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Sample records for bnip3 upregulation precedes

  1. PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

    Science.gov (United States)

    Qi, Y; Liu, J; Saadat, S; Tian, X; Han, Y; Fong, G-H; Pandolfi, P P; Lee, L Y; Li, S

    2015-01-01

    The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia- and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3. PMID:25394489

  2. VEGF masks BNIP3-mediated apoptosis of hypoxic endothelial cells.

    Science.gov (United States)

    Jurasz, Paul; Yurkova, Natasha; Kirshenbaum, Lorrie; Stewart, Duncan J

    2011-05-01

    Hypoxia results in the apoptotic death of myocytes, neurons, and epithelial cells, through the actions of Bcl-2 and Nineteen kilodalton Interacting Protein-3 (BNIP3). On the contrary, endothelial cells are especially adept at surviving conditions of oxygen deprivation via up-regulation of vascular endothelial growth factor (VEGF) the most potent endothelial survival factor. Both VEGF and BNIP3 expression are transcriptionally regulated by hypoxia inducible factor and may antagonize each other's affects in endothelial cells (ECs). Since factors that promote and inhibit apoptosis may be expressed at the same time in endothelial cells under hypoxic conditions, we decided to investigate whether VEGF and BNIP3 have opposing actions in endothelial cells. Human microvascular endothelial cells were exposed to hypoxic conditions in a Billups-Rothenburg chamber. Under hypoxic conditions BNIP3 expression by endothelial cells increased as measured by real-time PCR and immunoblot. After 48 h of hypoxia, EC apoptosis was assessed by flow cytometry and was lower than in corresponding normoxia serum starved controls. The increase in EC survival under hypoxic conditions corresponded with an increase in the expression of VEGF. Under normoxic conditions adenoviral BNIP3 over-expression promoted apoptosis of ECs; however, recombinant VEGF (100 pg/ml) antagonized the BNIP3 apoptosis promoting affects. SiRNA knockdown of VEGF expression by hypoxic ECs resulted in increased apoptosis with a concomitant increase in BNIP3 expression. SiRNA knockdown of BNIP3 expression by hypoxic ECs reduced the increase in EC apoptosis as a result of VEGF knockdown. We conclude that under hypoxic conditions VEGF counteracts and masks the apoptosis promoting affects of BNIP3.

  3. A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1.

    Directory of Open Access Journals (Sweden)

    Bo Han

    were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.

  4. Autophagy and BNIP3 protein in tumorogenesis

    Directory of Open Access Journals (Sweden)

    Ewelina Świderek

    2013-05-01

    Full Text Available Autophagy is a process necessary for maintaining cell homeostasis in physiological conditions, as well as during certain stresses like nutrients or oxygen deprivation. Autophagy also plays an essential role in tumorigenesis. It prevents cell transformation, but on the other hand, autophagy enables existing cancer cells to adapt to harmful conditions and increased glucose demand, supports maintaining of cellular metabolism and accelerates tumor growth. Among others, it refers to Ras-transformed cells. Recent research unveiled BNIP3 protein as one of the key players involved in autophagy. Although BNIP3 is classified as proapoptotic member of BH3-only subfamily, its proapoptotic activity is questionable. However, BNIP3 demonstrates ability to induce or stimulate autophagy and its specific variant – mitophagy. This paper aims to summarize the existing body of knowledge related to the role of BNIP3 in autophagy, as well as the importance of this process in tumorigenesis. In particular, we emphasize the relation between autophagy and BNIP3 expression induced by Ras oncogene.

  5. Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy

    Science.gov (United States)

    Wilfinger, Nastasia; Austin, Shane; Scheiber-Mojdehkar, Barbara; Berger, Walter; Reipert, Siegfried; Praschberger, Monika; Paur, Jakob; Trondl, Robert; Keppler, Bernhard K.; Zielinski, Christoph C.; Nowikovsky, Karin

    2016-01-01

    This study identifies BNIP3L as the key regulator of p53-dependent cell death mechanism in colon cancer cells targeted by the novel gallium based anticancer drug, KP46. KP46 specifically accumulated into mitochondria where it caused p53-dependent morphological and functional damage impairing mitochondrial dynamics and bioenergetics. Furthermore, competing with iron for cellular uptake, KP46 lowered the intracellular labile iron pools and intracellular heme. Accordingly, p53 accumulated in the nucleus where it activated its transcriptional target BNIP3L, a BH3 only domain protein with functions in apoptosis and mitophagy. Upregulated BNIP3L sensitized the mitochondrial permeability transition and strongly induced PARKIN-mediated mitochondrial clearance and cellular vacuolization. Downregulation of BNIP3L entirely rescued cell viability caused by exposure of KP46 for 24 hours, confirming that early induced cell death was regulated by BNIP3L. Altogether, targeting BNIP3L in wild-type p53 colon cancer cells is a novel anticancer strategy activating iron depletion signaling and the mitophagy-related cell death pathway. PMID:26517689

  6. Regulation of the mTOR Pathway by a Novel Rheb Binding Protein BNIP3

    National Research Council Canada - National Science Library

    Guan, Kun-Liang

    2008-01-01

    .... We demonstrate that BNIP3 plays a critical role in hypoxia-induced mTOR inhibition. Furthermore we found that BNIP3 itself has a growth inhibitory activity and inactivation of BNIP3 promotes cell growth...

  7. Down-regulation of transcription of the proapoptotic gene BNip3 in cultured astrocytes by murine coronavirus infection

    International Nuclear Information System (INIS)

    Cai Yingyun; Liu Yin; Yu Dongdong; Zhang Xuming

    2003-01-01

    Murine coronavirus mouse hepatitis virus (MHV) causes encephalitis and demyelination in the central nervous system of susceptible rodents. Astrocytes are the major target for MHV persistence. However, the mechanisms by which astrocytes survive MHV infection and permit viral persistence are not known. Here we performed DNA microarray analysis on differential gene expression in astrocyte DBT cells by MHV infection and found that the mRNA of the proapoptotic gene BNip3 was significantly decreased following MHV infection. This finding was further confirmed by quantitative reverse transcription-polymerase chain reaction, Western blot analysis, and BNip3-promoter-luciferase reporter system. Interestingly, infection with live and ultraviolet light-inactivated viruses equally repressed BNip3 expression, indicating that the down-regulation of BNip3 expression does not require virus replication and is mediated during cell entry. Furthermore, treatment of cells with chloroquine, which blocks the acidification of endosomes, significantly inhibited the repression of the BNip3 promoter activity induced by the acidic pH-dependent MHV mutant OBLV60, which enters cells via endocytosis, indicating that the down-regulation of BNip3 expression is mediated by fusion between viral envelope and cell membranes during entry. Deletion analysis showed that the sequence between nucleotides 262 and 550 of the 588-base-pair BNip3 promoter is necessary and sufficient for driving the BNip3 expression and that it contains signals that are responsible for MHV-induced down-regulation of BNip3 expression in DBT cells. These results may provide insights into the mechanisms by which MHV evades host antiviral defense and promotes cell survival, thereby allowing its persistence in the host astrocytes

  8. Inhibition of the vacuolar ATPase induces Bnip3-dependent death of cancer cells and a reduction in tumor burden and metastasis.

