text:
, Volume 7, Issue 4, pp 399-443
First online:
Information, learning, and drug diffusion: The case of Cox-2 inhibitors
- Pradeep K. ChintaguntaAffiliated withBooth School of Business, University of Chicago
- , Renna JiangAffiliated withGraduate School of Management, University of California at Davis Email author
- , Ginger Z. JinAffiliated withDepartment of Economics, University of MarylandNBER
The recent withdrawal of Cox-2 Inhibitors has generated debate on the role of information in drug diffusion: can the market learn the efficacy of new drugs, or does it depend solely on manufacturer advertising and FDA updates? In this study, we use a novel data set to study the role of learning in the diffusion of three Cox-2 Inhibitors—Celebrex, Vioxx and Bextra—before the Vioxx withdrawal. Our study has two unique features: first, we observe each patient's reported satisfaction after consuming a drug. This patient level data set, together with market level data on FDA updates, media coverage, academic articles, and pharmaceutical advertising, allows us to model individual prescription decisions. Second, we distinguish across-patient learning of a drug's general efficacy from the within-patient learning of the match between a drug and a patient. Our results suggest that prescription choice is sensitive to many sources of information. At the beginning of 2001 and upon Bextra entry in January 2002, doctors held a strong prior belief about the efficacy of Celebrex, Vioxx, and Bextra. As a result, the learning from patient satisfaction is gradual and more concentrated on drug-patient match than on across-patient spillovers. News articles are weakly beneficial for Cox-2 drug sales, but academic articles appear to be detrimental. The impact of FDA updates is close to zero once we control for academic articles, which suggests that FDA updates follow academic articles and therefore deliver little new information to doctors. Two counterfactual experiments are carried out to quantify the influence of information on market shares.
KeywordsLearning Drug diffusion Prescription choice Patient satisfaction
JEL ClassificationsD8 I1 M3 C5
Reference tools
- Title
- Information, learning, and drug diffusion: The case of Cox-2 inhibitors
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Journal
Volume 7, Issue 4 , pp 399-443
- Cover Date
- 2009-12
- 10.1007/s11129-009-9072-1
- Print ISSN
- 1570-7156
- Online ISSN
- Publisher
- Springer US
- Additional Links
- Topics
- Keywords
- Learning
- Drug diffusion
- Prescription choice
- Patient satisfaction
- Industry Sectors
- Authors
- Pradeep K. Chintagunta (1)
- Renna Jiang (2)
- Ginger Z. Jin (3) (4)
- Author Affiliations
- 1. Booth School of Business, University of Chicago, Chicago, IL, USA
- 2. Graduate School of Management, University of California at Davis, Davis, CA, USA
- 3. Department of Economics, University of Maryland, College Park, MD, USA
- 4. NBER, Cambridge, MA, USA


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Sunday, March 31, 2013Wisconsin
Great little cache on a cold spring day. I got out of work early, so what better to do than grab a cache on the way home. After a short hike dodging the ice patches I was able to find the cache quickly. Dropped off Lucky Tb. TFTC
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Dengue Fever, Cowboy Junkies Revisited, Black Mountain, More
On this edition of All Songs Considered: Cambodian-inspired rock from LA's Dengue Fever; revisiting the legendary Trinity Sessions by the Cowboy Junkies; psych-rock revivalists Black Mountain; gifted lyricist John Darnielle, A.K.A. the Mountain Goats; Baltimore's dream pop duo Beach House; and recapturing the banjo with Otis Taylor.
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Dengue Fever, Cowboy Junkies Revisited, Black Mountain, More
Dengue Fever
- Artist: Dengue Fever
- Song: Seeing Hands
- From: Venus on Earth
The Mountain Goats
- Artist: The Mountain Goats
- Song: Autoclave
- From: Heretic Pride
Black Mountain
- Artist: Black Mountain
- Song: Stormy High
- From: In the Future
Cowboy Junkies
- Artist: Cowboy Junkies
- Song: Blue Moon Revisited
- From: Trinity Revisited
Beach House
- Artist: Beach House
- Song: Heart of Chambers
- From: Devotion
Otis Taylor
- Artist: Otis Taylor
- Song: Ran So Hard the Sun Went Down
- From: Recapturing the Banjo
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Two faces by SerahStarkWatch
©2012-2016 SerahStark
Tali'Zorah ~ Again.
(c) Mass Effect (etc.)
(c) Mass Effect (etc.)
i forgot that tali does have 2 entities in her mind.
How does she have two entities?
Uhh...what second personality? I've followed ME for a long time, giant Talimancer, yet I've never seen an indication of more than one.
Technically, she does'nt have two entities.Or maybe if her shotgun can be considerate as a entity D:


text:
Ultrasound appointment at 14 weeks
Comments (9)
I've heard you have to be 16 weeks. They may be able to guess but I wouldn't start buying stuff until they look after 16 weeks :)
Colton David 06/13/2010, Angel 04/14/2012 <3, Our Sweet Angel Lily born too soon 9/17/2012 <3, Emelia Marie 9/29/13 <3
Last time I had to wait til 20 wks, but I asked my OB this time and she said she could take a look at 16 wks for me..... If I were you I would ask before the u/s and if they say no, then I'd see if they could push it back a few wks.
