we determined that H5-4 exerted a dominant phenotype. tsH5-4 is the first example of a dominant ts mutant isolated and characterized in vaccinia virus. PMID:10666270

  20. Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss

    PubMed Central

    Richards, Allan J; Fincham, Gregory S; McNinch, Annie; Hill, David; Poulson, Arabella V; Castle, Bruce; Lees, Melissa M; Moore, Anthony T; Scott, John D; Snead, Martin P

    2013-01-01

    Background Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler syndrome and COL9A2 type 5 Stickler syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler syndrome rather than fibrochondrogenesis. Methods Patients referred to the national Stickler syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1. Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed. Results In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing. Conclusion This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler syndrome. PMID:23922384

  1. nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

    PubMed Central

    Drury, Paul P.; Davidson, Joanne O.; Mathai, Sam; van den Heuij, Lotte G.; Ji, Haitao; Bennet, Laura; Tan, Sidhartha; Silverman, Richard B.; Gunn, Alistair J.

    2014-01-01

    Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are associated with neural outcome. 24 chronically instrumented preterm fetal sheep were randomized to either JI-10 (3 ml of 0.022 mg/ml, n=8) or saline (n=8) infusion 15 min before 25 min complete umbilical cord occlusion, or saline plus sham-occlusion (n=8). Umbilical cord occlusion was associated with reduced numbers of calbindin-28k-, GAD-, NPY-, PV-, Calretinin- and nNOS-positive striatal neurons (p < 0.05 vs. sham occlusion) but not ChAT-positive neurons. JI-10 was associated with increased numbers of calbindin-28k-, GAD-, nNOS-, NPY-, PV-, Calretinin- and ChAT-positive striatal neurons (p < 0.05 vs. saline+occlusion). Seizure burden was strongly associated with loss of calbindin-positive cells (p < 0.05), greater seizure amplitude was associated with loss of GAD-positive cells (p < 0.05), and with more activated microglia in the white matter tracts (p < 0.05). There was no relationship between EEG power after 7 days recovery and total striatal cell loss, but better survival of NPY-positive neurons was associated with lower EEG power. In summary, these findings suggest that selective nNOS inhibition during asphyxia is associated with protection of phenotypic striatal projection neurons and has potential to help reduce basal ganglia injury in some premature babies. PMID:24726307

  2. An Audit-Based, Infectious Disease Specialist-Guided Antimicrobial Stewardship Program Profoundly Reduced Antibiotic Use Without Negatively Affecting Patient Outcomes.

    PubMed

    Nilholm, Hannah; Holmstrand, Linnea; Ahl, Jonas; Månsson, Fredrik; Odenholt, Inga; Tham, Johan; Melander, Eva; Resman, Fredrik

    2015-04-01

    Background.  Antimicrobial stewardship programs are increasingly implemented in hospital care. They aim to simultaneously optimize outcomes for individual patients with infections and reduce financial and health-associated costs of overuse of antibiotics. Few studies have examined the effects of antimicrobial stewardship programs in settings with low proportions of antimicrobial resistance, such as in Sweden. Methods.  An antimicrobial stewardship program was introduced during 5 months of 2013 in a department of internal medicine in southern Sweden. The intervention consisted of audits twice weekly on all patients given antibiotic treatment. The intervention period was compared with a historical control consisting of patients treated with antibiotics in the same wards in 2012. Studied outcome variables included 28-day mortality and readmission, length of hospital stay, and use of antibiotics. Results.  A reduction of 27% in total antibiotic use (2387 days of any antibiotic) was observed in the intervention period compared with the control period. The reduction was due to fewer patients started on antibiotics as well as to significantly shorter durations of antibiotic courses (P < .001). An earlier switch to oral therapy and a specific reduction in use of third-generation cephalosporins and fluoroquinolones was also evident. Mortality, total readmissions, and lengths of stay in hospital were unchanged compared with the control period, whereas readmissions due to a nonresolved infection were fewer during the intervention of 2013. Conclusions.  This study demonstrates that an infectious disease specialist-guided antimicrobial stewardship program can profoundly reduce antibiotic use in a low-resistance setting with no negative effect on patient outcome.

  3. Profound Climatic Effects on Two East Asian Black-Throated Tits (Ave: Aegithalidae), Revealed by Ecological Niche Models and Phylogeographic Analysis

    PubMed Central

    Wang, Wenjuan; Lin, Congtian; Gao, Bin; Yang, Xiaojun; Zhang, Zhengwang; Lei, Fumin

    2011-01-01

    Although a number of studies have assessed the effects of geological and climatic changes on species distributions in East Asian, we still have limited knowledge of how these changes have impacted avian species in south-western and southern China. Here, we aim to study paleo-climatic effects on an East Asian bird, two subspecies of black-throated tit (A. c. talifuensis–concinnus) with the combined analysis of phylogeography and Ecological Niche Models (ENMs). We sequenced three mitochondrial DNA markers from 32 populations (203 individuals) and used phylogenetic inferences to reconstruct the intra-specific relationships among haplotypes. Population genetic analyses were undertaken to gain insight into the demographic history of these populations. We used ENMs to predict the distribution of target species during three periods; last inter-glacial (LIG), last glacial maximum (LGM) and present. We found three highly supported, monophyletic MtDNA lineages and different historical demography among lineages in A. c. talifuensis–concinnus. These lineages formed a narrowly circumscribed intra-specific contact zone. The estimated times of lineage divergences were about 2.4 Ma and 0.32 Ma respectively. ENMs predictions were similar between present and LGM but substantially reduced during LIG. ENMs reconstructions and molecular dating suggest that Pleistocene climate changes had triggered and shaped the genetic structure of black-throated tit. Interestingly, in contrast to profound impacts of other glacial cycles, ENMs and phylogeographic analysis suggest that LGM had limited effect on these two subspecies. ENMs also suggest that Pleistocene climatic oscillations enabled the formation of the contact zone and thus support the refuge theory. PMID:22195047

  4. 'I Never Thought They Would Enjoy the Fun of Science Just Like Ordinary Children Do'--Exploring Science Experiences with Early Years Teacher Training Students and Children with Severe and Profound Learning Difficulties.

    ERIC Educational Resources Information Center

    Bishop, Alison; Jones, Phyllis

    2003-01-01

    This paper evaluates a British program in which 20 undergraduate students training to be primary science teachers planned and delivered a science workshop to students with severe and profound learning difficulties. Analysis focuses on comments of the college students both before and after the workshop experience. The experience encouraged student…

  5. Can You Know Me Better? An Exploratory Study Combining Behavioural and Physiological Measurements for an Objective Assessment of Sensory Responsiveness in a Child with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Lima, Mariely; Silva, Karine; Magalhaes, Ana; Amaral, Isabel; Pestana, Helena; de Sousa, Liliana

    2012-01-01

    Background: Sensory assessment of individuals with profound intellectual and multiple disabilities (PIMD) can be difficult for several reasons, including the idiosyncratic reactions that these individuals exhibit to environmental stimuli. This case report presents a combination of behavioural and physiological measurements aimed at providing an…

  6. Together: A Look at the Effectiveness of Team Teaching To Meet the Needs of Students with Severe to Profound Disabilities in the Regular Education Environment. FY 1990 Data Effectiveness Grants Program.

    ERIC Educational Resources Information Center

    Dupre, Teresa; Hall, Patricia

    For the 1989-90 school year, two Minnesota elementary schools developed a program in which 14 students with severe to profound disabilities became full-time members of regular education classrooms. The program maintained functional programming for the students with disabilities within the context of the activities and materials used by regular…

  7. In Vivo Analysis of Disease-Associated Point Mutations Unveils Profound Differences in mRNA Splicing of Peripherin-2 in Rod and Cone Photoreceptors.

    PubMed

    Becirovic, Elvir; Böhm, Sybille; Nguyen, Ong Nam Phuong; Riedmayr, Lisa Maria; Koch, Mirja Annika; Schulze, Elisabeth; Kohl, Susanne; Borsch, Oliver; Santos-Ferreira, Tiago; Ader, Marius; Michalakis, Stylianos; Biel, Martin

    2016-01-01

    Point mutations in peripherin-2 (PRPH2) are associated with severe retinal degenerative disorders affecting rod and/or cone photoreceptors. Various disease-causing mutations have been identified, but the exact contribution of a given mutation to the clinical phenotype remains unclear. Exonic point mutations are usually assumed to alter single amino acids, thereby influencing specific protein characteristics; however, they can also affect mRNA splicing. To examine the effects of distinct PRPH2 point mutations on mRNA splicing and protein expression in vivo, we designed PRPH2 minigenes containing the three coding exons and relevant intronic regions of human PRPH2. Minigenes carrying wild type PRPH2 or PRPH2 exon 2 mutations associated with rod or cone disorders were expressed in murine photoreceptors using recombinant adeno-associated virus (rAAV) vectors. We detect three PRPH2 splice isoforms in rods and cones: correctly spliced, intron 1 retention, and unspliced. In addition, we show that only the correctly spliced isoform results in detectable protein expression. Surprisingly, compared to rods, differential splicing leads to lower expression of correctly spliced and higher expression of unspliced PRPH2 in cones. These results were confirmed in qRT-PCR experiments from FAC-sorted murine rods and cones. Strikingly, three out of five cone disease-causing PRPH2 mutations profoundly enhanced correct splicing of PRPH2, which correlated with strong upregulation of mutant PRPH2 protein expression in cones. By contrast, four out of six PRPH2 mutants associated with rod disorders gave rise to a reduced PRPH2 protein expression via different mechanisms. These mechanisms include aberrant mRNA splicing, protein mislocalization, and protein degradation. Our data suggest that upregulation of PRPH2 levels in combination with defects in the PRPH2 function caused by the mutation might be an important mechanism leading to cone degeneration. By contrast, the pathology of rod