    Science.gov (United States)

    Graham, Regina M; Thompson, John W; Webster, Keith A

    2014-03-15

    The pro-apoptotic protein Bnip3 is induced by hypoxia and is present in the core regions of most solid tumors. Bnip3 induces programmed necrosis by an intrinsic caspase independent mitochondrial pathway. Many tumor cells have evolved pathways to evade Bnip3-mediated death attesting to the physiological relevance of the survival threat imposed by Bnip3. We have reported that acidosis can trigger the Bnip3 death pathway in hypoxic cells therefore we hypothesized that manipulation of intracellular pH by pharmacological inhibition of the vacuolar (v)ATPase proton pump, a significant pH control pathway, may activate Bnip3 and promote death of hypoxic cells within the tumor. Here we confirm that bafilomycin A1 (BafA1), a selective vATPase inhibitor, significantly increased death of breast cancer cells in a hypoxia and Bnip3-dependent manner and significantly reduced tumor growth in MCF7 and MDA-MB-231 mouse xenografts. Combined treatment of cells with BafA1 and the ERK1/2 inhibitor U0126 further augmented cell death. Combined treatment of mice containing MDA-MB-231 xenografts with BafA1 and the ERK1/2 inhibitor sorafenib was superior to either treatment alone and supported tumor regression. BafA1 and sorafenib treatments alone reduced MDA-MB-231 cell metastasis and again the combination was significantly more effective than either treatment alone and was without apparent side effects. These results present a novel mechanism to destroy hypoxic tumor cells that may help reverse the resistance of hypoxic tumors to radiation and chemotherapy and perhaps target tumor stem cells.

  9. Cadmium induces BNIP3-dependent autophagy in chicken spleen by modulating miR-33-AMPK axis.

    Science.gov (United States)

    Chen, Menghao; Li, Xiaojing; Fan, Ruifeng; Yang, Jie; Jin, Xi; Hamid, Sattar; Xu, Shiwen

    2018-03-01

    Cadmium (Cd), a widespread environmental pollutant, has toxic effects on organs including spleen. However, the underlying mechanisms of Cd induced spleen toxicity and the roles of micro-RNA (miRNA) in this process remain poorly understood. To investigate this, cadmium chloride (CdCl 2 , 10 mg/kg) was administered in the diet of chickens for 90 days. Electron microscopy, qPCR and Western blot were performed. Results showed that Cd exposure suppressed miR-33-5q which increased the levels of AMPK. Subsequently, significant decrease in AKT/mTOR signaling and HSP70 were observed. Concurrently, levels of NF-κB, p-JNK/JNK increased significantly. Moreover, the expression of BNIP3 and other autophagy markers (LC3-I, LC3-II, Beclin-1) increased significantly. Additionally, the levels of ions (Ca, Cr, Se, Sr, Sn, Ba) and (Na, Mg, V, Fe, Mo, Cu, Zn, Cd) significantly decreased and increased, respectively. Taken together, we conclude that Cd induced the deregulation of miR-33-AMPK axis led to BNIP3-dependent autophagy in chicken spleen through AKT/mTOR and HSP70-NF-κB/JNK signal pathways. In-addition Cd could affect ion homeostasis in chicken spleen. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Expression of apoptosis-related genes in the mouse skin during the first postnatal catagen stage, focused on localization of Bnip3L and caspase-12

    Czech Academy of Sciences Publication Activity Database

    Veselá, Barbora; Matalová, Eva

    2015-01-01

    Roč. 56, č. 4 (2015), s. 326-335 ISSN 0300-8207 Grant - others:GA ČR(CZ) GAP502/12/1285 Program:GA Institutional support: RVO:67985904 Keywords : apoptosis * Bnip3L * caspase-12 Subject RIV: ED - Physiology Impact factor: 1.411, year: 2015

  11. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

    Science.gov (United States)

    Serban, Andreea Iren; Stanca, Loredana; Geicu, Ovidiu Ionut; Dinischiotu, Anca

    2015-08-25

    Advanced glycation end products (AGEs) can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293) upon exposure to 200 μg/mL bovine serum albumine (BSA) or AGEs-BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE) and heat shock proteins (HSPs) 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6), HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs-BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells.

  12. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

    Directory of Open Access Journals (Sweden)

    Andreea Iren Serban

    2015-08-01

    Full Text Available Advanced glycation end products (AGEs can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293 upon exposure to 200 μg/mL bovine serum albumine (BSA or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE and heat shock proteins (HSPs 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6, HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs–BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells.

  13. Interferon-Stimulated Gene 15 Upregulation Precedes the Development of Blood-Brain Barrier Disruption and Cerebral Edema after Traumatic Brain Injury in Young Mice.

    Science.gov (United States)

    Rossi, Janet L; Todd, Tracey; Daniels, Zachary; Bazan, Nicolas G; Belayev, Ludmila

    2015-07-15

    Recent studies show that myosin light chain kinase (MLCK) plays a pivotal role in development of cerebral edema, a known complication following traumatic brain injury (TBI) in children and a contributing factor to worsened neurologic recovery. Interferon-stimulated gene 15 (ISG15) is upregulated after cerebral ischemia and is neuroprotective. The significant role of ISG15 after TBI has not been studied. Postnatal Day (PND) 21 and PND24 mice were subjected to lateral closed-skull injury with impact depth of 2.0 or 2.25 mm. Behavior was examined at 7 d using two-object novel recognition and Wire Hang tests. Mice were sacrificed at 6 h, 12 h, 24 h, 48 h, 72 h, and 7 d. ISG15 and MLCK were analyzed by Western blot and immunohistochemistry, blood-brain barrier (BBB) disruption with Evans Blue (EB), and cerebral edema with wet/dry weights. EB extravasation and edema peaked at 72 h in both ages. PND21 mice had more severe neurological deficits, compared with PND24 mice. PND24 mice showed peak ISG15 expression at 6 h, and PND21 mice at 72 h. MLCK peaked in both age groups at 12 h and co-localized with ISG15 on immunohistochemistry and co-immunoprecipitation. These studies provide evidence, ISG15 is elevated following TBI in mice, preceding MLCK elevation, development of BBB disruption, and cerebral edema.

  14. Hedgehog-dependent down-regulation of the tumor suppressor, vitamin D3 up-regulated protein 1 (VDUP1), precedes lamina development in Drosophila.