Becky (29) & Jason (29) since 6/28/02
Daughter Ava Lynn (4) 7/30/08
Testicles don't drop until later in the 3rd trimester or sometimes not even until birth. 14 weeks they all still look similar, but they can take a guess. 16 weeks is the best time for early gender determination because the genitals should be different enough for a trianed professional to tell. By 20 weeks the genitals are fully formed.
I just called to schedule an elective gender ultrasound and they said they do 14 weeks. I had never heard it was accurate this early and I don't trust it so I'm going at 16.5 weeks.
What is an elective ultrasound and should I ask my OB for one? Hmm Insurance may not cover an elective ultrasound with no medical purpose but Im still going to inquire about it. :)
My office doesn't do them either. We have some places around here that you can make an appointment at to find out the gender or do 3D or 4D ultrasounds.


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Are you Wanchao Ma?Claim your profile
Publications (26)85.35 Total impact
Article: Bioactive Lysophospholipids Generated by Hepatic Lipase Degradation of Lipoproteins Lead to Complement Activation via the Classical Pathway[Show abstract] [Hide abstract]
ABSTRACT: Purpose: We determined bioactivity of lysophospholipids generated by degradation of the low-density (LDL), very low-density (VLDL), and high-density (HDL) lipoproteins with hepatic lipase (HL), cholesterol esterase (CE), and lipoprotein-associated phospholipase A2 (Lp-PLA2). Methods: The LDL, VLDL, and HDL were treated with HL, CE, and Lp-PLA2 after immobilization on plates, and complement activation studies were performed with diluted human serum. Complement component 3 (C3) fixation, a marker for complement activation, was determined with a monoclonal anti-human C3d antibody. Enzymatic properties of HL and CE were assayed with triglyceride and phosphatidylcholine substrates for triglyceride hydrolase and phospholipase A activities. The ARPE-19 cells were used for viability studies. Results: The HL degradation of human lipoproteins LDL, VLDL, or HDL results in the formation of modified lipoproteins that can activate the complement pathway. Complement activation is dose- and time-dependent upon HL and occurs via the classical pathway. Enzymatic studies suggest that the phospholipase A1 activity of HL generates complement-activating lysophospholipids. C-reactive protein (CRP), known to simultaneously interact with complement C1 and complement factor H (CFH), further enhances HL-induced complement activation. The lysophospholipids, 1-Palmitoyl-sn-glycero-3-phosphocholine and 1-Oleoyl-sn-glycero-3-phosphocholine, can be directly cytotoxic to ARPE-19 cells. Conclusions: The HL degradation of lipoproteins, known to accumulate in the outer retina and in drusen, can lead to the formation of bioactive lysophospholipids that can trigger complement activation and induce RPE cellular dysfunction. Given the known risk associations for age-related macular degeneration (AMD) with HL, CRP, and CFH, this study elucidates a possible damage pathway for age-related macular degeneration (AMD) in genetically predisposed individuals, that HL activity may lead to accumulation of lysophospholipids to initiate complement activation, with CFH dysregulation exacerbating the effects of this process.
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ABSTRACT: RAGE, the multiligand receptor of the immunoglobulin superfamily of cell surface molecules, is implicated in innate and adaptive immunity. Complement component C1q serves roles in complement activation and antibody-independent opsonization. Using soluble forms of RAGE (sRAGE) and RAGE-expressing cells, we determined that RAGE is a native C1q globular domain receptor. Direct C1q-sRAGE interaction was demonstrated with surface plasmon resonance (SPR), with minimum K(d) 5.6 μM, and stronger binding affinity seen in ELISA-like experiments involving multivalent binding. Pull-down experiments suggested formation of a receptor complex of RAGE and Mac-1 to further enhance affinity for C1q. C1q induced U937 cell adhesion and phagocytosis was inhibited by antibodies to RAGE or Mac-1. These data link C1q and RAGE to the recruitment of leukocytes and phagocytosis of C1q-coated material.
Article: Ultrastructural Features of Retinal Capillary Basement Membrane Thickening in Diabetic Swine[Show abstract] [Hide abstract]
ABSTRACT: To assess retinal capillary basement membrane thickening (BMT) in a swine model of type 1 diabetes. Yorkshire pigs were rendered diabetic with streptozotocin and dyslipidemic with a high fat and cholesterol diet. At 18, 26, and 32 weeks of diabetes, the retina sections within 3 disc diameters from the optic disc were examined under transmission electron microscopy to evaluate the ultrastructural features of the capillary BM. Digital morphometric analysis was performed to measure BMT. Diabetic swine had significantly thicker retinal capillary BMs compared to controls. Pigs that sustained diabetes for longer periods or experienced severe diabetes tended to have more BMT. Those pigs that did not sustain glucose levels above 200 mg/dL did not demonstrate thicker retinal capillary BMs. Characteristic ultrastructural features of diabetic vasculopathy observed included rarefaction as an early stage of Swiss cheese cavitation, lamellation with multiplication of electron dense layers, and fibrillar materials within capillary BM. Diabetic Yorkshire pigs develop characteristic features of an early retinal microvasculopathy fairly rapidly and may serve as a higher-order animal model for studies of type 1 diabetes.