  8. Reduction of isoprenaline-induced myocardial TGF-{beta}1 expression and fibrosis in osthole-treated mice

    SciTech Connect

    Chen Rong; Xue Jie; Xie Meilin

    2011-10-15

    Peroxisome proliferator-activated receptor (PPAR) {alpha} and PPAR{gamma} ligands can attenuate myocardial fibrosis. Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, may be a dual PPAR{alpha}/{gamma} agonist, but there has been no report on its effect on myocardial fibrosis. In the present study, we investigated the inhibitory effect of osthole on myocardial fibrotic formation in mice and its possible mechanisms. A mouse model with myocardial fibrosis was induced by hypodermic injection of isoprenaline while the mice were simultaneously treated with 40 and 80 mg/kg osthole for 40 days. After the addition of osthole, the cardiac weight index and hydroxyproline content in the myocardial tissues were decreased, the degree of collagen accumulation in the heart was improved, and the downregulation of myocardial PPAR{alpha}/{gamma} mRNA expression induced by isoprenaline was reversed. Moreover, the mRNA expression of transforming growth factor (TGF)-{beta}1 and the protein levels of nuclear factor (NF)-{kappa}B and TGF-{beta}1 in the myocardial tissues were decreased. These findings suggest that osthole can prevent isoprenaline-induced myocardial fibrosis in mice, and its mechanisms may be related to the reduction of TGF-{beta}1 expression via the activation of PPAR{alpha}/{gamma} and subsequent inhibition of NF-{kappa}B in myocardial tissues. - Highlights: > Osthole could inhibit the myocardial fibrosis induced by isoprenaline in mice. > The mechanism was related to reduction of TGF-{beta}1 expression in myocardial tissue. > The result of osthole was from the activation of PPAR{alpha}/{gamma} and inhibition of NF-{kappa}B.

  9. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness.

    PubMed

    van den Berghe, G; Weekers, F; Baxter, R C; Wouters, P; Iranmanesh, A; Bouillon, R; Veldhuis, J D

    2001-07-01

    . Serum interleukin-1beta concentrations were normal, whereas interleukin-6 and tumor necrosis factor-alpha were elevated. Serum tumor necrosis factor-alpha was positively correlated with the molar E(2)/testosterone ratio and with type 1 procollagen; the latter was elevated, whereas osteocalcin was decreased. Ureagenesis and breakdown of bone were increased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compared with placebo by an increment of +8.1 +/- 8.1 IU/L at 24 h (P = 0.001). This increase was only partially maintained after 5 days of treatment. GnRH pulses transiently increased serum testosterone by +174% on day 2 (P = 0.05), whereas all other endocrine parameters remained unaltered. GnRH tended to increase type 1 procollagen (P = 0.06), but did not change serum osteocalcin levels or bone breakdown. Ureagenesis was suppressed (P < 0.0001), and white blood cell count (P = 0.0001), C-reactive protein (P = 0.03), and lactate level (P = 0.01) were increased by GnRH compared with placebo infusions. In conclusion, hypogonadotropic hypogonadism in prolonged critically ill men is only partially overcome with exogenous iv GnRH pulses, pointing to combined hypothalamic-pituitary-gonadal origins of the profound hypoandrogenism evident in this context. In view of concomitant central hyposomatotropism and hypothyroidism, evaluating the effectiveness of pulsatile GnRH intervention together with GH and TSH secretagogues will be important.

  10. DEVELOPMENTAL HYPOTHYROIDISM INDUCES A NEURONAL HETEROTOPIA IN THE CORPUS CALLOSUM OF THE RAT.

    EPA Science Inventory

    It is well established that severe hypothyroidism leads to profound alterations in brain development and mental retardation. In this study we examined the effect of subtle decreases in maternal thyroid hormones (TH) on brain development in the rat. To induce TH insufficiency pr...

  11. Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.

    PubMed

    Murase, Takatoshi; Misawa, Koichi; Haramizu, Satoshi; Minegishi, Yoshihiko; Hase, Tadashi

    2010-08-01

    AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver. PMID:20501876

  12. Induced Abortion

    MedlinePlus

    ... Induced Abortion Patient Education FAQs Induced Abortion Patient Education Pamphlets - Spanish Induced Abortion FAQ043, May 2015 PDF Format Induced ... Your Practice Patient Safety & Quality Payment Reform (MACRA) Education & Events Annual ... Pamphlets Teen Health About ACOG About Us Leadership & ...

  13. Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes

    PubMed Central

    Stadelmann, Britta; Aeschbacher, Denise; Huber, Cristina; Spiliotis, Markus; Müller, Joachim; Hemphill, Andrew

    2014-01-01

    A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI) assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ), a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors. PMID:25474446

  14. Changes in white adipose tissue metabolism induced by resveratrol in rats

    PubMed Central

    2011-01-01

    Background A remarkable range of biological functions have been ascribed to resveratrol. Recently, this polyphenol has been shown to have body fat lowering effects. The aim of the present study was to assess some of the potential underlying mechanisms of action which take place in adipose tissue. Methods Sixteen male Sprague-Dawley rats were randomly divided into two groups: control and treated with 30 mg resveratrol/kg body weight/d. All rats were fed an obesogenic diet and after six weeks of treatment white adipose tissues were dissected. Lipoprotein lipase activity was assessed by fluorimetry, acetyl-CoA carboxylase by radiometry, and malic enzyme, glucose-6P-dehydrogenase and fatty acid synthase by spectrophotometry. Gene expression levels of acetyl-CoA carboxylase, fatty acid synthase, lipoprotein lipase, hormone-sensitive lipase, adipose triglyceride lipase, PPAR-gamma, SREBP-1c and perilipin were assessed by Real time RT-PCR. The amount of resveratrol metabolites in adipose tissue was measured by chromatography. Results There was no difference in the final body weight of the rats; however, adipose tissues were significantly decreased in the resveratrol-treated group. Resveratrol reduced the activity of lipogenic enzymes, as well as that of heparin-releasable lipoprotein lipase. Moreover, a significant reduction was induced by this polyphenol in hormone-sensitive lipase mRNA levels. No significant changes were observed in other genes. Total amount of resveratrol metabolites in adipose tissue was 2.66 ± 0.55 nmol/g tissue. Conclusions It can be proposed that the body fat-lowering effect of resveratrol is mediated, at least in part, by a reduction in fatty acid uptake from circulating triacylglycerols and also in de novo lipogenesis. PMID:21569266

  15. Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment

    SciTech Connect

    Johnson, Timothy E. . E-mail: Timothy_Johnson@merck.com; Zhang, Xiaohua; Shi, Shu; Umbenhauer, Diane R.

    2005-11-01

    Statins and fibrates (weak PPAR{alpha} agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPAR{alpha} agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPAR{alpha} compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPAR{gamma} agonist Rosiglitazone caused little or no cell death at up to 10 {mu}M and the PPAR{delta} ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPAR{alpha} agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPAR{alpha} agonism mediates in part the toxicity response to PPAR{alpha} compounds. Furthermore, PPAR{alpha} agonists and statins cause myotoxicity through distinct and independent pathways.

  16. GLI1 Confers Profound Phenotypic Changes upon LNCaP Prostate Cancer Cells That Include the Acquisition of a Hormone Independent State

    PubMed Central

    Nadendla, Sandeep K.; Hazan, Allon; Ward, Matt; Harper, Lisa J.; Moutasim, Karwan; Bianchi, Lucia S.; Naase, Mahmoud; Ghali, Lucy; Thomas, Gareth J.; Prowse, David M.; Philpott, Michael P.; Neill, Graham W.

    2011-01-01

    The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and

  17. In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts.

    PubMed

    Hostettler, Isabel; Müller, Joachim; Hemphill, Andrew

    2016-06-01

    Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance development has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites, such as Plasmodium Here, we present the results of a screen of 400 compounds included in the open-access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized by T. annulata schizonts. Using a combination of the classical alamarBlue vitality assay and a recently developed quantitative reverse transcriptase real-time PCR method based on the Theileria TaSP gene, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have 50% inhibitory concentrations (IC50s) of 0.5 and 0.2 μM on TaC12 cells and 5.3 and 5.2 μM on BoMac cells, respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of antitheilerial chemotherapeutics. PMID:26976863

  18. Genetically Altering the Thermodynamics and Kinetics of Hepatitis B Virus Capsid Assembly Has Profound Effects on Virus Replication in Cell Culture

    PubMed Central

    Tan, Zhenning; Maguire, Megan L.; Loeb, Daniel D.

    2013-01-01

    Capsid (core) assembly is essential for hepatitis B virus (HBV) replication. We hypothesize that assembly kinetics and stability are tuned for optimal viral replication, not maximal assembly. Assembly effectors (AEfs) are small molecules proposed to disrupt this balance by inappropriately enhancing core assembly. Guided by the structure of an AEf-bound core, we designed a structural mimic of AEf-bound core protein, the V124W mutant. In biochemical studies, the V124W mutant recapitulated the effects of AEfs, with fast assembly kinetics and a strong protein-protein association energy. Also, the mutant was resistant to exogenous AEfs. In cell culture, the V124W mutant behaved like a potent AEf: expression of HBV carrying the V124W mutant was defective for genome replication. Critically, the V124W mutant interfered with replication of wild-type HBV in a dose-dependent manner, mimicking AEf activity. In addition, the V124W mutant was shown to adopt a more compact conformation than that of the wild type, confirming the allosteric regulation in capsid assembly. These studies show that the heteroaryldihydropyrimidine (HAP) binding pocket is a promiscuous target for inducing assembly. Suppression of viral replication by the V124W mutant suggests that mutations that fill the HAP site are not a path for HBV to escape from AEfs. PMID:23283960

  19. Selective expansion followed by profound deletion of mature V beta 8.3+ T cells in vivo after exposure to the superantigenic lectin Urtica dioica agglutinin.