    Science.gov (United States)

    Chang, Solomon; Mandalaywala, Neil V; Snyder, Randall G; Levendusky, Mark C; Dearborn, Richard E

    2010-04-09

    The tumor suppressor vitamin D(3) up-regulated protein 1 (VDUP1) is expressed throughout the developing and mature Drosophila nervous system, but its regulatory pathways are not well understood. Within the developing Drosophila visual system, down-regulation of VDUP1 in lamina precursor cells (LPCs) coincided with the arrival of retinal axons into the lamina target field, suggesting VDUP1 regulation by an axonally transmitted signal. Hedgehog (Hh) is a signal well known to coordinate LPC proliferation and differentiation in response to retinal axon innervation, and analysis of orthologous dvdup1 promoters identified an evolutionarily conserved binding site for the Hh-dependent transcription factor cubitus interruptus (Ci). Hh-dependent regulation of VDUP1 in the developing lamina was confirmed in Hh loss-of-function backgrounds where VDUP1 expression was maintained in LPCs, inhibiting both cell proliferation and lamina neurogenesis. This putative coupling of VDUP1 to the Hh signaling pathway may provide novel insights into the mechanisms controlling brain growth and development. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  15. Coordinated Upregulation of Mitochondrial Biogenesis and Autophagy in Breast Cancer Cells: The Role of Dynamin Related Protein-1 and Implication for Breast Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Peng Zou

    2016-01-01

    Full Text Available Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1, was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells. This contrast might be owing to enhanced mitochondrial turnover through autophagy, because an increased population of autophagic vacuoles engulfing mitochondria was observed in the cancer cells. Consistently, BNIP3 (a mitochondrial autophagy marker and autophagic flux were significantly upregulated, indicative of augmented mitochondrial autophagy (mitophagy. The upregulation of Drp1 and BNIP3 was also observed in vivo (human breast carcinomas. Importantly, inhibition of Drp1 significantly suppressed mitochondrial autophagy, metabolic reprogramming, and cancer cell viability. Together, this study reveals coordinated increase of mitochondrial biogenesis and mitophagy in which Drp1 plays a central role regulating breast cancer cell metabolism and survival. Given the emerging evidence of PGC1α contributing to tumor growth, it will be of critical importance to target both mitochondrial biogenesis and mitophagy for effective cancer therapeutics.

  16. Information, Precedent, and Statute

    NARCIS (Netherlands)

    O. Yalnazov (Orlin)

    2017-01-01

    textabstractI compare precedent and statute in cost-effectiveness terms. To make laws, a lawmaker needs information. Information has a cost. That cost is sensitive to the choice of law production technology. The orthodoxy is that the courts acquire information more cheaply. Litigants volunteer it in

  17. Conditions precedent and indemnities

    International Nuclear Information System (INIS)

    Nielsen, A.D.

    1999-01-01

    The use of certain conditions which allow purchase and sale agreements to be voided without any liability to either the vendor or purchaser are discussed. The drafting issues that arise when preparing these conditions are described and some common types of conditions precedent found in oil and gas purchase and sale transactions are explained. A 'conditions precedent' was defined as being something which must happen before an interest can vest or grow or before an obligation can be performed. Vendors and purchasers use conditions precedent to provide protection against having to conclude a transaction in circumstances that are not acceptable to them. The manner in which indemnity provisions in an oil and gas purchase and sale agreement work, is also explained. These usually relate to breaches of the contract by either vendors or purchasers. Indemnity clauses are used to allocate risk between the vendor and the purchaser and to set out the mechanics by which either party may make a claim against the other. Ways in which to prepare indemnity clauses are described. 2 refs

  18. PRECEDENCE AS A PSYCHOLINGUISTIC CATEGORY

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    Panarina Nadezhda Sergeevna

    2015-06-01

    Full Text Available The use of particular linguistic units by representatives of a linguacultural community as the most preferable verbal actions is not necessary to be a case of verbal operations with some culturally specific knowledge. The analysis of a psychosocial mechanism used for generation and verbalization of such a knowledge allows to define the nature of precedence as a characteristic of meaning that is being effected in a speech act. The development of precedent meaning indispensably assumes not only generation of the definition component, but also entry into a structure of a culturological component meaning. The culturological component reflects a relationship between a subject-concept component of the meaning and the other elements of a speech situation – the relationship, which is notional for a person. Importance of the relationship consists in fact that definition of its content represents to a person their social identity. Until a person understands the content of relationship, which is represented by the culturological component, the use of corresponding linguistic units to nominate new objects of reality is a supraliminal appeal to the precedent knowledge, a speech act. But for new acts of usage the main thing is definitely quality of relationship as a characteristic of the cultural group stability, and the linguistic unit usage derives a new function. When the culturological component of the meaning is not included into generalization, since it is irrelevant one, and the core of meaning is composed of new and more relevant for the usage features, you can no more realize the inner form of the precedent meaning. The outer form is still relevant, since it is kept in mind by the representatives of linguaculture as the one which is preferable for usage. In this case the linguistic unit is just a tool not related to verbal representation of socially significant attitude, and its usage is a speech operation, a way to perform different speech acts

  19. Mandatory Vaccinations: Precedent and Current Laws

    National Research Council Canada - National Science Library

    Welborn, Angie A

    2005-01-01

    This report discusses the history legal precedent for mandatory vaccination laws and provides a brief overview of state laws that require certain individuals or populations to be vaccinated against...

  20. Optimal Solutions for the Temporal Precedence Problem

    DEFF Research Database (Denmark)

    Brodal, Gerth Stølting; Makris, Christos; Sioutas, Spyros

    2002-01-01

    a in the structure, while the operation precedes (a,b) returns true iff element a was inserted before element b temporally. In [11] a solution was provided to the problem with worst-case time complexity O (log log n ) per operation and O(n log log n) space, where n is the number of elements inserted. It was also...... demonstrated that the precedes operation has a lower bound of Ω (log log n ) for the Pure Pointer Machine model of computation. In this paper we present two simple solutions with linear space and worst-case constant insertion time. In addition, we describe two algorithms that can handle the precedes (a...