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ABSTRACT: In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.
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ABSTRACT: The importance of VEGF in stimulating neovascular age-related macular degeneration (AMD) is well-recognized, but the initiating factors that induce local upregulation of VEGF remain unclear. The current study was conducted to test the hypothesis that activation of RAGE (receptor for advanced glycation end products [AGEs]) by its ligands, including AGEs, amyloid-beta peptide (Abeta), and S100B/calgranulins, some of which are known components of drusen and Bruch's membrane deposits, modulate secretion of VEGF by retinal pigment epithelial (RPE) cells. ARPE-19 cells were used for all experiments. The cells were transfected with constructs encoding a signal transduction mutant of human RAGE to assess the RAGE-dependence of intracellular signaling. VEGF secretion and gene expression were assessed by ELISA and quantitative real-time PCR. SDS-PAGE and size exclusion chromatography were performed to analyze the structural changes of S100B after oxidation of its thiol groups under denaturing and nondenaturing conditions, respectively. NF-kappaB activation was assessed via electrophoretic mobility shift assay (EMSA). The impact of the NF-kappaB inhibition was assessed by using parthenolide. ARPE-19 cells basally secreted VEGF under normal cell culture conditions. Immobilized ligands of RAGE increased VEGF secretion in a RAGE-dependent manner. In contrast, soluble AGE-BSA, fresh Abeta, and S100B were less effective in increasing VEGF secretion. Studies with Abeta demonstrated that oligomeric and surface-immobilized forms of Abeta, but not soluble monomeric forms of Abeta, were effective upregulators of VEGF secretion via RAGE. Oxidation of S100B's thiol groups resulted in the formation of oligomers that displayed distinct RAGE biological activity compared with the simple dimeric form. RAGE-mediated upregulation of VEGF secretion by ARPE-19 cells was largely dependent on NF-kappaB, as indicated by studies with parthenolide. Immobilized or oligomerized ligands for RAGE induce RPE cells to increase VEGF secretion. NF-kappaB plays a central role in RAGE-dependent RPE secretion of VEGF. In AMD, activation of the RAGE axis in RPE cells may contribute to upregulation of VEGF, potentially inciting or propagating neovascular macular disease.
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ABSTRACT: We sought to study the presence of the receptor for advanced glycation endproducts (RAGE) and its ligands, advanced glycation endproducts (AGEs), S100/calgranulins and amphoterin (high mobility group box 1 protein; HMGB1), in the vitreous cavity and epiretinal membranes (ERMs) of eyes of patients with proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). Undiluted vitreous specimens were collected from 30 eyes of 30 patients undergoing pars plana vitrectomy for repair of retinal detachment (RD) secondary to PDR (n = 15) or PVR (n = 15). The vitreous samples obtained from 10 eyes undergoing macular hole repair were used as controls. Epiretinal membranes were obtained from eight eyes with PDR and from 10 eyes with PVR. The levels of AGEs in the vitreous were measured using ELISA. The vitreous levels of soluble RAGE (sRAGE), S100/calgranulins and amphoterin were measured using Western blot analyses. The localization of RAGE and its ligands in ERMs was determined with immunohistochemistry. The vitreous levels of sRAGE were significantly increased in both PDR and PVR (p < or = 0.05) compared to control vitreous. In both PDR and PVR, the vitreous levels of AGEs (p < or = 0.01), S100/calgranulins (p < or = 0.05), and amphoterin (p < or = 0.01) were also elevated compared to control eyes. Expression of RAGE was detected in six of eight ERMs from eyes with PDR and eight of 10 ERMs from eyes with PVR. Many cells expressing RAGE also expressed vimentin, suggesting a glial cell origin. Ligands for RAGE were also detected in ERMs, with AGEs detected in five eyes with PDR and eight eyes with PVR. Similarly, S100 and amphoterin ERM expression was observed in six eyes with PDR; these ligands were also expressed in ERMs from eyes with PVR (8 and 7 cases, respectively). We conclude that RAGE and its ligands are increased in the vitreous cavity of eyes with PDR and PVR and are present in ERMs of eyes with these proliferative retinal disorders. These findings suggest a role for the proinflammatory RAGE axis in the pathogenesis of proliferative retinal diseases.
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ABSTRACT: Since oxidative stress has been implicated in the development of numerous diseases including cataract, this laboratory has created and investigated the stress response of murine immortal lens epithelial cell lines (alphaTN4-1) conditioned to withstand lethal peroxide concentrations. Two of a group of antioxidative defense (AOD) enzymes found in such cells to have markedly enhanced activity are catalase (CAT) and GSH S-transferase alpha2 (GST). In order to determine if enrichment of one or both of these AODs is sufficient to protect alphaTN4-1 cells from lethal H(2)O(2) levels, these cells were infected with adenovirus vectors capable of expressing these AODs at a high level. With this system, gene enrichment and increased enzyme activity were observed with both CAT and GST vectors. The percentage of cells infected ranged from about 50 to 90% depending on the multiplicity of infection (MOI). CAT but not GST protected the cells from H(2)O(2) stress. The CAT activity was increased from 15- to 150-fold and even at the lower levels protected the cells from H(2)O(2) concentrations as high as 200 microM or more (H(2)O(2) levels which rapidly kill non-enriched cells). Even when only about 50% of the cell population is infected as judged by GFP infection, the entire population appeared to be protected based on cell viability. The CAT enrichment appears to protect other intracellular defense systems such as GSH from being depleted in contrast to non-enriched cell populations where GSH is rapidly exhausted. The overall results suggest that enriching the cellular CAT gene level with an appropriate recombinant viral vector may be sufficient to protect in vivo systems from peroxide stress.