    PubMed

    Galelli, A; Delcourt, M; Wagner, M C; Peumans, W; Truffa-Bachi, P

    1995-03-15

    Urtica dioica agglutinin (UDA) is a superantigen that, in vitro, binds to specific carbohydrate structures on class II and induces a sixfold enrichment of V beta 8.3+ BALB/c mice splenic T cells. Superantigens have pleiotropic effects in vivo, causing the activation, proliferation, and deletion of specific T cells, but are heterogenous in regard to their effects on T cell tolerization. We, therefore, compared the responses of peripheral T cells from adult BALB/c mice with the i.v. injection of 50 micrograms UDA or the bacterial superantigen staphylococcal enterotoxin B (SEB) that also recognizes the V beta 8.3 gene product. The data presented indicate that activation, clonal expansion, anergy, and death of V beta 8.3+ T cells occur sequentially after UDA administration. Two days after UDA injection, the proportion of V beta 8.3+ T cells in the periphery is elevated to approximately twice that of normal mice. This expansion occurs in both CD4+ and CD8+ subsets. V beta 8.3+ T cells from UDA-primed mice are anergic to UDA restimulation and fail to proliferate or to produce IL-2. Futhermore, the proliferation of V beta 8.3+ T cells is followed by their rapid disappearance concomitant with their specific elimination by apoptosis. In 1 wk, all CD4+ V beta 8.3+ peripheral T cells are deleted. The decline of V beta 8.3+ T cells in the CD4+ subset is more than in the CD8+ subset. This occurs in thymectomized and in thymus-intact animals. Two months after UDA priming, the percentage of V beta 8.3+ T cells is still lower than in control mice. PMID:7876535

  20. Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review.

    PubMed

    Salter, Benjamin S; Weiner, Menachem M; Trinh, Muoi A; Heller, Joshua; Evans, Adam S; Adams, David H; Fischer, Gregory W

    2016-05-31

    Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low-molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia's risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality.

  1. Low Dose IR Creates an Oncogenic Microenvironment by Inducing Premature

    SciTech Connect

    Yuan, Zhi-Min

    2013-04-28

    Introduction Much of the work addressing ionizing radiation-induced cellular response has been carried out mainly with the traditional cell culture technique involving only one cell type, how cellular response to IR is influenced by the tissue microenvironment remains elusive. By use of a three-dimensional (3D) co-culture system to model critical interactions of different cell types with their neighbors and with their environment, we recently showed that low-dose IR-induced extracellular signaling via the tissue environment affects profoundly cellular responses. This proposal aims at determining the response of mammary epithelial cells in a tissue-like setting.

  2. Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice

    SciTech Connect

    Lee, Myoung-Su; Kim, Daeyoung; Jo, Keunae; Hwang, Jae-Kwan

    2010-10-08

    Research highlights: {yields} NDGA decreases high-fat diet-induced body weight gain and adiposity. {yields} NDGA reduces high-fat diet-induced triglyceride accumulation in liver. {yields} NDGA improves lipid storage in vitro through altering lipid regulatory proteins. {yields} Inhibition of lipid storage in vivo and in vitro is mediated by AMPK activation. -- Abstract: Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200 mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR){alpha}, PPAR{gamma} coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD.

  3. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

    SciTech Connect

    Ye, Tianyu; Liu, Han -Chun; Wang, Zhuo; Wegscheider, W.; Mani, Ramesh G.

    2015-10-09

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. As a result, for circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ.

  4. The potential biological mechanisms of arsenic-induced diabetes mellitus.

    PubMed

    Tseng, Chin-Hsiao

    2004-06-01

    chronic arsenic exposure, oxidative stress is increased and the expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) is upregulated. Both of these two cytokines have been well known for their effect on the induction of insulin resistance. Arsenite at physiologically relevant concentration also shows inhibitory effect on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor important for activating insulin action. Oxidative stress has been suggested as a major pathogenic link to both insulin resistance and beta cell dysfunction through mechanisms involving activation of nuclear factor-kappaB (NF-kappaB), which is also activated by low levels of arsenic. Although without supportive data, superoxide production induced by arsenic exposure can theoretically impair insulin secretion by interaction with uncoupling protein 2 (UCP2), and oxidative stress can also cause amyloid formation in the pancreas, which could progressively destroy the insulin-secreting beta cells. Individual susceptibility with respect to genetics, nutritional status, health status, detoxification capability, interactions with other trace elements, and the existence of other well-recognized risk factors of diabetes mellitus can influence the toxicity of arsenic on organs involved in glucose metabolism and determine the progression of insulin resistance and impaired insulin secretion to a status of persistent hyperglycemia or diabetes mellitus. In conclusions, insulin resistance and beta cell dysfunction can be induced by chronic arsenic exposure. These defects may be responsible for arsenic-induced diabetes mellitus, but investigations are required to test this hypothesis.

  5. Effectiveness of instruction and video feedback on staff's use of prompts and children's adaptive responses during one-to-one training in children with severe to profound intellectual disability.

    PubMed

    van Vonderen, Annemarie; de Swart, Charlotte; Didden, Robert

    2010-01-01

    Although relatively many studies have addressed staff training and its effect on trainer behavior, the effects of staff training on trainee's adaptive behaviors have seldom been examined. We therefore assessed effectiveness of staff training, consisting of instruction and video feedback, on (a) staff's response prompting, and (b) staff's trainer behavior during one-to-one training with four direct-care staff who acted as trainers. Next to this, we evaluated the effects of staff training on adaptive skills in four children with severe to profound intellectual disability. A non-concurrent multiple baseline design across staff-trainee dyads was used. Intervention resulted in an immediate and substantial increase in percentage correct response prompting and percentage correct trainer behavior by staff. The intervention was also effective in increasing percentage of trainee's correct responses. Staff rated instruction and video feedback as effective and acceptable. Results are discussed in terms of their implications for future research.

  6. Mechanism of HIV protein induced modulation of mesenchymal stem cell osteogenic differentiation

    PubMed Central

    Cotter, Eoin J; Ip, Herbert Shi Ming; Powderly, William G; Doran, Peter P

    2008-01-01

    Background A high incidence of decreased bone mineral density (BMD) has been associated with HIV infection. Normal skeletal homeostasis is controlled, at least in part, by the maturation and activity of mature osteoblasts. Previous studies by our group have demonstrated the ability of HIV proteins to perturb osteoblast function, and the degree of osteogenesis in differentiating mesenchymal stem cells (MSCs). This study attempts to further dissect the dynamics of this effect. Methods MSCs were cultured under both osteogenic (cultured in commercially available differentiation media) and quiescent (cultured in basal medium) conditions. Both cell populations were exposed to HIV p55-gag and HIV rev (100 ng/ml). Time points were taken at 3, 6, 9, and 15 days for osteogenic conditions, while quiescent cells were treated for 1 week. Cell function (alkaline phosphatase [ALP] activity, calcium deposition, and lipid levels) and the activity of the key MSC transcription factors, RUNX-2 and PPARgamma were determined post-exposure. Also, in cells cultured in differentiating conditions, cellular levels of connective tissue growth factor (CTGF) were analysed using whole cell ELISA, while BMP-2 secretion was also examined. Results In differentiating MSCs, exposure to HIV proteins caused significant changes in both the timing and magnitude of key osteogenic events and signals. Treatment with REV increased the overall rate of mineralization, and induced earlier increases in CTGF levels, RUNX-2 activity and BMP-2 secretion, than those observed in the normal course of differntiation. In contrast, p55-gag reduced the overall level of osteogenesis, and reduced BMP-2 secretion, RUNX-2 activity, CTGF levels and ALP activity at many of the timepoints examined. Finally, in cells cultured in basal conditions, treatment with HIV proteins did not in and of itself induce a significant degree of differentiation over the time period examined. Conclusion These data demonstrate that the effect of

  7. Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism

    PubMed Central

    2015-01-01

    Given its profound analgesic nature, neuraxial opioids are frequently used for pain management. Unfortunately, the high incident rate of itch/pruritus after spinal administration of opioid analgesics reported in postoperative and obstetric patients greatly diminishes patient satisfaction and thus the value of the analgesics. Many endeavors to solve the mystery behind neuraxial opioid-induced itch had not been successful, as the pharmacological antagonism other than the blockade of mu opioid receptors remains elusive. Nevertheless, as the characteristics of all opioid receptor subtypes have become more understood, more studies have shed light on the potential effective treatments. This review discusses the mechanisms underlying neuraxial opioid-induced itch and compares pharmacological evidence in nonhuman primates with clinical findings across diverse drugs. Both nonhuman primate and human studies corroborate that mixed mu/kappa opioid partial agonists seem to be the most effective drugs in ameliorating neuraxial opioid-induced itch while retaining neuraxial opioid-induced analgesia. PMID:25861787

  8. Speech Motor Learning in Profoundly Deaf Adults

    PubMed Central

    Nasir, Sazzad M.; Ostry, David J.