  1. More Than the Rules of Precedence

    Science.gov (United States)

    Liang, Yawei

    2005-01-01

    In a fundamental computer-programming course, such as CSE101, questions about how to evaluate an arithmetic expression are frequently used to check if our students know the rules of precedence. The author uses two of our final examination questions to show that more knowledge of computer science is needed to answer them correctly. Furthermore,…

  2. Operator precedence for data-dependent grammars

    NARCIS (Netherlands)

    A. Afroozeh (Ali); A. Izmaylova (Anastasia)

    2016-01-01

    textabstractConstructing parsers based on declarative specification of operator precedence is a very old research topic, and there are various existing approaches. However, these approaches are either tied to a particular parsing technique, or cannot deal with all corner cases found in programming

  3. Oral lichen planus preceding concomitant lichen planopilaris.

    Science.gov (United States)

    Stoopler, Eric T; Alfaris, Sausan; Alomar, Dalal; Alawi, Faizan

    2016-09-01

    Lichen planus (LP) is an immune-mediated mucocutaneous disorder with a wide array of clinical presentations. Oral lichen planus (OLP) is characterized clinically by striae, desquamation, and/or ulceration. Lichen planopilaris (LPP), a variant of LP, affects the scalp, resulting in perifollicular erythema and scarring of cutaneous surfaces accompanied by hair loss. The association between OLP and LPP has been reported previously with scant information on concomitant or sequential disease presentation. We describe a patient with concomitant OLP and LPP, and to the best of our knowledge, this is the first report on OLP preceding the onset of LPP. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Preceding movement effects on sequential aiming.

    Science.gov (United States)

    Cheng, Darian T; De Grosbois, John; Smirl, Jonathan; Heath, Matthew; Binsted, Gordon

    2011-11-01

    In this study, two experiments were devised to examine the control strategy used by individuals when performing sequential aiming movements. Of particular interest was the aiming behavior displayed when task difficulty was changed midway through a sequence of movements. In Experiment 1, target size was manipulated, as the targets were made either larger or smaller, between the 8th and 12th movement of the sequence. In Experiment 2, the amplitude between the two targets was similarly changed while the target size remained constant. Results revealed that in Experiment 1, individuals took two movements following the perturbation to target size, to re-tune their movement times in order to correspond with the new task difficulty. Conversely for Experiment 2, movement time changed immediately and in correspondence with the new target amplitude. These findings demonstrate that participants can use information from the preceding movement to prepare and guide subsequent movements--but only when target size is changed. When response amplitude changes mid-sequence, it seems individuals rely more on immediate, target-derived information. Therefore, counter to some current accounts of visual movement control, it appears that memory representations of the preceding movement can guide subsequent movements; however, this information appears selectively accessed in a context-dependent fashion.

  5. [Wide QRS tachycardia preceded by pacemaker spikes].

    Science.gov (United States)

    Romero, M; Aranda, A; Gómez, F J; Jurado, A

    2014-04-01

    The differential diagnosis and therapeutic management of wide QRS tachycardia preceded by pacemaker spike is presented. The pacemaker-mediated tachycardia, tachycardia fibrillo-flutter in patients with pacemakers, and runaway pacemakers, have a similar surface electrocardiogram, but respond to different therapeutic measures. The tachycardia response to the application of a magnet over the pacemaker could help in the differential diagnosis, and in some cases will be therapeutic, as in the case of a tachycardia-mediated pacemaker. Although these conditions are diagnosed and treated in hospitals with catheterization laboratories using the application programmer over the pacemaker, patients presenting in primary care clinic and emergency forced us to make a diagnosis and treat the haemodynamically unstable patient prior to referral. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  6. Cerebral Hypoperfusion Precedes Nausea During Centrifugation

    Science.gov (United States)

    Serrador, Jorge M.; Schlegel, Todd T.; Black, F. Owen; Wood, Scott J.

    2004-01-01

    Nausea and motion sickness are important operational concerns for aviators and astronauts. Understanding underlying mechanisms associated with motion sickness may lead to new treatments. The goal of this work was to determine if cerebral blood flow changes precede the development of nausea in motion sick susceptible subjects. Cerebral flow velocity in the middle cerebral artery (transcranial Doppler), blood pressure (Finapres) and end-tidal CO2 were measured while subjects were rotated on a centrifuge (250 degrees/sec). Following 5 min of rotation, subjects were translated 0.504 m off-center, creating a +lGx centripetal acceleration in the nasal-occipital plane. Ten subjects completed the protocol without symptoms while 5 developed nausea (4 while 6ff-center and 1 while rotating on-center). Prior to nausea, subjects had significant increases in blood pressure (+13plus or minus 3 mmHg, P less than 0.05) and cerebrovascular resistance (+46 plus or minus 17%, P less than 0.05) and decreases in cerebral flow velocity both in the second (-13 plus or minus 4%) and last minute (-22 plus or minus 5%) before symptoms (P less than 0.05). In comparison, controls demonstrated no change in blood pressure or cerebrovascular resistance in the last minute of off-center rotation and only a 7 plus or minus 2% decrease in cerebral flow velocity. All subjects had significant hypocapnia (-3.8 plus or minus 0.4 mmHg, P less than 0.05), however this hypocapnia could not fully explain the cerebral hypoperfusion associated with the development of nausea. These data indicate that reductions in cerebral blood flow precede the development of nausea. Further work is necessary to determine what role cerebral hypoperfusion plays in motion sickness and whether cerebral hypoperfusion can be used to predict the development of nausea in susceptible individuals.

  7. Amyloid plaque formation precedes dendritic spine loss.

    Science.gov (United States)

    Bittner, Tobias; Burgold, Steffen; Dorostkar, Mario M; Fuhrmann, Martin; Wegenast-Braun, Bettina M; Schmidt, Boris; Kretzschmar, Hans; Herms, Jochen

    2012-12-01

    Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics of these processes. In particular, the question as to whether synapse loss precedes or follows plaque formation remains unanswered. To address this question, and to learn more about the underlying kinetics, we simultaneously imaged amyloid plaque deposition and dendritic spine loss by applying two-photon in vivo microscopy through a cranial window in double transgenic APPPS1 mice. As a result, we first observed that the rate of dendritic spine loss in proximity to plaques is the same in both young and aged animals. However, plaque size only increased significantly in the young cohort, indicating that spine loss persists even many months after initial plaque appearance. Tracking the fate of individual spines revealed that net spine loss is caused by increased spine elimination, with the rate of spine formation remaining constant. Imaging of dendritic spines before and during plaque formation demonstrated that spine loss around plaques commences at least 4 weeks after initial plaque formation. In conclusion, spine loss occurs, shortly but with a significant time delay, after the birth of new plaques, and persists in the vicinity of amyloid plaques over many months. These findings hence give further hope to the possibility that there is a therapeutic window between initial amyloid plaque deposition and the onset of structural damage at spines.

  8. Can monaural temporal masking explain the ongoing precedence effect?

    Science.gov (United States)

    Freyman, Richard L; Morse-Fortier, Charlotte; Griffin, Amanda M; Zurek, Patrick M

    2018-02-01

    The precedence effect for transient sounds has been proposed to be based primarily on monaural processes, manifested by asymmetric temporal masking. This study explored the potential for monaural explanations with longer ("ongoing") sounds exhibiting the precedence effect. Transient stimuli were single lead-lag noise burst pairs; ongoing stimuli were trains of 63 burst pairs. Unlike with transients, monaural masking data for ongoing sounds showed no advantage for the lead, and are inconsistent with asymmetric audibility as an explanation for ongoing precedence. This result, along with supplementary measurements of interaural time discrimination, suggests different explanations for transient and ongoing precedence.