Article: Barile GR et al.The RAGE axis in early diabetic retinopathy. Invest Ophthalmol Vis Sci 46: 2916-2924[Show abstract] [Hide abstract]
ABSTRACT: The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E(-/-) db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.
Article: ΔFosB expression and cataract[Show abstract] [Hide abstract]
ABSTRACT: DeltaFosB is a truncated form of a FosB transcription factor, which is created by alternative splicing. Previous work has shown that transgenic mice expressing DeltaFosB both in the retina and in the lens developed a posterior subcapsular cataract resulting from the misalignment of the fibres in the suture region. In the previous study, it was not clear whether DeltaFosB expression was required in both tissues to produce the cataract. Therefore, DeltaFosB expression targeted to either the lens or the retina was undertaken in order to clarify the contribution of each tissue to cataract development. For lens expression, the R2betaB1DeltaFosB construct was synthesized (R2, an enhancer; betaB1, a chicken betaB1 crystallin gene promoter fragment). For the retina, RhoDeltaFosB was prepared. As a promoter, the bovine rhodopsin upstream region was used. DeltaFosB expression in heterozygote animals was monitored by Western blotting. Cataract development in heterozygotes of R2betaB1DeltaFosB transgenics and in both heterozygotes and homozygotes of RhoDeltaFosB transgenics was followed by slitlamp examination. The transgenic mice prepared with RhoDeltaFosB expressed DeltaFosB only in the retina and showed no sign of lens opacity. One line of the R2betaB1DeltaFosB transgenic was found to have expression only in the lens and developed posterior subcapsular cataract. We concluded that retinal expression of DeltaFosB is not sufficient to cause cataract while expression exclusively in the lens produces posterior subcapsular cataract.
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ABSTRACT: Matrix metalloproteinases are important biological effectors of tissue remodelling. Increased MMP expression occurs during injury, inflammation, cellular transformation, and oxidative stress. Oxidative stress in the lens, a causal factor in cataractogenesis, has been shown to induce MMP secretion. The objective of this study was to assess the expression of MMPs and their regulators in an oxidative stress model of cataract, where epithelial cell death and cortical fibre cell swelling occurs in rat lenses after exposure to riboflavin, oxygen, and light. Two time points (4 and 7 hr of exposure) were chosen in order to compare transparent lenses with partially opaque lenses. MMP activity, protein, and mRNA levels were measured. The results show that MMP-2, MMP-9, MT1-MMP, and MT3-MMP are down-regulated by oxidative stress and that the down-regulation is most likely due to reduced gene transcription. In contrast, genes for catalase, glutathione peroxidase, and GAPDH are essentially unaffected, while beta-actin mRNA and protein levels are markedly increased at both time points. The down-regulation of MMPs occurs in lenses still seemingly transparent after 4 hr of exposure, indicating that reduced MMP activity is a relatively early response to the oxidative stress. Moreover, in our model system, MMP inhibition, not induction, is associated with cataractogenesis.
Article: Comparison of characteristics of peroxide-conditioned immortal human lens-epithelial cell lines with their murine counterparts[Show abstract] [Hide abstract]
ABSTRACT: Previously, this laboratory has reported the characteristics of murine immortal lens-epithelial cells (alphaTN4-1) conditioned to survive either H2O2 or tertiary butyl hydroperoxide (TBOOH) stress. This communication now describes similar observations upon human HLE-B3 cells. It was found that the human cells are more sensitive to peroxides than their murine counterpart. Similar to the murine cells, conditioning to TBOOH endows the HLE-B3 cells with resistance to H2O2 but unlike the murine cells, conditioning to H2O2 gives the human cells resistance to TBOOH. Furthermore, while withdrawal of TBOOH stress from TBOOH-conditioned alphaTN4-1 cells causes a loss of resistance to this peroxide but not H2O2, with human cells resistance to both peroxides is retained. Examination of the antioxidative defense (AOD) enzyme activities show an extraordinary increase in catalase activity and significant augmentation of most other enzymes assayed in all conditioned human cell lines. In contrast, it was previously found that only catalase and glutathione-S-transferase have considerable increases in activity in the murine lines. However, in most cases, the AOD enzyme activity in murine-control cells is about 2-fold higher than in human control cells. The gene expression of human TBOOH-conditioned (Thum) and control (Chum) lines were also examined utilizing microarray analysis. Surprisingly, no significant change in gene expression was found for any of the prominent AOD enzymes. Such results differ from the response of murine cells where many AOD enzymes have increased expression. These observations suggest while the same AOD enzymes may be utilized in both murine and human lens-epithelial cells, the levels at which they are maintained and the manner in which they are recruited in response to stress may differ.