    2008-01-01

    Speech production, like other sensorimotor behaviors, relies on multiple sensory inputs — audition, proprioceptive inputs from muscle spindles, and cutaneous inputs from mechanoreceptors in the skin and soft tissues of the vocal tract. However, the capacity for intelligible speech by deaf speakers suggests that somatosensory input on its own may contribute to speech motor control and perhaps even to speech learning. We assessed speech motor learning in cochlear implant recipients who were tested with their implants turned off. A robotic device was used to alter somatosensory feedback by displacing the jaw during speech. We found that with training implant subjects progressively adapted to the mechanical perturbation. Moreover, the corrections we observed were for movement deviations that were exceedingly small, on the order of millimetres, indicating that speakers have precise somatosensory expectations. Speech motor learning is significantly dependent on somatosensory input. PMID:18794839

  9. Unexplained Profound Hypoglycemia After Vocal Fold Lipoinjection.

    PubMed

    Modanlou, Shohreh; Marie Giglio, Nicole; Carroll, Thomas; Pancaro, Carlo

    2016-02-01

    Vocal fold injection is used for the management of glottal incompetence from various causes. The procedure is well tolerated and has few reported complications. We present a case of a 66-year-old man with long-lasting hoarseness secondary to vocal fold atrophy, who underwent an uneventful bilateral vocal fold injection with autologous fat. While in the recovery area, he experienced profuse sweating approximately 30 minutes after the surgical procedure. His blood glucose value was measured at 24 mg/dL, and plasmatic insulin level was 246 mU/L. To our knowledge, this is the first reported case of a systemic side effect after vocal fold lipoinjection. PMID:26491839

  10. An interesting case of profound hypoxemia.

    PubMed

    Fu, Jennifer; Nguyen, Luan; Nguyen, Elise; Lau, Nick; Ji, Ping; French, Samuel W; Stringer, William W

    2016-04-01

    A 58 year old male with a history of cirrhosis (hepatitis B and C), a long smoking history, and a recently diagnosed high-grade transitional cell carcinoma of the bladder wall presented three days after a biopsy procedure with abdominal pain, nausea, and new hypoxemia on room air. The chest radiograph was clear and the CT angiogram showed only a borderline large pulmonary artery, two small nodules (3mm and 4mm) in the right middle lobe of the lung, and emphysematous changes throughout the lung parenchyma. There was no evidence of pulmonary embolism. A wide range of diagnostic possibilities were entertained, including pneumonia (community or aspiration related to the procedure), COPD exacerbation, pulmonary emboli, porto-pulmonary syndrome, pulmonary hypertension with right to left shunt, tumor emboli, allergic reaction to a medication or chemotherapeutic agent, or lymphangitic/hematogenous spread of tumor to the lungs. The diagnosis was only established on a post mortem examination. The progressive hypoxia was due to diffuse spread of tumor within alveolar capillaries. PMID:26939911

  11. Emerging targets for treating sulfur mustard-induced injuries.

    PubMed

    Ahmad, Shama; Ahmad, Aftab

    2016-06-01

    Sulfur mustard (SM; bis-(2-chlororethyl) sulfide) is a highly reactive, potent warfare agent that has recently reemerged as a major threat to military and civilians. Exposure to SM is often fatal, primarily due to pulmonary injuries and complications caused by its inhalation. Profound inflammation, hypercoagulation, and oxidative stress are the hallmarks that define SM-induced pulmonary toxicities. Despite advances, effective therapies are still limited. This current review focuses on inflammatory and coagulation pathways that influence the airway pathophysiology of SM poisoning and highlights the complexity of developing an effective therapeutic target. PMID:27285828

  12. Induced Probabilities.

    ERIC Educational Resources Information Center

    Neel, John H.

    Induced probabilities have been largely ignored by educational researchers. Simply stated, if a new or random variable is defined in terms of a first random variable, then induced probability is the probability or density of the new random variable that can be found by summation or integration over the appropriate domains of the original random…

  13. Citrus auraptene acts as an agonist for PPARs and enhances adiponectin production and MCP-1 reduction in 3T3-L1 adipocytes

    SciTech Connect

    Kuroyanagi, Kayo; Kang, Min-Sook; Goto, Tsuyoshi; Hirai, Shizuka; Ohyama, Kana; Kusudo, Tatsuya; Yu, Rina; Yano, Masamichi; Sasaki, Takao; Takahashi, Nobuyuki; Kawada, Teruo

    2008-02-01

    Citrus fruit compounds have many health-enhancing effects. In this study, using a luciferase ligand assay system, we showed that citrus auraptene activates peroxisome proliferator-activated receptor (PPAR)-{alpha} and PPAR{gamma}. Auraptene induced up-regulation of adiponectin expression and increased the ratio of the amount of high-molecular-weight multimers of adiponectin to the total adiponectin. In contrast, auraptene suppressed monocyte chemoattractant protein (MCP)-1 expression in 3T3-L1 adipocytes. Experiments using PPAR{gamma} antagonist demonstrated that these effects on regulation of adiponectin and MCP-1 expression were caused by PPAR{gamma} activations. The results indicate that auraptene activates PPAR{gamma} in adipocytes to control adipocytekines such as adiponectin and MCP-1 and suggest that the consumption of citrus fruits, which contain auraptene can lead to a partial prevention of lipid and glucose metabolism abnormalities.

  14. Flow induced migration in polymer melts – Theory and simulation

    SciTech Connect

    Dorgan, John Robert Rorrer, Nicholas Andrew

    2015-04-28

    Flow induced migration, whereby polymer melts are fractionated by molecular weight across a flow field, represents a significant complication in the processing of polymer melts. Despite its long history, such phenomena remain relatively poorly understood. Here a simple analytical theory is presented which predicts the phenomena based on well-established principles of non-equilibrium thermodynamics. It is unambiguously shown that for purely viscous materials, a gradient in shear rate is needed to drive migration; for purely viscometric flows no migration is expected. Molecular scale simulations of flow migration effects in dense polymer melts are also presented. In shear flow the melts exhibit similar behavior as the quiescent case; a constant shear rate across the gap does not induce chain length based migration. In comparison, parabolic flow causes profound migration for both unentangled and entangled melts. These findings are consistent with the analytical theory. The picture that emerges is consistent with flow induced migration mechanisms predominating over competing chain degradation mechanisms.

  15. Peripheral nerve morphogenesis induced by scaffold micropatterning

    PubMed Central

    Memon, Danish; Boneschi, Filippo Martinelli; Madaghiele, Marta; Brambilla, Paola; Del Carro, Ubaldo; Taveggia, Carla; Riva, Nilo; Trimarco, Amelia; Lopez, Ignazio D.; Comi, Giancarlo; Pluchino, Stefano; Martino, Gianvito; Sannino, Alessandro; Quattrini, Angelo

    2014-01-01

    Several bioengineering approaches have been proposed for peripheral nervous system repair, with limited results and still open questions about the underlying molecular mechanisms. We assessed the biological processes that occur after the implantation of collagen scaffold with a peculiar porous microstructure of the wall in a rat sciatic nerve transection model compared to commercial collagen conduits and nerve crush injury using functional, histological and genome wide analyses. We demonstrated that within 60 days, our conduit had been completely substituted by a normal nerve. Gene expression analysis documented a precise sequential regulation of known genes involved in angiogenesis, Schwann cells/axons interactions and myelination, together with a selective modulation of key biological pathways for nerve morphogenesis induced by porous matrices. These data suggest that the scaffold’s microstructure profoundly influences cell behaviors and creates an instructive micro-environment to enhance nerve morphogenesis that can be exploited to improve recovery and understand the molecular differences between repair and regeneration. PMID:24559639

  16. Reciprocal roles between caffeine and estrogen on bone via differently regulating cAMP/PKA pathway: the possible mechanism for caffeine-induced osteoporosis in women and estrogen's antagonistic effects.

    PubMed

    Zhou, Yi; Zhu, Zhuo-Li; Guan, Xiao-Xu; Hou, Wei-Wei; Yu, Hai-Yang

    2009-07-01

    Caffeine is consumed by most people in Europe and North America. As a risk factor for osteoporosis, caffeine has been reported to decrease bone mineral density, negatively influence calcium absorption and increase the risk of bone fracture in women. Except for the epidemiological observations and several studies which proved caffeine's unfavorable effects on osteoblast proliferation and impaired ability to form bone, little mechanism is known for the caffeine-induced osteoporosis. Since our unpublished studies showed that the precursor cells of osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), were more sensitive than osteoblasts when exposed to the same dose of caffeine. We herein hypothesize that MSCs may be the primary target cells for caffeine-induced osteoporosis. It is well established that increasing cyclic 3',5'-adenosine monophosphate (cAMP) can regulate the expression of key genes involved in bone metabolism, including Cbfa1, PPARgamma, RANKL and OPG. We thereby propose the hypothesis that caffeine, a known inhibitor of cAMP phosphodiesterase, may affect bone metabolism by activating cAMP-dependent protein kinase A (PKA) pathway. In addition, considering the fact observed in epidemiology that caffeine's negative effects on bone only occurred in postmenopausal women and the inverse roles of caffeine and estrogen on bone metabolism, we postulate that caffeine may exert its undesirable influences on bone only in absence or low level of estrogen in vivo and estrogen may antagonize the adverse effect of caffeine on bone. Since several studies have demonstrated that estrogen may have ability to temper the biological effects of cAMP stimulators' roles on bone through cAMP to regulate some important genes' expression in bone metabolism. We assume that estrogen may block cAMP-dependent PKA pathway which is shared by caffeine, to exhibit its antagonistic roles. PMID:19278793

  17. Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response

    SciTech Connect

    Frericks, Markus; Burgoon, Lyle D.; Zacharewski, Timothy R.; Esser, Charlotte

    2008-10-15

    Activation of the aryl hydrocarbon receptor (AhR{sup 1}) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NF{kappa}B-Rel, HRE, PPAR{gamma}, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl{sub 2}, to induce hypoxia, or TCDD and 17-{beta}-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in the immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.

  18. Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

    PubMed Central

    van't Hof, R. J.; Armour, K. J.; Smith, L. M.; Armour, K. E.; Wei, X. Q.; Liew, F. Y.; Ralston, S. H.