  9. Complexity Analysis of Precedence Terminating Infinite Graph Rewrite Systems

    Directory of Open Access Journals (Sweden)

    Naohi Eguchi

    2015-05-01

    Full Text Available The general form of safe recursion (or ramified recurrence can be expressed by an infinite graph rewrite system including unfolding graph rewrite rules introduced by Dal Lago, Martini and Zorzi, in which the size of every normal form by innermost rewriting is polynomially bounded. Every unfolding graph rewrite rule is precedence terminating in the sense of Middeldorp, Ohsaki and Zantema. Although precedence terminating infinite rewrite systems cover all the primitive recursive functions, in this paper we consider graph rewrite systems precedence terminating with argument separation, which form a subclass of precedence terminating graph rewrite systems. We show that for any precedence terminating infinite graph rewrite system G with a specific argument separation, both the runtime complexity of G and the size of every normal form in G can be polynomially bounded. As a corollary, we obtain an alternative proof of the original result by Dal Lago et al.

  10. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

    OpenAIRE

    Serban, Andreea Iren; Stanca, Loredana; Geicu, Ovidiu Ionut; Dinischiotu, Anca

    2015-01-01

    Advanced glycation end products (AGEs) can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293) upon exposure to 200 μg/mL bovine serum albumine (BSA) or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression ...

  11. Ludic Function of Precedent-Related Phenomena in Media Discourse

    Directory of Open Access Journals (Sweden)

    Yu. M. Velykoroda

    2016-12-01

    Full Text Available The aim of this paper is to determine the ludic function of precedent-related phenomena as a type of intertextuality. The analysis is done on the basis of relevance theoretic approach, through which we aim to show the additional cognitive effect which is created by precedent-related phenomena in media discourse, and this comic effect serves as a foundation for the ludic function of these units.

  12. Cytosolic DNA Sensor Upregulation Accompanies DNA Electrotransfer in B16.F10 Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Katarina Znidar

    2016-01-01

    Full Text Available In several preclinical tumor models, antitumor effects occur after intratumoral electroporation, also known as electrotransfer, of plasmid DNA devoid of a therapeutic gene. In mouse melanomas, these effects are preceded by significant elevation of several proinflammatory cytokines. These observations implicate the binding and activation of intracellular DNA-specific pattern recognition receptors or DNA sensors in response to DNA electrotransfer. In tumors, IFNβ mRNA and protein levels significantly increased. The mRNAs of several DNA sensors were detected, and DAI, DDX60, and p204 tended to be upregulated. These effects were accompanied with reduced tumor growth and increased tumor necrosis. In B16.F10 cells in culture, IFNβ mRNA and protein levels were significantly upregulated. The mRNAs for several DNA sensors were present in these cells; DNA-dependent activator of interferon regulatory factor (DAI, DEAD (Asp-Glu-Ala-Asp box polypeptide 60 (DDX60, and p204 were significantly upregulated while DDX60 protein levels were coordinately upregulated. Upregulation of DNA sensors in tumors could be masked by the lower transfection efficiency compared to in vitro or to dilution by other tumor cell types. Mirroring the observation of tumor necrosis, cells underwent a significant DNA concentration-dependent decrease in proliferation and survival. Taken together, these results indicate that DNA electrotransfer may cause the upregulation of several intracellular DNA sensors in B16.F10 cells, inducing effects in vitro and potentially in vivo.

  13. A Visual lexicon to Handle Semantic Similarity in Design precedents

    DEFF Research Database (Denmark)

    Restrepo-Giraldo, John Dairo

    2007-01-01

    . The shaping and establishing of this image is supported by creating sketches, collages, models and other types of external representations. This process is largely supported by the use of design precedents. In design, precedents provide the frame of reference for the development of new solution principles...... for visual information. The reason is that the algorithms available cannot recognize what the image contains (in semantic terms) but humans can, and with great facility. This ability was reflected in the searching process of the designers in our studies. It is very natural for them to expect living room...

  14. Preceding trauma in childhood hematogenous bone and joint infections.

    Science.gov (United States)

    Pääkkönen, Markus; Kallio, Markku J T; Lankinen, Petteri; Peltola, Heikki; Kallio, Pentti E

    2014-03-01

    Preceding trauma may play a role in the etiology and pathogenesis of hematogenous bone and joint infections. Among 345 children with an acute hematogenous bone and/or joint infection, 20% reported trauma during a 2-week period leading to infection. Blunt impact, bruises, or excoriations were commonly reported. The rate was similar to that in the general pediatric population obtained from the literature. In the study group, patients with and without trauma were similar in age, serum C-reactive protein and erythrocyte sedimentation rate, length of hospitalization, and late sequelae. Preceding minor trauma did not prove to be significant as an etiological or as a prognostic factor.

  15. Impact of preceding crop on alfalfa competitiveness with weeds

    Science.gov (United States)

    Organic producers would like to include no-till practices in their farming systems. We are seeking to develop a continuous no-till system for organic farming, based on a complex rotation that includes a 3-year sequence of alfalfa. In this study, we evaluated impact of preceding crop on weed infest...

  16. Page JUDICIAL PRECEDENT IN THE NIGERIAN LEGAL SYSTEM

    African Journals Online (AJOL)

    Fr. Ikenga

    …since courts place a high value on similar treatment of similar cases, and on the predictability of judicial decision, the reasons derived from precedent cases tend to be fairly strong. Nevertheless, they are supposed to be reasons like any other without any special pedigree and capable of being overridden by stronger.

  17. The South African constitutional court's use of foreign precedent in ...

    African Journals Online (AJOL)

    ... Court or whether it is a characteristic of a court which is confident enough that its independence will remain intact in spite of its looking elsewhere for answers. KEYWORDS: transjudicialism; foreign precedent, comparative judicialism, stare decisis; foreign case law; comparative constitutionalism; Constitutional Court.

  18. Microbial lysate upregulates host oxytocin

    Science.gov (United States)

    Varian, Bernard J.; Poutahidis, Theofilos; DiBenedictis, Brett T.; Levkovich, Tatiana; Ibrahim, Yassin; Didyk, Eliska; Shikhman, Lana; Cheung, Harry K.; Hardas, Alexandros; Ricciardi, Catherine E.; Kolandaivelu, Kumaran; Veenema, Alexa H.; Alm, Eric J.; Erdman, Susan E.