Article: Ho YS, Xiong Y, Ma W, Spector A, Ho DSMice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 279:32804-32812[Show abstract] [Hide abstract]
ABSTRACT: Catalase plays a major role in cellular antioxidant defense by decomposing hydrogen peroxide, thereby preventing the generation of hydroxyl radical by the Fenton reaction. The degree of catalase deficiency in acatalasemic and hypocatalasemic mice varies from tissue to tissue. They therefore may not be suitable for studying the function of this enzyme in certain models of oxidant-mediated tissue injury. We sought to generate a new line of catalase null mice by the gene targeting technique. The mouse catalase (Cat or Cas1) gene was disrupted by replacing parts of intron 4 and exon 5 with a neomycin resistance cassette. Homozygous Cat knockout mice, which are completely deficient in catalase expression, develop normally and show no gross abnormalities. Slices of liver and lung and lenses from the knockout mice exhibited a retarded rate in decomposing extracellular hydrogen peroxide compared with those of wild-type mice. However, mice deficient in catalase were not more vulnerable to hyperoxia-induced lung injury; nor did their lenses show any increased susceptibility to oxidative stress generated by photochemical reaction, suggesting that the antioxidant function of catalase in these two models of oxidant injury is negligible. Further studies showed that cortical injury from physical impact caused a significant decrease in NAD-linked electron transfer activities and energy coupling capacities in brain mitochondria of Cat knockout mice but not wild-type mice. The observed decrease in efficiency of mitochondrial respiration may be a direct result of an increase in mitochondrion-associated calcium, which is secondary to the increased oxidative stress. These studies suggest that the role of catalase in antioxidant defense is dependent on the type of tissue and the model of oxidant-mediated tissue injury.
Article: Characteristics of tertiary butyl hydroperoxide and hydrogen peroxide conditioned cells withdrawn from peroxide stress[Show abstract] [Hide abstract]
ABSTRACT: This laboratory has recently reported the preparation of immortal lens epithelial cell lines conditioned to survive in concentrations of peroxide sufficient to cause cataract with in vitro lens culture conditions. The cell conditioning process takes many months during which time the peroxide concentration is gradually increased. It was found that while the acquired resistance to H2O2 was permanent, if tertiary butyl hydroperoxide (TBOOH) was used the resistance was lost within 6-8 weeks of the withdrawal of the peroxide. We now report that resistance is lost within a few days but can be regained within 48 hr. Furthermore, cells resistant to H2O2 while vulnerable to TBOOH could also be rapidly conditioned to tolerate TBOOH in a manner similar to the reconditioning of cells that had lost their TBOOH resistance. The results suggest that a history of exposure to certain oxidative stresses produces a change in cell biology which allows the cell to rapidly respond to the same or other stresses and survive.
Article: Cluster analysis of genes with significant change in expression in cells conditioned to survive TBOOH[Show abstract] [Hide abstract]
ABSTRACT: Immortal murine lens epithelial cells, alphaTN4-1 have been conditioned to survive H2O2, H cells, or TBOOH, T cells, at concentrations that will cause cataract in vitro. Since H cells are killed by TBOOH but T cells survive H2O2, it is of interest to examine the gene expression of these cell lines. We now report the results of cluster analysis of genes whose expression is significantly changed by TBOOH. The analysis has revealed a small group of antioxidative defense genes that contribute to the survival of T and H cells when exposed to oxidative stress.
Article: The effect of stress withdrawal on gene expression and contain biochemical and cell biological properties of peroxside and have cell lines[Show abstract] [Hide abstract]
ABSTRACT: Maturity onset cataract is a disease that afflicts >25% of the U.S. population over 65. Oxidative stress is believed to be a major factor in the development of this disease and peroxides are suspected to be prominent stressing agents. To elucidate mechanisms involved in the protection of cells against oxidative stress, immortal murine lens epithelial cells (alphaTN4-1) have been conditioned to survive lethal concentrations of either tertiary butyl hydroperoxide, TBOOH (a lipid peroxide prototype) (T cells), or H2O2 (H cells). It was found that T cells survived exposure to H2O2 but H cells were killed by TBOOH. In this communication, biological characteristics of the T cells are reported. It is shown that the T cell's ability to survive TBOOH is lost if the cells are grown in the absence of this peroxide (denoted as T- cells). By comparing the differential gene expression of 12,422 genes and ESTs from T and T- and the unconditioned control cells, 16 genes were found that may account for the loss of resistance to TBOOH. They include 5 glutathione-S-transferases, superoxide dismutase 1, zeta crystallin, a NADPH quinone reductase, as well as genes involved in detoxifying aldehydes, controlling iron metabolism, and degrading toxic lipoproteins.