    2000-01-01

    Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFκB and in NFκB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFκB in osteoclast precursors. PMID:10869429

  19. Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis.

    PubMed

    David, Valentin; Martin, Aline; Lafage-Proust, Marie-Hélène; Malaval, Luc; Peyroche, Sylvie; Jones, David B; Vico, Laurence; Guignandon, Alain

    2007-05-01

    Because a lack of mechanical information favors the development of adipocytes at the expense of osteoblasts, we hypothesized that the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent balance between osteoblasts and adipocytes is affected by mechanical stimuli. We tested the robustness of this hypothesis in in vivo rodent osteogenic exercise, in vitro cyclic loading of cancellous haversian bone samples, and cyclic stretching of primary stromal and C3H10T1/2 cells. We found that running rats exhibit a decreased marrow fat volume associated with an increased bone formation, presumably through recruitment of osteoprogenitors. In the tissue culture model and primary stromal cells, cyclic loading induced higher Runx2 and lower PPARgamma2 protein levels. Given the proadipocytic and antiosteoblastic activities of PPARgamma, we studied the effects of cyclic stretching in C3H10T1/2 cells, treated either with the PPARgamma activator, Rosiglitazone, or with GW9662, a potent antagonist of PPARgamma. We found, through both cytochemistry and analysis of lineage marker expression, that under Roziglitazone cyclic stretch partially overcomes the induction of adipogenesis and is still able to favor osteoblast differentiation. Conversely, cyclic stretch has additive effects with GW9662 in inducing osteoblastogenesis. In conclusion, we provide evidence that mechanical stimuli are potential PPARgamma modulators counteracting adipocyte differentiation and inhibition of osteoblastogenesis.

  20. Inducing Metaassociations and Induced Relationships

    NASA Astrophysics Data System (ADS)

    Burgués, Xavier; Franch, Xavier; Ribó, Josep M.

    In the last years, UML has been tailored to be used as a domain-specific modelling notation in several contexts. Extending UML with this purpose entails several advantages: the integration of the domain in a standard framework; its potential usage by the software engineering community; and the existence of supporting tools. In previous work, we explored one particular issue of heavyweight extensions, namely, the definition of inducing meta-associations in metamodels as a way to induce the presence of specific relation-ships in their instances. Those relationships were intended by the metamodel specifier but not forced by the metamodel itself. However, our work was restricted to the case of induced associations. This paper proposes an extension to the general case in which inducing metaassociations may force the existence of arbitrary relationships at M1. To attain this goal, we provide a general defini-tion of inducing metaassociation that covers all the possible cases. After revisi-ting induced associations, we show the inducement of the other relationship types defined in UML: association classes, generalization and dependencies.

  1. Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents.

    PubMed

    Xiong, Xishan; Wang, Li; Ye, Yangliang; Fu, Lili; Chen, Minli; Wang, Qingyi; Liu, Moyan; Tang, Jing; Dai, Bing; Shen, Jianhua; Mei, Changlin

    2010-08-01

    Numerous studies have documented that various naturally derived ligands or synthetic non-thiazolidinediones (TZD) as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown moderate or potent antitumor activities, which is PPARgamma independent or partially dependent. However, the PPARgamma agonistic or glucose-lowering activity is ranked first more often than antitumor activity to determine promising novel PPARgamma agonists for potential clinical use. In this study, we hypothesized that there might exist some compounds with less PPARgamma agonistic activity but potent antitumor activity. Thereafter, we evaluated the PPARgamma agonistic and antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives synthesized with the initial aim of developing novel PPARgamma agonists as hypoglycemic agents. MTT assay results revealed that several compounds were able to inhibit cell proliferation in a dose-dependent manner with IC(50) 12.7-29.7 microM, better than that of rosiglitazone (45.9-141 microM), although the PPARgamma agonistic activity of most compounds is much lower than rosiglitazone. Some compounds induced cell cycle arrest and apoptosis tested by Flow Cytometry. Oral administration of DH9 (100 mg/kg/d) for 21 days to BALB/c nude mice bearing xenografts including MGC-803, NCI-H460, HT-29 and OS-RC-2 cells significantly retarded tumor growth. DG8 and DJ5 showed benefits in some of the above four xenografts. Our findings demonstrate that these compounds have potent antitumor activity in vitro and in vivo and pyrimidinyl-arylpropionic acid derivatives might be viable resources in the development of new antineoplastic agents.

  2. A Resource Manual for the Development and Evaluation of Special Programs for Exceptional Students. Volume III-J: Interagency Service Plans for the Profoundly Mentally Handicapped. Part 3: Partners in Planning--A Participant's Manual, July 1, 1981-June 30, 1983.

    ERIC Educational Resources Information Center

    Leon County Schools, Tallahassee, FL.

    The manual, part of a series on serving Florida's profoundly mentally handicapped (PMH) students through interagency coordination, presents a set of materials for self paced study. Each of four modules includes a pretest, a self-check exercise, a posttest, and questions that ask participants to apply information presented to their local…

  3. Modelling flow-induced crystallisation in polymers.

    PubMed

    Graham, Richard S

    2014-04-01

    Flow profoundly influences the crystallisation kinetics and morphology of polymeric materials. By distorting the configuration of polymer chains, flow breaks down the kinetic barriers to crystallisation and directs the resulting crystallisation. This flow-induced crystallisation (FIC) in polymers is a fascinating, externally driven, non-equilibrium phase transition, which is controlled by kinetics. Furthermore, the effect is of central importance to the polymer industry as crystallisation determines virtually all of the useful properties of semi-crystalline polymer products. However, simulating flow-induced crystallisation in polymers is notoriously difficult due to the very wide spread of length and timescales, especially as the most pronounced flow-induced effects occur for long chains at low undercooling. In this article I will discuss multiscale modelling techniques for polymer FIC. In particular, I will review recent attempts to connect modelling approaches across different levels of coarse-graining. This has the ultimate aim of passing insight from the most detailed simulation techniques to more tractable approaches intended to model polymer processing. I will discuss the exciting prospects for future work in this area.

  4. Inhibition of thermal induced protein denaturation of extract/fractions of Withania somnifera and isolated withanolides.

    PubMed

    Khan, Murad Ali; Khan, Haroon; Rauf, Abdul; Ben Hadda, Taibi

    2015-01-01

    This study describes the in vitro inhibition of protein denaturation of extract/fractions of Withania somnifera and isolated withanolides including 20β hydroxy-1-oxo(22R)-witha-2,5,24 trienolide (1), (20R,22R-14α,20α)-dihydroxy-1-oxowitha-2,5,16,24 tetraenolide (2). The results showed that the extract/fractions of the plant evoked profound inhibitory effect on thermal-induced protein denaturation. The chloroform fraction caused the most dominant attenuation of 68% at 500 μg/mL. The bioactivity-guided isolation from chloroform fraction led to the isolation of compounds 1 and 2 that showed profound protein inhibition with 78.05% and 80.43% effect at 500 μg/mL and thus strongly complimented the activity of extract/fractions. In conclusion, extract/fractions of W. somnifera possessed strong inhibition of protein denaturation that can be attributed to these isolated withanolides.

  5. Ascofuranone stimulates expression of adiponectin and peroxisome proliferator activated receptor through the modulation of mitogen activated protein kinase family members in 3T3-L1, murine pre-adipocyte cell line

    SciTech Connect

    Chang, Young-Chae; Cho, Hyun-Ji

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Ascofuranone increases expression of adiponectin and PPAR{gamma}. Black-Right-Pointing-Pointer Inhibitors for MEK and JNK increased the expression of adiponectin and PPAR{gamma}. Black-Right-Pointing-Pointer Ascofuranone significantly suppressed phosho-ERK, while increasing phospho-p38. -- Abstract: Ascofuranone, an isoprenoid antibiotic, was originally isolated as a hypolipidemic substance from a culture broth of the phytopathogenic fungus, Ascochyta visiae. Adiponectin is mainly synthesized by adipocytes. It relieves insulin resistance by decreasing the plasma triglycerides and improving glucose uptake, and has anti-atherogenic properties. Here, we found that ascofuranone increases expression of adiponectin and PPAR{gamma}, a major transcription factor for adiponectin, in 3T3-L1, murine pre-adipocytes cell line, without promoting accumulation of lipid droplets. Ascofuranone induced expression of adiponectin, and increases the promoter activity of adiponectin and PPRE, PPAR response element, as comparably as a PPAR{gamma} agonist, rosiglitazone, that stimulates lipid accumulation in the preadipocyte cell line. Moreover, inhibitors for MEK and JNK, like ascofuranone, considerably increased the expression of adiponectin and PPAR{gamma}, while a p38 inhibitor significantly suppressed. Ascofuranone significantly suppressed ERK phosphorylation, while increasing p38 phosphorylation, during adipocyte differentiation program. These results suggest that ascofuranone regulates the expression of adiponectin and PPAR{gamma} through the modulation of MAP kinase family members.

  6. Quinine-induced thrombocytopenia following intravenous use of heroin

    SciTech Connect

    Christie, D.J.; Walker, R.H.; Kolins, M.D.; Wilner, F.M.; Aster, R.H.

    1983-06-01

    Profound thrombocytopenia developed in a 22-year-old man after intravenous use of heroin. A high-titer, quinine-dependent, platelet-specific antibody was detected in his serum using lysis of normal platelets labeled with chromium 51 and an electroimmunoassay for measurement of platelet-associated IgG. The antibody was specific for quinine and failed to react with platelets in the presence of quinidine hydrochloride or two structural analogues of heroin. Quinine, a common adulterant found in heroin, was detected in the patient's blood and urine. On the basis of these observations, the patient was judged to have quinine-induced immunologic thrombocytopenia. To our knowledge, this report is the first to confirm that quinine used as an adulterant can induce immunologic thrombocytopenia following an injection of heroin.