    2017-01-01

    Neuropeptide hormone oxytocin has roles in social bonding, energy metabolism, and wound healing contributing to good physical, mental and social health. It was previously shown that feeding of a human commensal microbe Lactobacillus reuteri (L. reuteri) is sufficient to up-regulate endogenous oxytocin levels and improve wound healing capacity in mice. Here we show that oral L. reuteri-induced skin wound repair benefits extend to human subjects. Further, dietary supplementation with a sterile lysate of this microbe alone is sufficient to boost systemic oxytocin levels and improve wound repair capacity. Oxytocin-producing cells were found to be increased in the caudal paraventricular nucleus [PVN] of the hypothalamus after feeding of a sterile lysed preparation of L. reuteri, coincident with lowered blood levels of stress hormone corticosterone and more rapid epidermal closure, in mouse models. We conclude that microbe viability is not essential for regulating host oxytocin levels. The results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals. PMID:27825953

  19. Extended precedence preservative crossover for job shop scheduling problems

    Science.gov (United States)

    Ong, Chung Sin; Moin, Noor Hasnah; Omar, Mohd

    2013-04-01

    Job shop scheduling problems (JSSP) is one of difficult combinatorial scheduling problems. A wide range of genetic algorithms based on the two parents crossover have been applied to solve the problem but multi parents (more than two parents) crossover in solving the JSSP is still lacking. This paper proposes the extended precedence preservative crossover (EPPX) which uses multi parents for recombination in the genetic algorithms. EPPX is a variation of the precedence preservative crossover (PPX) which is one of the crossovers that perform well to find the solutions for the JSSP. EPPX is based on a vector to determine the gene selected in recombination for the next generation. Legalization of children (offspring) can be eliminated due to the JSSP representation encoded by using permutation with repetition that guarantees the feasibility of chromosomes. The simulations are performed on a set of benchmarks from the literatures and the results are compared to ensure the sustainability of multi parents recombination in solving the JSSP.

  20. ARMA-GARCH Model and temporal precedence between stock indices

    Directory of Open Access Journals (Sweden)

    Diego Garcia Angelico

    2016-03-01

    Full Text Available Faced with the need for risk valuation of financial assets, investors demand sophisticated methods of modeling that can judge the variability of their investments. At the same time, financial globalization has been characterized by common movements and trends between different international markets. In this context, the main objective of this paper was to model the statistical volatility of the Bovespa Index (Ibovespa and the Dow Jones Industrial Average Index, using ARMA-GARCH adjustments, in addition to checking the existence of a long- -term balance and temporal precedence between these variables, using the Johansen co-integration and Granger causality tests, respectively. The results established a higher heterogeneous variance for Ibovespa and the existence of temporal precedence for the Dow Jones Index, despite the absence of any long-term balance between the series. It is understood that the latter behavior may have been caused by the existing difference between the conditional heteroscedasticity of each index.

  1. A Visual lexicon to Handle Semantic Similarity in Design precedents

    DEFF Research Database (Denmark)

    Restrepo-Giraldo, John Dairo

    2007-01-01

    . The shaping and establishing of this image is supported by creating sketches, collages, models and other types of external representations. This process is largely supported by the use of design precedents. In design, precedents provide the frame of reference for the development of new solution principles...... by many researchers that have tried to support the process by providing computer tools. Many of these tools have the drawback of relying on metadata added to the image by the editor of the collection. In all the tools studies for this research, such metadata contained, among other things, descriptions...... recognition techniques to index and retrieve visual information called Content Based Image Retrieval (CBIR). In this approach, the designer gives the computer tool an image and the computer searches for images that are similar to the example given. For this, the computer looks for geometrical features...

  2. Cardiac tamponade preceding skin involvement in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    L. Bozzola

    2011-09-01

    Full Text Available The frequency of pericardial involvement in Systemic Sclerosis (SSc is high on autoptic or echocardiographic studies, but the clinical recognition of pericarditis with or without effusion is rare. We describe a case of a 71-year-old female with no previous history of heart disease, who presented with a large pericardial effusion and tamponade that required pericardial drain. She had suffered from Raynaud’s phenomenon since 25 years. Six weeks after hospital discharge she complained of skin hardening on left leg. Pericardial tamponade is a very rare manifestation of SSc and occurs both early or late in the course of the disease, but in our case it preceded the recognition of scleroderma. We have only identified two other cases of pericardial effusion preceding cutaneous involvement in scleroderma.

  3. Radiation protection: precedents, principles and practices - a regulatory viewpoint

    International Nuclear Information System (INIS)

    Jennekens, J.H.

    1986-06-01

    Radiation protection in its broadest sense is a multidisciplinary human function exemplifying in all meaningful respects the innate ability of dedicated persons to apply with both general and specialized expertise knowledge derived from a great many scientific and technical fields. The aim of this address is to outline from a regulatory viewpoint the precedents, principles and practices of radiation protection, a very essential human function

  4. Explicit Precedence Constraints in Safety-Critical Java

    DEFF Research Database (Denmark)

    Puffitsch, Wolfgang; Noulard, Eric; Pagetti, Claire

    2013-01-01

    Safety-critical Java (SCJ) aims at making the amenities of Java available for the development of safety-critical applications. The multi-rate synchronous language Prelude facilitates the specification of the communication and timing requirements of complex real-time systems. This paper combines...... to provide explicit support for precedence constraints. We present the considerations behind the design of this extension and discuss our experiences with a first prototype implementation based on the SCJ implementation of the Java Optimized Processor....

  5. Experimental Evidence for a Cochlear Source of the Precedence Effect

    DEFF Research Database (Denmark)

    Bianchi, Federica; Verhulst, Sarah; Dau, Torsten

    2013-01-01

    The precedence effect (PE) refers to the dominance of directional information carried by a direct sound (lead) over the spatial information contained in its multiple reflections (lags) in sound localization. Although the processes underlying the PE have been largely investigated, the extent...... range from 1 to 4 ms, as indicated by the suppression of the lag-CEOAE, was the source of the reduction in the lag-ABRs and a possible peripheral contributor to the PE for click stimuli....

  6. Efficient and Flexible Crowdsourcing of Specialized Tasks with Precedence Constraints

    OpenAIRE

    Chatterjee, Avhishek; Borokhovich, Michael; Varshney, Lav R.; Vishwanath, Sriram

    2016-01-01

    Many companies now use crowdsourcing to leverage external (as well as internal) crowds to perform specialized work, and so methods of improving efficiency are critical. Tasks in crowdsourcing systems with specialized work have multiple steps and each step requires multiple skills. Steps may have different flexibilities in terms of obtaining service from one or multiple agents, due to varying levels of dependency among parts of steps. Steps of a task may have precedence constraints among them....