Article: Peroxide toxicity in conditioned lens epithelial cells - Evaluation of multi-defense systems[Show abstract] [Hide abstract]
ABSTRACT: Immortal murine lens epithelial cells which were conditioned to survive peroxide stress were found to have a remarkable increase in catalase activity as well as lesser changes in a number of other antioxidative defense systems [Invest. Ophthalmol. Vis. Sci. 43 (2002) 3251]. Furthermore, the gene expression of hundreds of other genes was altered. In order to determine the relative importance of catalase, other enzyme systems which maintain the reducing environment of the cell and the involvement of Fenton chemistry, an analysis of the effect of inhibiting catalase, disruption of the cells' reducing environment by inhibition of GSSG reductase (GR) and chelation of metal ion was investigated. It was found that inhibition of catalase caused peroxide resistant cells to die within 48-72 hr when exposed to normally tolerated concentrations of peroxide. If 1,10-phenanthroline (OP), an effective metal ion chelator was present, the cells were not affected by catalase inhibition and survived peroxide stress. Peroxide vulnerable unconditioned control cells were similarly protected by the chelator. The results demonstrate that H2O2 itself has minimal toxicity and that it is the products resulting from interaction with metal ion that produces lethal toxicity. In stark contrast, however, metal chelation did not protect the cells when GR was inhibited by BCNU. Examination of non-protein thiol (NP-SH), which is primarily GSH, indicated that rapid and extensive oxidation occurred almost immediately after exposure to peroxide under all conditions. However, NP-SH returns to the normal range in the conditioned cells even though later cell death is observed in some cases, suggesting fatal damage during the period when the cell is exposed to an oxidizing environment. Examination of DNA damage by alkaline elution indicated that H2O2 caused little observed strand breakage in peroxide resistant cells even if catalase is inhibited, suggesting that such cells have developed other systems to protect DNA and that H2O2 induced death is probably not related to DNA single strand breaks. In contrast, unconditioned cells (C cells) show extensive H2O2 induced DNA damage which is prevented by OP. Thus, depending on the conditions, DNA damage may contribute to cell death. The overall results indicate that the conditioned cell lines are not simply dependent on catalase activity but have developed a complex defense which includes GSH dependent systems and possibly more effective regulation of metal ion concentrations to resist oxidative stress.
Article: The Effect of H2O2 and Tertiary Butyl Hydroperoxide Upon a Murine Immortal Lens Epithelial Cell Line, αTN4-1[Show abstract] [Hide abstract]
ABSTRACT: The effect of comparable concentrations of H(2)O(2) and tertiary butyl hydroperoxide (TBHP) upon an immortal murine lens epithelial cell line was examined as part of an ongoing effort to delineate differences in the mechanism by which these peroxides cause cell death. Both compounds result in cell death of normal, unconditioned cells within 24hr. It was found that with similar conditions, TBHP conditioned alphaTN4-1 cells survive H(2)O(2) stress while H(2)O(2) conditioned cells are killed by TBHP. To better understand how these peroxides act, their effect upon unconditioned cells has been investigated. Both peroxides cause a rapid loss of GSH and disruption of pump activity as illustrated by (14)C-choline transport and (86)Rb uptake. While H(2)O(2) exposure resulted in extensive DNA damage, TBHP had a minimal effect. DNA damage caused by H(2)O(2) was shown to activate polyADP-ribosyl polymerase (PARP), leading to depletion of NAD and ATP. H(2)O(2) induced cell death could be delayed by addition of 3-aminobenzamide (3AB), an inhibitor of PARP. ATP levels in cells subjected to H(2)O(2) were also maintained by the presence of 3AB. H(2)O(2) stress also disrupted glycolysis and mitochondrial activity but these parameters were not affected by TBHP. TBHP induced cell death, under the relatively mild conditions used in this work, appears to be caused by membrane disruption and loss of a reducing environment.
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ABSTRACT: The response of lens systems to oxidative stress is confusing. Antioxidative defense systems are not mobilized as expected, and unanticipated defenses appear important. Therefore, mouse lens cell lines conditioned to survive different peroxide stresses have been analyzed to determine their global changes in gene expression. The immortal mouse lens epithelial cell line alphaTN4-1 was conditioned to survive 125 microM H2O2 (H cells) or a combination of both 100 microM tertiary butyl hydroperoxide (TBHP) and 125 microM H2O2 (HT cells), by a methodology previously described. The total RNA was isolated from the different cell lines and analyzed with oligonucleotide mouse expression microarrays. Four microarrays were used for each cell line. Microarray results were confirmed by real-time RT-PCR. A new cell line resistant to both 125 microM H2O2 and 100 micro M TBHP was developed, because cells resistant to H2O2 were killed by TBHP. Analysis of classic antioxidative enzyme activities showed little change between cells that survive H2O2 (H) and those that survive H2O2 and TBHP (HT). Therefore, the global change in gene expression in these cell lines was determined with gene expression microarrays. The fluorescent signal changes of the genes within the three cell lines, H, HT, and control (C), were analyzed by statistical methods including Tukey analysis. It was found that from the 12,422 gene fragments and expressed sequence tags (ESTs) analyzed--based on a one-way ANOVA with a stringent cutoff of one false positive per 1000 genes and correcting for microarray background and noise--approximately 950 (7.6%) genes had a significant change in expression in comparing the C, H, and HT groups. A small group of antioxidative defense genes were found in this population, including catalase, members of the glutathione (GSH)-S-transferase family, NAD(P)H menadione oxidoreductase 1, and the ferritin light chain. The remaining genes are involved in a broad spectrum of other biological systems. In the HT versus H comparison, only a few genes were found that had increased expression in the HT line compared with expression in the H line, including GSH-S-transferase alpha 3 and hephaestin. Many genes that are frequently considered antioxidative defense genes, including most of the GSH peroxidases, unexpectedly showed little change. An unusual and generally unexpected small group of antioxidative defense genes appear to have increased expression in response to H2O2 stress. Cell lines resistant to H2O2 do not appear to survive challenge with another type of peroxide, TBHP, a lipid peroxide prototype. However, acquisition of TBHP resistance by H cells was found to be accompanied by significantly amplified expression of only a few additional antioxidative defense genes. Many of the amplified genes do not appear to be involved with antioxidative systems, reflecting the complexity of the cells' response to oxidative stress.