  7. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

    DOE PAGES

    Ye, Tianyu; Liu, Han -Chun; Wang, Zhuo; Wegscheider, W.; Mani, Ramesh G.

    2015-10-09

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. As a result, for circularly polarized radiation, the oscillatory magnetoresistive response ismore » hardly sensitive to θ.« less

  8. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

    SciTech Connect

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Masuelli, Laura; Marchese, Rodolfo; Misiti, Silvia; De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo; Stigliano, Antonio

    2011-06-10

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  9. Observed and modeled multi-year evaporation from three field-scale experiments using water balance and Penman-Monteith methods: Profound effect of material type and wind exposure

    NASA Astrophysics Data System (ADS)

    Peterson, H. E.; Fretz, N.; Bay, D.; Mayer, K. U.; Smith, L.; Beckie, R. D.

    2013-12-01

    2, and greatly overestimated observed evaporation for Pile 3. The depth of the soil layer which is susceptible to evaporation, Ze, was calibrated from the base-case value of Ze= 0.10 m to values of Ze= 0.27 m (Pile 1), Ze= 0.05 m (Pile 2), and Ze= 0.02 m (Pile 3) to provide a good fit with observed evaporation. It is hypothesized that the Pile 3 calibration of Ze = 0.02 m is less physically realistic than accounting for preferential flow directly. A possible approach would be to modify the FAO-PM formulation by including a coefficient of preferential flow, KPF, on days that exceed a specified threshold daily precipitation, Pi,TH. The results highlight the profound effect of material type on evaporation from waste rock. Fine-grained, relatively homogeneous materials tend to follow traditional evaporation patterns both on the crowns and slopes of waste rock piles. Coarser-grained and more heterogeneous waste rock can have higher or lower evaporation than expected.

  10. How is the AIE mechanism profoundly changed in an ESIPT family: the novel introduction of a tetraphenylethene group onto (Z)-3-(quinolin-2-ylmethylene)-3,4-dihydroquinoxalin-2(1H)-one.

    PubMed

    Wu, Ding-Er; Yao, Qi-Chao; Xia, Min

    2015-02-01

    It is reported that two derivatives of (Z)-3-(quinolin-2-ylmethylene)-3,4-dihydroquinoxalin-2-(1H)-one (1) with a tetraphenylethene (TPE) group introduced at amide N atom of the dihydroquinoxalinone moiety (2) or at phenyl ring of the quinoline fragment (3) are synthesized, and the derivatives exhibit a remarkably enhanced aggregation-induced emission (AIE) activity than the parent. Although both the parent and the derivatives have the characteristic of an excited state intramolecular proton transfer (ESIPT), the AIE mechanism of 2 and 3 is totally different from that of 1. The considerably stronger emission of 3 than that of 2 should be attributed to the unique crystallization-induced emission enhancement (CIEE) effect.

  11. Exercise-Induced Bronchoconstriction

    MedlinePlus

    ... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

  12. Inducing puberty.

    PubMed

    Delemarre, Eveline M; Felius, Bram; Delemarre-van de Waal, Henriette A

    2008-12-01

    Puberty is the result of increasing pulsatile secretion of the hypothalamic gonadotropin releasing hormone (GnRH), which stimulates the release of gonadotropins and in turn gonadal activity. In general in females, development of secondary sex characteristics due to the activity of the gonadal axis, i.e., the growth of breasts, is the result of exposure to estrogens, while in boys testicular growth is dependent on gonadotropins and virilization on androgens. Hypogonadotropic hypogonadism is a rare disease. More common is the clinical picture of delayed puberty, often associated with a delay of growth and more often familial occurring. Especially, boys are referred because of the delay of growth and puberty. A short course (3-6 months) of androgens may help these boys to overcome the psychosocial repercussions, and during this period an increase in the velocity of height growth and some virilization will occur. Hypogonadotropic hypogonadism may present in a congenital form caused by developmental disorders, some of which are related to a genetic disorder, or secondary to hypothalamic-pituitary dysfunction due to, among others, a cerebral tumor. In hypogonadotropic hypogonadism puberty can be initiated by the use of pulsatile GnRH, gonadotropins, and sex steroids. Sex steroids will induce development of the secondary sex characteristics alone, while combined administration of gonadotropins and GnRH may induce gonadal development including fertility.

  13. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells.

    PubMed

    Sozio, Margaret S; Lu, Changyue; Zeng, Yan; Liangpunsakul, Suthat; Crabb, David W

    2011-10-01

    AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR-α and PPAR-γ expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-α activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-γ were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-γ activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-α (RAR-α), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-α binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-α subunits. Expression of either a constitutively active or dominant negative AMPK-α inhibited basal and WY-14,643-stimulated PPAR-α activity and basal and rosiglitazone-stimulated PPAR-γ activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to rely on the activated conformation of AMPK. AMPK inhibition of PPAR-α and -γ may allow for short-term processes to increase energy generation before the cells devote resources to increasing their capacity for fatty acid oxidation.

  14. PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.

    PubMed

    Yousefi, B; Shafiei-Irannejad, V; Azimi, A; Samadi, N; Zarghami, N

    2016-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment. PMID:27545215

  15. Constraining X-ray-Induced Photoevaporation of Protoplanetary Disks Orbiting Low-Mass Stars

    NASA Astrophysics Data System (ADS)

    Punzi, Kristina M.; Kastner, Joel H.; Rodriguez, David; Principe, David A.; Vican, Laura

    2016-01-01

    Low-mass, pre-main sequence stars possess intense high-energy radiation fields as a result of their strong stellar magnetic activity. This stellar UV and X-ray radiation may have a profound impact on the lifetimes of protoplanetary disks. We aim to constrain the X-ray-induced photoevaporation rates of protoplanetary disks orbiting low-mass stars by analyzing serendipitous XMM-Newton and Chandra X-ray observations of candidate nearby (D < 100 pc), young (age < 100 Myr) M stars identified in the GALEX Nearby Young-Star Survey (GALNYSS).

  16. Hypokalemia-Induced Rhabdomyolysis by Primary Aldosteronism Coexistent With Sporadic Inclusion Body Myositis.

    PubMed

    Lee, Jong Ha; Kim, Eunkuk; Chon, Suk

    2015-10-01

    We describes a patient with hypokalemia-induced rhabdomyolysis due to primary aldosteronism (PA), who suffered from slowly progressive muscle weakness after laparoscopic adrenalectomy, and was later diagnosed with coexisting sporadic inclusion body myositis (sIBM). A 54-year-old Asian male presented with severe muscle weakness of both lower extremities. Laboratory findings showed profound hypokalemia, and extreme elevation of the serum creatine phosphokinase levels, suggestive of hypokalemia-induced rhabdomyolysis. Further evaluation strongly suggested PA by an aldosterone-producing adenoma, which was successfully removed surgically. However, muscle weakness slowly progressed one year after the operation and a muscle biopsy demonstrated findings consistent with sIBM. This case is the first report of hypokalemia-induced rhabdomyolysis by PA coexistent with sIBM, to the best of our knowledge.

  17. Defective virus is associated with induction of murine retrovirus-induced immunodeficiency syndrome.

    PubMed Central

    Chattopadhyay, S K; Morse, H C; Makino, M; Ruscetti, S K; Hartley, J W

    1989-01-01

    C57BL/6 mice infected with a mixture of murine leukemia viruses (MuLV) develop a syndrome characterized by lymphoproliferation and profound immunodeficiency. Analyses of this viral mixture (LP-BM5 MuLV) showed that it includes replication-competent ecotropic and mink cell focus-inducing MuLV and defective viruses with genome sizes of 3.8-6.5 kilobases. The ecotropic and mink cell focus-inducing MuLV biologically cloned from the mixture did not induce disease, whereas viral preparations containing the ecotropic MuLV and 4.8-kilobase defective virus were active. Cells producing the 4.8-kilobase defective virus expressed an unusual gag-encoded polyprotein of Mr 60,000. Images PMID:2542949

  18. Genetic background influences loss of heterozygosity patterns in radiation-induced mouse thymic lymphoma

    PubMed Central

    Hang, Michael; Huang, Yurong; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Previous studies have revealed that p53 heterozygous (p53+/−) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/− 129/Sv mice with genetically diverse strains to generate p53+/− F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/− mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers. PMID:25932465

  19. [Induced "acarophobia"].

    PubMed

    Mester, H

    1975-01-01

    Although only ablut 240 cases of 'acarophobia' are on record in zoological and medical literature, it can be seen that this delusional syndrome without doubt leads to psychoses of association more frequently than any other mental disturbance. The literature contains many references, and the author can give two examples from personal esperience. At least every sixth patient suffering from delusions of parasitosis 'infects' relations. This really remarkable tendency to spread by psychological contagion on one or more dependent persons has been ignored by many writers. The supposition that such occurrences are very rare proves to be false. Sometimes the associated who acquired the symptons in an absolutely identical fashion seem to be more worried by the vermin they hallucinate than the initiators are. The number of patients constituting an affected group is following a Neyman distribution. Emphasis is laid on the finding that the proportion of consanguineous persons within the sample of patients who showed an induced delusion of parasitosis is by far less high than in other psychopathological forms of communicated insanity.