  7. Bereitschaftspotential preceding eyelid blinks in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Isabella Araújo Mota

    Full Text Available ABSTRACT The Bereitschaftspotential (BP is a negative wave observed in EEG retrograde averaging, preceding a motor act. The objective was to study the BP preceding voluntary eyelid blinks in Parkinson’s disease (PD patients during off and on phases of levodopa. Methods Ten PD patients in stages 1 and 2 of the Hoehn & Yahr classification were compared to 18 healthy controls. Artifact-free EEG segments of two seconds preceding the onset of the blink potential were averaged and analyzed, and the statistical significance of the measured amplitudes were evaluated by analysis of variance models. Results The presence of a BP in the PD patients was demonstrated. The mean amplitudes at 0 ms were respectively 0.6 µV and 3.3 µV for the BP patients and the normal controls, respectively. Conclusions The BP amplitudes were significantly smaller in PD patients than normal participants. The amplitudes of the BP were not modified by levodopa.

  8. Circulating thyrotropin is upregulated by estradiol

    Directory of Open Access Journals (Sweden)

    Salvatore Benvenga

    2018-03-01

    Full Text Available After encountering two women with serum thyrotropin (TSH levels greater in periovulatory phase than in other days of the menstrual cycle, we hypothesized that TSH levels could be sensitive to changes in circulating estrogens in women.The objective of this study was to evaluate whether serum TSH increases after an induced acute increase of serum estradiol, and compare serum TSH increase with that of prolactin (PRL which is a classic estradiol-upregulated pituitary hormone.In this retrospective study, we resorted to stored frozen sera from 55 women who had undergone the GnRH agonist (buserelin-acute stimulation test of ovarian steroidogenesis. This test, that is preceded by dexamethasone administration to suppress adrenal steroidogenesis, had been performed to show an increased buserelin-stimulated response of 17-hydroxyprogesterone, a response that is frequent in polycystic ovary syndrome. Fifty-five women had enough serum volume at pertinent times (first observation early in the follicular phase and all times of the test to permit assay of serum estradiol, TSH and PRL.Before dexamethasone administration, estradiol averaged 26.4 ± 15.5 pg/ml (reference range 23–139, follicular phase, TSH 1.78 ± 0.86 mU/L (reference range 0.3–4.2 and PRL 409.4 ± 356 mU/L (reference range 70.8–556 (mean ± SD.Serum estradiol, TSH and PRL averaged 47.2 ± 27 pg/ml, 0.77 ± 0.48 mU/L and 246.4 ± 206.8 mU/L just prior to the buserelin injection, but they peaked at 253.4 ± 113.5 pg/ml (nv 83–495, midcycle, 3.30 ± 1.65 mU/L and 540.3 ± 695.2 mU/L after injection. The responses to buserelin of estradiol, TSH and PRL were of wide magnitude. There was a significant correlation between TSH peak and serum estradiol peak, betweeen AUC0-24 h-TSH and AUC0-24 h-estradiol, or between PRL peak and estradiol peak and AUC0-24 h -PRL and AUC0-24 h-estradiol in only a subgroup of women.Therefore, women

  9. APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage.

    Science.gov (United States)

    Phuah, Chia-Ling; Raffeld, Miriam R; Ayres, Alison M; Gurol, M Edip; Viswanathan, Anand; Greenberg, Steven M; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D

    2016-08-01

    We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk. We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects. A total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends. APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.

  10. USING PRECEDENTS FOR REDUCTION OF DECISION TREE BY GRAPH SEARCH

    Directory of Open Access Journals (Sweden)

    I. A. Bessmertny

    2015-01-01

    Full Text Available The paper considers the problem of mutual payment organization between business entities by means of clearing that is solved by search of graph paths. To reduce the decision tree complexity a method of precedents is proposed that consists in saving the intermediate solution during the moving along decision tree. An algorithm and example are presented demonstrating solution complexity coming close to a linear one. The tests carried out in civil aviation settlement system demonstrate approximately 30 percent shortage of real money transfer. The proposed algorithm is planned to be implemented also in other clearing organizations of the Russian Federation.

  11. Design of a Secure RFID Authentication Scheme Preceding Market Transactions

    Directory of Open Access Journals (Sweden)

    Chin-Ling Chen

    2011-01-01

    Full Text Available In recent years, as RFID reader equipment is ever more widely deployed in handled devices, the importance of security problems among RFID reader, tags and server have obviously gained increased attention. However, there are still many security issues preceding transactions; these issues are well worth discussing. In this paper, we propose a novel authentication scheme, conforming EPC C1G2 standards, at a low implementation cost for market application. In order to achieve mutual authentication, the proposed scheme integrates fingerprint biometrics, related cryptology and a hash function mechanism to ensure the security of the transmitted messages. The proposed scheme also can resist known attacks.

  12. Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues

    International Nuclear Information System (INIS)

    Vickers, Alison E.M.; Sinclair, John R.; Fisher, Robyn L.; Morris, Stephen R.; Way, William

    2010-01-01

    A novel in vitro model to investigate time-dependent and concentration-dependent responses in blood cells and hemolytic events is studied for rat, dog, and human tissues. Whole blood is co-cultured with a precision-cut liver slice. Methimazole (MMI) was selected as a reference compound, since metabolism of its imidazole thione moiety is linked with hematologic disorders and hepatotoxicity. An oxidative stress response occurred in all three species, marked by a decline in blood GSH levels by 24 h that progressed, and preceded hemolysis, which occurred at high MMI concentrations in the presence of a liver slice with rat (≥ 1000 μM at 48 h) and human tissues (≥ 1000 μM at 48 h, ≥ 750 μM at 72 h) but not dog. Human blood-only cultures exhibited a decline of GSH levels but minimal to no hemolysis. The up-regulation of liver genes for heme degradation (Hmox1 and Prdx1), iron cellular transport (Slc40a1), and GSH synthesis and utilization (mGST1 and Gclc) were early markers of the oxidative stress response. The up-regulation of the Kupffer cell lectin Lgals3 gene expression indicated a response to damaged red blood cells, and Hp (haptoglobin) up-regulation is indicative of increased hemoglobin uptake. Up-regulation of liver IL-6 and IL-8 gene expression suggested an activation of an inflammatory response by liver endothelial cells. In summary, MMI exposure led to an oxidative stress response in blood cells, and an up-regulation of liver genes involved with oxidative stress and heme homeostasis, which was clearly separate and preceded frank hemolysis.