Article: The Effect of Aging on Glutathione Peroxidase-I Knockout Mice—Resistance of the Lens to Oxidative Stress[Show abstract] [Hide abstract]
ABSTRACT: Populations of control, C, and glutathione peroxidase-1 (GPx-1) knockout mice, K, were studied over a period of 2 years. No significant difference was observed between the C and K populations with respect to longevity, vitality, weight, lens biochemistry or morphology based on light and electron microscopy. It was concluded that under normal animal room barrier facilities, GPx-1 is not required. Furthermore, C and K lenses placed in organ culture and observed over a 24 hr period were indistinguishable. Organ cultured C lenses degraded medium H(2)O(2)levels at only a slightly greater rate than K lenses and this did not appear to change with age. However, tertiary butyl hydroperoxide (TBHP) was degraded less effectively by K lenses and this deficiency increased with age. No indication of change in redox non-protein SH (equivalent to GSH) status was observed between C and K whole lenses or epithelial cell fractions. With H(2)O(2)stress, the drop in C and K non-protein SH was comparable and there was little change with age. Examination of the impact of photochemical stress with 1.5 microM riboflavin and 4% O(2)upon choline transport indicated considerable damage with both C and K lenses, but little difference between the two populations until 1 or 2 years of age when the K lenses appear more vulnerable. With TBHP, the detrimental effect on the K lenses is greater and is observed earlier than with photochemical stress suggesting that the K lens membrane function is more susceptible to phospholipid hydroperoxide stress than are C lenses. Light and electron microscopy of the oxidative stressed lenses indicates significant damage which was generally somewhat greater in the K lenses. TBHP was a more potent oxidant than photochemically generated oxidants particularly at the anterior pole. The overall results suggest that under normal conditions, at any age, the lens does not require the presence of GPx-1 but depending on the type of oxidative stress, the enzyme may significantly contribute to its defense and this dependency may increase with age.
Article: ΔFosB-induced cataract[Show abstract] [Hide abstract]
ABSTRACT: The objective of this study was to investigate a possible relationship between posterior subcapsular cataract (PSC) formation and expression of the transcription factor DeltaFosB. Western blot analysis was performed on bitransgenic NSE-tTA, TetOp-DeltaFosB, and single-transgenic NSE-tTA control mice to determine the pattern of DeltaFosB expression within the eye. Light and scanning electron microscopy and biochemical analyses were also performed. In mice expressing DeltaFosB, cataract developed that initially appeared to be posterior subcapsular and gradually matured to involve the entire lens. The enlarged posterior ends of developing secondary fibers curved away from the visual axis to form an elevated opaque posterior plaque. As a result, posterior suture formation did not occur. At a later time, the attenuated posterior capsule overlying the plaque ruptured and the lens nucleus subluxated into the vitreous. Retinal damage was also observed but only from postnatal day 65, a time when extensive lens degeneration had already occurred. DeltaFosB expression was observed well before the detection of morphologic change in both the lens and the retina. Within the lens, DeltaFosB expression was found in both the epithelium and fibers. The development of cataracts was a direct consequence of DeltaFosB expression and was not due to the disruption of an endogenous gene by transgene integration since cataracts could be prevented by silencing expression of DeltaFosB by feeding bitransgenic animals doxycycline (Dox). Moreover, cataracts were observed in bitransgenic mice derived from two independent TetOp-DeltaFosB founder lines but not in single NSE-tTA transgenic controls. Cataractogenesis was not a consequence of abnormal development, because mice conceived and raised on Dox to prevent expression of DeltaFosB also were subject to formation of PSC when expression of DeltaFosB was turned on in adult animals by removing Dox. Examination of biochemical parameters indicated that the earliest change observed was the disruption of calcium homeostasis with a significant increase in Ca(2+) influx, followed by a gradual but marked decrease in protein content. Significant changes in certain metabolic parameters and protein composition were also observed. The DeltaFosB-induced cataract in which the major morphologic early event was the disruption of normal posterior fiber formation, may be a good model for PSC. By identifying DeltaFosB-regulated target genes, it should be possible to achieve a better understanding of the molecular mechanisms through which PSC is formed.