  20. Morphine-induced cognitive impairment is attenuated by induced pain in rats.

    PubMed

    Baiamonte, Brandon A; Lee, Franklin A; Gould, Harry J; Soignier, R Denis

    2013-08-01

    Opioid medications are frequently used in the effective treatment of intractable pain, but prolonged use of such medications can be complicated by a host of adverse effects. Among these adverse effects, tolerance and mental clouding can be especially disabling and can lead to both a reduced effectiveness of treatment and a reduced quality of life for many requiring treatment with these medications. Here we examined the relative contributions of complete Freund's adjuvant (CFA)-induced inflammatory pain and opioid medication on spatial memory for a well-learned task in male Sprague-Dawley rats. Although CFA, by itself, had little effect on spatial memory, morphine administered to pain-free animals produced profound detrimental effects on spatial memory that persisted longer than the analgesic effectiveness of the drug. However, no significant cognitive deficits were observed in animals receiving morphine in the presence of CFA-induced pain. Taken together, these results are evidence that the pain state of the organism can alter some of the negative effects of morphine.

  1. Radiation-induced brain injury: A review

    PubMed Central

    Greene-Schloesser, Dana; Robbins, Mike E.; Peiffer, Ann M.; Shaw, Edward G.; Wheeler, Kenneth T.; Chan, Michael D.

    2012-01-01

    Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their

  2. Food protein-induced enterocolitis syndrome from the parent perspective

    PubMed Central

    Schultz, Fallon; Westcott-Chavez, Amity

    2014-01-01

    Purpose of review To describe the obstacles that parents face when caring for a child with food protein-induced enterocolitis syndrome (FPIES) and discuss initiatives of key importance to the FPIES community. Recent findings Findings from a previous survey indicate that 80% of pediatricians have little or no knowledge of FPIES, suggesting that awareness is severely lacking among frontline providers. A preliminary study also indicates that the condition can have a profound effect on quality of life for patients and families. Summary FPIES is a rare but growing condition that poses significant personal and familial challenges for parents before and after diagnosis. Increased efforts from the medical community are needed to raise awareness among medical providers, establish improved criteria and guidelines for diagnosis and management, increase understanding through research, and offer parent information and support at every stage. PMID:24732296

  3. Aneuploidy-induced cellular stresses limit autophagic degradation

    PubMed Central

    Santaguida, Stefano; Vasile, Eliza; White, Eileen; Amon, Angelika

    2015-01-01

    An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Aneuploid cells experience a number of stresses that are caused by aneuploidy-induced proteomic changes. How the aneuploidy-associated stresses affect cells and whether cells respond to them are only beginning to be understood. Here we show that autophagosomal cargo such as protein aggregates accumulate within lysosomes in aneuploid cells. This causes a lysosomal stress response. Aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. Accumulation of autophagic cargo within the lysosome and activation of TFEB-responsive genes are also observed in cells in which proteasome function is inhibited, suggesting that proteotoxic stress causes TFEB activation. Our results reveal a TFEB-mediated lysosomal stress response as a universal feature of the aneuploid state. PMID:26404941

  4. Peroxisome-proliferator-activated receptor-{gamma} agonists inhibit the release of proinflammatory cytokines from RSV-infected epithelial cells

    SciTech Connect

    Arnold, Ralf . E-mail: ralf.arnold@medizin.uni-magdeburg.de; Koenig, Wolfgang

    2006-03-15

    The epithelial cells of the airways are the target cells for respiratory syncytial virus (RSV) infection and the site of the majority of the inflammation associated with the disease. Recently, peroxisome-proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we investigated the role of PPAR{gamma} agonists (15d-PGJ{sub 2}, ciglitazone and troglitazone) on the synthesis of RSV-induced cytokine release from RSV-infected human lung epithelial cells (A549). We observed that all PPAR{gamma} ligands inhibited dose-dependently the release of TNF-{alpha}, GM-CSF, IL-1{alpha}, IL-6 and the chemokines CXCL8 (IL-8) and CCL5 (RANTES) from RSV-infected A549 cells. Concomitantly, the PPAR{gamma} ligands diminished the cellular amount of mRNA encoding for IL-6, CXCL8 and CCL5 and the RSV-induced binding activity of the transcription factors NF-{kappa}B (p65/p50) and AP-1 (c-fos), respectively. Our data presented herein suggest a potential application of PPAR{gamma} ligands in the anti-inflammatory treatment of RSV infection.

  5. Coral calcium hydride prevents hepatic steatosis in high fat diet-induced obese rats: A potent mitochondrial nutrient and phase II enzyme inducer.

    PubMed

    Hou, Chen; Wang, Yongyao; Zhu, Erkang; Yan, Chunhong; Zhao, Lin; Wang, Xiaojie; Qiu, Yingfeng; Shen, Hui; Sun, Xuejun; Feng, Zhihui; Liu, Jiankang; Long, Jiangang

    2016-03-01

    Diet-induced nonalcoholic fatty liver disease (NAFLD) is characterized by profound lipid accumulation and associated with an inflammatory response, oxidative stress and hepatic mitochondrial dysfunction. We previously demonstrated that some mitochondrial nutrients effectively ameliorated high fat diet (HFD)-induced hepatic steatosis and metabolic disorders. Molecular hydrogen in hydrogen-rich liquid or inhaling gas, which has been confirmed in scavenging reactive oxygen species and preventing mitochondrial decay, improved metabolic syndrome in patients and animal models. Coral calcium hydride (CCH) is a new solid molecular hydrogen carrier made of coral calcium. However, whether and how CCH impacts HFD-induced hepatic steatosis remains uninvestigated. In the present study, we applied CCH to a HFD-induced NAFLD rat model for 13 weeks. We found that CCH durably generated hydrogen in vivo and in vitro. CCH treatment significantly reduced body weight gain, improved glucose and lipid metabolism and attenuated hepatic steatosis in HFD-induced obese rats with no influence on food and water intake. Moreover, CCH effectively improved HFD-induced hepatic mitochondrial dysfunction, reduced oxidative stress, and activated phase II enzymes. Our results suggest that CCH is an efficient hydrogen-rich agent, which could prevent HFD-induced NAFLD via activating phase II enzymes and improving mitochondrial function. PMID:26774456

  6. Heme oxygenase-1 alleviates cigarette smoke-induced restenosis after vascular angioplasty by attenuating inflammation in rat model.

    PubMed

    Ni, Leng; Wang, Zhanqi; Yang, Genhuan; Li, Tianjia; Liu, Xinnong; Liu, Changwei

    2016-03-14

    Cigarette smoke is not only a profound independent risk factor of atherosclerosis, but also aggravates restenosis after vascular angioplasty. Heme oxygenase-1 (HO-1) is an endogenous antioxidant and cytoprotective enzyme. In this study, we investigated whether HO-1 upregulating by hemin, a potent HO-1 inducer, can protect against cigarette smoke-induced restenosis in rat's carotid arteries after balloon injury. Results showed that cigarette smoke exposure aggravated stenosis of the lumen, promoted infiltration of inflammatory cells, and induced expression of inflammatory cytokines and adhesion molecules after balloon-induced carotid artery injury. HO-1 upregulating by hemin treatment reduced these effects of cigarette smoke, whereas the beneficial effects were abolished in the presence of Zincprotoporphyrin IX, an HO-1 inhibitor. To conclude, hemin has potential therapeutic applications in the restenosis prevention after the smokers' vascular angioplasty.

  7. The mitochondrial H(+)-ATP synthase and the lipogenic switch: new core components of metabolic reprogramming in induced pluripotent stem (iPS) cells.

    PubMed

    Vazquez-Martin, Alejandro; Corominas-Faja, Bruna; Cufi, Sílvia; Vellon, Luciano; Oliveras-Ferraros, Cristina; Menendez, Octavio J; Joven, Jorge; Lupu, Ruth; Menendez, Javier A

    2013-01-15

    Induced pluripotent stem (iPS) cells share some basic properties, such as self-renewal and pluripotency, with cancer cells, and they also appear to share several metabolic alterations that are commonly observed in human tumors. The cancer cells' glycolytic phenotype, first reported by Otto Warburg, is necessary for the optimal routing of somatic cells to pluripotency. However, how iPS cells establish a Warburg-like metabolic phenotype and whether the metabolic pathways that support the bioenergetics of iPS cells are produced by the same mechanisms that are selected during the tumorigenic process remain largely unexplored. We recently investigated whether the reprogramming-competent metabotype of iPS cells involves changes in the activation/expression status of the H(+)-ATPase, which is a core component of mitochondrial oxidative phosphorylation that is repressed at both the activity and protein levels in human carcinomas, and of the lipogenic switch, which refers to a marked overexpression and hyperactivity of the acetyl-CoA carboxylase (ACACA) and fatty acid synthase (FASN) lipogenic enzymes that has been observed in nearly all examined cancer types. A comparison of a starting population of mouse embryonic fibroblasts and their iPS cell progeny revealed that somatic cell reprogramming involves a significant increase in the expression of ATPase inhibitor factor 1 (IF1), accompanied by extremely low expression levels of the catalytic β-F1-ATPase subunit. The pharmacological inhibition of ACACA and FASN activities markedly decreases reprogramming efficiency, and ACACA and FASN expression are notably upregulated in iPS cells. Importantly, iPS cells exhibited a significant intracellular accumulation of neutral lipid bodies; however, these bodies may be a reflection of intense lysosomal/autophagocytic activity rather than bona fide lipid droplet formation in iPS cells, as they were largely unresponsive to pharmacological modulation of PPARgamma and FASN activities. The

  8. Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.

    PubMed

    Dennis, Siobhan H; Pasqui, Francesca; Colvin, Ellen M; Sanger, Helen; Mogg, Adrian J; Felder, Christian C; Broad, Lisa M; Fitzjohn, Steve M; Isaac, John T R; Mellor, Jack R

    2016-01-01

    Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans. PMID:26472558

  9. Cross-species malaria immunity induced by chemically attenuated parasites

    PubMed Central

    Good, Michael F.; Reiman, Jennifer M.; Rodriguez, I. Bibiana; Ito, Koichi; Yanow, Stephanie K.; El-Deeb, Ibrahim M.; Batzloff, Michael R.; Stanisic, Danielle I.; Engwerda, Christian; Spithill, Terry; Hoffman, Stephen L.; Lee, Moses; McPhun, Virginia

    2013-01-01

    Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with seco-cyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4+ T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species. PMID:23863622

  10. Dimensional transformation of defect-induced noise, dissipation, and nonlinearity

    NASA Astrophysics Data System (ADS)

    Behunin, R. O.; Intravaia, F.; Rakich, P. T.

    2016-06-01

    In recent years, material-induced noise arising from defects has emerged as an impediment to quantum-limited measurement in systems ranging from microwave qubits to gravity-wave interferometers. As experimental systems push to ever smaller dimensions, extrinsic system properties can affect its internal material dynamics. In this paper, we identify intriguing regimes of material physics (defect-phonon and defect-defect dynamics) that are produced by dimensional confinement. Our models show that a range of tell-tale signatures, encoded in the characteristics of defect-induced noise, dissipation, and nonlinearity, are profoundly altered by geometry. Building on this insight, we demonstrate that the magnitude and character of this material-induced noise is transformed in microscale systems, providing an opportunity to improve the fidelity of quantum measurements. Moreover, we show that many emerging nanoelectromechanical, cavity optomechanical, and superconducting resonator systems are poised to probe these regimes of dynamics, in both high- and low-field limits, providing a way to explore the fundamental tenets of glass physics.

  11. Protective effect of taurine on the light-induced disruption of isolated frog rod outer segments

    SciTech Connect

    Pasantes-Morales, H.; Ademe, R.M.; Quesada, O.

    1981-01-01

    Isolated frog rod outer segments (ROS) incubated in a Krebs-bicarbonate medium, and illuminated for 2 h, show a profound alteration in their structure. This is characterized by distention of discs, vesiculation, and a marked swelling. The light-induced ROS disruption requires the presence of bicarbonate and sodium chloride. Replacement of bicarbonate by TRIS or HEPES protects ROS structure. Also, substitution of sodium chloride by sucrose or choline chloride maintains unaltered the ROS structure. Deletion of calcium, magnesium, or phosphate does not modify the effect produced by illumination. An increased accumulation of labeled bicarbonate and tritiated water is observed in illuminated ROS, as compared with controls in the dark. The presence of taurine, GABA, or glycine, at concentrations of 5-25 mM, effectively counteracts the light-induced ROS disruption. Taurine (25 mM) reduces labeled bicarbonate and tritiated water levels to those observed in the dark incubated ROS.

  12. Herpes simplex virus 1 induces egress channels through marginalized host chromatin.

    PubMed

    Myllys, Markko; Ruokolainen, Visa; Aho, Vesa; Smith, Elizabeth A; Hakanen, Satu; Peri, Piritta; Salvetti, Anna; Timonen, Jussi; Hukkanen, Veijo; Larabell, Carolyn A; Vihinen-Ranta, Maija

    2016-01-01

    Lytic infection with herpes simplex virus type 1 (HSV-1) induces profound modification of the cell nucleus including formation of a viral replication compartment and chromatin marginalization into the nuclear periphery. We used three-dimensional soft X-ray tomography, combined with cryogenic fluorescence, confocal and electron microscopy, to analyse the transformation of peripheral chromatin during HSV-1 infection. Our data showed an increased presence of low-density gaps in the marginalized chromatin at late infection. Advanced data analysis indicated the formation of virus-nucleocapsid-sized (or wider) channels extending through the compacted chromatin of the host. Importantly, confocal and electron microscopy analysis showed that these gaps frequently contained viral nucleocapsids. These results demonstrated that HSV-1 infection induces the formation of channels penetrating the compacted layer of cellular chromatin and allowing for the passage of progeny viruses to the nuclear envelope, their site of nuclear egress. PMID:27349677

  13. Quasi-static elastography and its application in investigation of focused ultrasound induced tissue lesions

    NASA Astrophysics Data System (ADS)

    Wang, Bin; Ling, Tao; Shen, Yong; Wang, Yan; Zheng, Hairong; Li, Faqi

    2012-10-01

    Monitoring of Focused Ultrasound (FUS) therapy has always been a key factor for a successful therapy. Although B-mode ultrasound has long been used for monitoring FUS therapy, the gray scale changes can not precisely reflect the lesion formation inside the tissue, while MR thermometry is considered to be too expensive. In this study, elastography had been performed using a commercial ultrasound system to investigate lesions produced by FUS irradiation in vitro. Several motion detection algorithms had been performed to improve the motion detection accuracy in the elastography. The effects of different algorithms on the motion detection accuracy were compared. Experimental results on the FUS induced lesion in swine muscle were introduced. The results indicated that lesions induced by small dosage of FUS inside the tissue can be successfully detected, which has a profound clinical meaning for the monitoring of FUS therapy.

  14. Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma.

    PubMed

    Mastropasqua, Leonardo; Agnifili, Luca; Mastropasqua, Rodolfo; Fasanella, Vincenzo

    2013-02-01

    Lowering intra-ocular pressure, either medically or surgically, is the proven strategy to control glaucoma, though profound changes to the ocular surface and conjunctiva are caused. Toxicity and allergy initiated by medical therapy induce modifications, which progressively worsen with the length of treatment and number of drugs. Conjunctival changes lead to symptoms of ocular surface disease, reduced quality of life, reduced therapeutic compliance and increased risk of surgical failure. Surgery modifies conjunctiva by inducing bleb formation in fistulizing techniques, and by activating secondary aqueous humour outflow pathways, such as trans-scleral routes, in both filtration and bleb-less approaches. The use of unpreserved medications, limitation of intra-operative conjunctival damage and development of bleb-less surgery are advisable.

  15. Bioactive substance from Grifola frondosa (maitake) mushroom inhibits CCAAT enhancer binding protein beta and delta expression on C3H10T1/2 B2C1 adipocyte cells.

    PubMed

    Minamino, Katsuhiko; Yanaga, Yuri; Ohtsuru, Masaru

    2008-06-01

    Bioactive compound substances from Grifola frondosa (maitake) inhibited adipocyte differentiation of B(2)C(1) preadipocytes. This compound is not related to MAP kinase (ERK1 and ERK2) cascades or beta-catenin, which inhibit the expression of Glut4, PPARgamma and C/EBPalpha. The compound reduced the expression time of C/EBPbeta and C/EBPdelta. These results suggest that the inhibitory action of these bioactive compounds on adipocyte differentiation is exhibited through preadipocytes. They cannot induce the expression of PPARgamma or C/EBPalpha because of the reduced expression time of C/EBPbeta and C/EBPdelta. PMID:18635913

  16. Antibodies Are Required for Complete Vaccine-Induced Protection against Herpes Simplex Virus 2

    PubMed Central

    Halford, William P.; Geltz, Joshua; Messer, Ronald J.; Hasenkrug, Kim J.

    2015-01-01

    Herpes simplex virus 2 (HSV-2) 0ΔNLS is a live HSV-2 ICP0- mutant vaccine strain that is profoundly attenuated in vivo due to its interferon-hypersensitivity. Recipients of the HSV-2 0ΔNLS vaccine are resistant to high-dose HSV-2 challenge as evidenced by profound reductions in challenge virus spread, shedding, disease and mortality. In the current study, we investigated the requirements for HSV-2 0ΔNLS vaccine-induced protection. Studies using (UV)-inactivated HSV-2 0ΔNLS revealed that self-limited replication of the attenuated virus was required for effective protection from vaginal or ocular HSV-2 challenge. Diminished antibody responses in recipients of the UV-killed HSV-2 vaccine suggested that antibodies might be playing a critical role in early protection. This hypothesis was investigated in B-cell-deficient μMT mice. Vaccination with live HSV-2 0ΔNLS induced equivalent CD8+ T cell responses in wild-type and μMT mice. Vaccinated μMT mice shed ~40-fold more infectious HSV-2 at 24 hours post-challenge relative to vaccinated wild-type (B-cell+) mice, and most vaccinated μMT mice eventually succumbed to a slowly progressing HSV-2 challenge. Importantly, passive transfer of HSV-2 antiserum restored full protection to HSV-2 0ΔNLS-vaccinated μMT mice. The results demonstrate that B cells are required for complete vaccine-induced protection against HSV-2, and indicate that virus-specific antibodies are the dominant mediators of early vaccine-induced protection against HSV-2. PMID:26670699

  17. mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.

    PubMed

    Jin, Zhe-Zhu; Wang, Wei; Fang, Di-Long; Jin, Yong-Jun

    2016-09-30

    We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells. PMID:27565731

  18. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    SciTech Connect

    Mitterberger, Maria C.; Kim, Geumsoo; Rostek, Ursula; Levine, Rodney L.; Zwerschke, Werner

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.

  19. Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81).

    PubMed

    Jeninga, Ellen H; Bugge, Anne; Nielsen, Ronni; Kersten, Sander; Hamers, Nicole; Dani, Christian; Wabitsch, Martin; Berger, Ruud; Stunnenberg, Hendrik G; Mandrup, Susanne; Kalkhoven, Eric

    2009-09-25

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPARgamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPARgamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPARgamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPARgamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR:retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPARgamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.

  20. [Heparin-induced thrombocytopenia].

    PubMed

    Franchini, Massimo; Veneri, Dino

    2005-09-01

    Heparin-induced thrombocytopenia is a serious and underestimated adverse drug effect. We briefly discuss the main features of heparin-induced thrombocytopenia, particularly analyzing the most recent advances in the pathophysiology, diagnosis and treatment of this syndrome.