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M.A. Art and Design for the Public Space
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The need for interaction and involvement with the public domain has been progressively affirming itself as an artistic, aesthetic and creative concern within diverse circuits of knowledge and artistic pratice. Internationally, this territory already has a considerable implementation, both at an academic level and as a profissional pratice, in Portugal the offer of a 2nd Cycle course with this profile allows for an approach that conveys operative skills and reflexive tools adequate to address said territory. Thus, on the one hand, the character of expertise of the programme of studies addresses very specific needs of the spacial intervention operativeness; on the other, its pluri and interdisciplinary roots establish from the outset a focus on developing critical and reflexive tools.
The current Masters allows further education for graduate students holding a Degree from any of the Pathways of the Art or Design Courses in this Faculty, but also for graduate students coming from areas of study such as Architecture, Urban Planning, Landscaping, Product Design. The course celebrates co-operation with other Faculties and Research Centres, namely CCRE (Centre for Spacial Representation) at the Architecture Faculty of Porto, with the aim of furthering cientific dialogue and enabling a groundwork for thinking and acting upon the city, the landscape, the community and the museum, in a multidisciplinary mode.
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O valor da propina anual é de 1600,00 que pode ser pago: a. na totalidade, no acto da inscrição, acrescido do Seguro Escolar (1,80) b. em duas prestações de 800,00: o a 1.ª no acto da inscrição, acrescida do Seguro Escolar (1,80); o a 2.ª paga até 31 de Março de 2008. o O pagamento de propinas deve ser efectuado na Caixa Geral de Depósitos, através de: · talão próprio disponível na Tesouraria da Faculdade, · depósito, em qualquer Agência da CGD, na conta n.º 0748001260230. Em
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Close to 31,000 students, 2,300 teachers and researchers along with 1,700 administrative staff attend its 15 schools and 69 scientific research units, spread across 3 university campuses located in the city of Porto. With 14 faculties and a business school, the University of Porto provides an exceptional variety of courses, covering the whole range of study areas and all levels of higher education. In fact, offering over 700 training programmes per year (from degrees to continuous professional training), the University of Porto has teaching solutions for everyone.
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Started in 1996, the LWR Coffee Project is a collaboration between Equal Exchange and Lutheran World Relief to involve Lutheran communities and individuals in supporting small farmers around the world.
For each pound of fairly traded coffee, tea, and foods Lutherans purchase through the LWR Coffee Project, 20 cents per pound goes to LWR's Small Farmer Fund. That Fund amounted to $34,435.48 in 2014 alone!
The Small Farmers Fund has supported a number of LWR projects across multiple regions. Below, are a few projects that the SFF supported in recent years:
- "Strengthening Small Coffee Farmers in Flores through Capacity Building;" Program Dates 10/14– 9/15; This project aims to improve the livelihood and strengthen the ability of 100 small-scale farmers in Flores, Indonesia through teaching sustainable agriculture efforts. Farmers on the island of Flores have practiced agriculture that relied on access to the forests covering the island. However, in 2005 much of the forest was reserved as a public trust by the government, and several communities lost the ability to practice their traditional agricultural methods. Currently, LWR is working with farmers and cooperatives in two villages in the Ngada district to improve cultivation techniques that will increase the quantity and quality of coffee production and improve the post-harvest processing system.
- "Strengthening Food Autonomy and Self Government in Arhuaca Communities of Ye; " Program Dates: 5/13 – 7/14; ). In partnership with Programa de Desarrollo y Paz del Cesar, LWR worked to reduce food insecurity by improving the marketing, production and institutional organization for coffee produced by three indigenous communities. This project directly worked with 4, 629 individuals, specifically 1,929 men and 2,700 women, while promoting sustainable agriculture and strengthening self-government among the Arhuaca communities to improve indigenous economies and food autonomy.
- APOKO: Coffee producers working together in Rachuonyo South to sustain their livelihoods; Program Dates: 8/12 – 9/14; LWR worked to improve the livelihood of more than 5,500 coffee producers in the Rachounyao South district in Kenya by significantly increasing both coffee production and farmers' income. LWR aided these producers in having ownership in and access to quality services from 3 Coffee Cooperative Societies with strong systems to organize, serve their members, and provide quality services to their membership.
Get Involved
With 100 local partners, LWR works to improve harvests, health and education in some 35 countries each year. LWR partners train local women and men to produce local foods, dig low-cost wells and protect and restore their local environments. Some partners are small village groups on the edge of the Sahara. Others are nationwide programs that may reach across the Andes. LWR has learned that the future in health, agriculture and education often lies with the hearts and hands of women. We have learned that disaster can sometimes be prevented or withstood by effective development programs and that, when disasters do occur, LWR partners may be on the spot well before the world notices and still needed long after the crisis no longer commands front-page headlines.
Throughout its history, LWR has worked on behalf of U.S. Lutherans. Basic support today is provided through the Evangelical Lutheran Church in America World Hunger Appeal and by the Lutheran Church Missouri Synod World Relief.
Equal Exchange is a Fair Trade organization that buys directly from small-scale farmer cooperatives, owned and run by the farmers themselves. Because our farmer partners are paid above market prices for their crops, they are able to make investments in community projects, educational programs, and technical trainings. These cooperative organizations also help keep rural communities healthy and strong, and keep local cultures vibrant. Equal Exchange is also committed to supporting sustainable farming methods that help green the earth through reforestation, natural resource conservation and organic practices.
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Call (774) 776-7340 or email.