  13. Selective attention in the honeybee optic lobes precedes behavioral choices

    Science.gov (United States)

    Paulk, Angelique C.; Stacey, Jacqueline A.; Pearson, Thomas W. J.; Taylor, Gavin J.; Moore, Richard J. D.; Srinivasan, Mandyam V.; van Swinderen, Bruno

    2014-01-01

    Attention allows animals to respond selectively to competing stimuli, enabling some stimuli to evoke a behavioral response while others are ignored. How the brain does this remains mysterious, although it is increasingly evident that even animals with the smallest brains display this capacity. For example, insects respond selectively to salient visual stimuli, but it is unknown where such selectivity occurs in the insect brain, or whether neural correlates of attention might predict the visual choices made by an insect. Here, we investigate neural correlates of visual attention in behaving honeybees (Apis mellifera). Using a closed-loop paradigm that allows tethered, walking bees to actively control visual objects in a virtual reality arena, we show that behavioral fixation increases neuronal responses to flickering, frequency-tagged stimuli. Attention-like effects were reduced in the optic lobes during replay of the same visual sequences, when bees were not able to control the visual displays. When bees were presented with competing frequency-tagged visual stimuli, selectivity in the medulla (an optic ganglion) preceded behavioral selection of a stimulus, suggesting that modulation of early visual processing centers precedes eventual behavioral choices made by these insects. PMID:24639490

  14. Burnout: co-workers' perceptions of signs preceding workmates' burnout.

    Science.gov (United States)

    Ericson-Lidman, Eva; Strandberg, Gunilla

    2007-10-01

    This paper is a report of a study to describe co-workers' perceptions of signs preceding workmates' burnout. Burnout engenders emotional and economic suffering, both individual and societal. It is therefore important to learn to recognize early signs to prevent burnout and co-workers, who have opportunities to recognize such signs, are valuable resources in this context. Fifteen interviews were conducted with nursing and medical staff in Sweden who had worked with a person who developed burnout. The interviews took place in 2004 and were analysed using a thematic content analysis. The narratives were obtained when co-workers already knew that their workmates were on sick leave because of burnout or had left their employment after sick leave because of burnout. The findings show that co-workers retrospectively recalled a multiplicity of signs. They perceived that the people concerned were struggling to manage alone, showing self-sacrifice, struggling to achieve unattainable goals, becoming distanced and isolated, and showing signs of falling apart. Some of the signs preceding workmates' burnout may be difficult to interpret as signs of burnout, because they may be regarded as qualities which are to some extent encouraged in the prevailing culture. The findings provide a complex picture of these signs that will hopefully increase our awareness of and ability to recognize such signs to facilitate the possibilities of our helping in time. The sub-themes and themes in the present study may also serve as a basis for supervisors involved in supporting clinical staff.

  15. Human behavior preceding dog bites to the face.

    Science.gov (United States)

    Rezac, P; Rezac, K; Slama, P

    2015-12-01

    Facial injuries caused by dog bites pose a serious problem. The aims of this study were to determine human behavior immediately preceding a dog bite to the face and to assess the effects of victim age and gender and dog sex and size on the location of the bite to the face and the need for medical treatment. Complete data on 132 incidents of bites to the face were analysed. A human bending over a dog, putting the face close to the dog's face, and gazing between victim and dog closely preceded a dog bite to the face in 76%, 19% and 5% of cases, respectively. More than half of the bites were directed towards the central area of the victim's face (nose, lips). More than two thirds of the victims were children, none of the victims was an adult dog owner and only adult dogs bit the face. Victim's age and gender and dog's sex and size did not affect the location of the bite on the face. People who were bitten by large dogs sought medical treatment more often than people who were bitten by small dogs (P face close to the dog's face and gazing between human and dog should be avoided, and children should be carefully and constantly supervised when in the presence of dogs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Self-potential variations preceding earthquakes in central california

    International Nuclear Information System (INIS)

    Corwin, R.F.; Morrison, H.G.

    1977-01-01

    Two earthquakes in central California were preceded by anomalous variations in the horizontal electric field (self-potential) of the earth. The first variation was an anomaly of 90 mV amplitude across electrode dipoles of 630 and 640 m, which began 55 days before an earthquake of M=5, located 37 km NW of the dipoles. The second variation had an amplitude of 4 mV across a 300 m dipole, and began 110 hours before an event of M=2.4 located on the San Andreas fault, 2.5 km from the dipole. Streaming potentials generated by the flow of groundwater into a dilatant zone are proposed as a possible mechanism for the observed variations

  17. Revisiting Precede-Proceed: A Leading Model for Ecological and Ethical Health Promotion

    Science.gov (United States)

    Porter, Christine M.

    2016-01-01

    Background: The Precede-Proceed model has provided moral and practical guidance for the fields of health education and health promotion since Lawrence Green first developed Precede in 1974 and Green and Kreuter added Proceed in 1991. Precede-Proceed today remains the most comprehensive and one of the most used approaches to promoting health.…

  18. Ceramide-induced TCR up-regulation

    DEFF Research Database (Denmark)

    Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J

    2000-01-01

    inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3gamma L-based motif and thus acted on TCR engaged in the recycling......The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein...... kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected...

  19. Upstream Subtropical Signals Preceding the Asian Summer Monsoon Circulation.

    Science.gov (United States)

    Yang, Song; Lau, K.-M.; Yoo, S.-H.; Kinter, J. L.; Miyakoda, K.; Ho, C.-H.

    2004-11-01

    In this study, the authors address several issues with respect to the antecedent signals of the large-scale Asian summer monsoon that were earlier identified by Webster and Yang. In particular, they revisit the changes in the subtropical upper-tropospheric westerlies preceding the monsoon, depict the detailed structure of the monsoon's antecedent signals, and investigate the physical processes from the signals to the monsoon. They also explore the teleconnection of these signals to various large-scale climate phenomena and emphasize the importance of the upstream location of the signals relative to the Tibetan Plateau and the monsoon.Before a strong (weak) Asian summer monsoon, the 200-mb westerlies over subtropical Asia are weak (strong) during the previous winter and spring. A significant feature of these signals is represented by the variability of the Middle East jet stream whose changes are linked to the Arctic Oscillation, North Atlantic Oscillation, El Niño Southern Oscillation, and other climate phenomena. When this jet stream intensifies and shifts southeastward, cold air intrudes frequently from eastern Europe into the Middle East and southwestern Asia. As a result, in subtropical Asia, snow and precipitation increase, the ground wetness increases, and surface temperature decreases. A strengthening Middle East jet stream is also accompanied by increases in both stationary wave activity flux and higher-frequency eddy activities. The Tibetan Plateau acts to block these westerly activities propagating eastward and increase the persistence of the low-temperature anomalies, which in turn prolongs the atmospheric signals from winter to spring.A strong link is found between the persistent low-temperature anomalies and the decrease in geopotential height over southern Asia, including the Tibetan Plateau, in spring. The latter indicates a late establishment of the South Asian high, and implies a delay in the atmospheric transition from winter to summer conditions

  20. The Kosovo Precedent in the Secession and Recognition of Crimea

    Directory of Open Access Journals (Sweden)

    Dr.Sc. Elvina Jusufaj

    2015-06-01

    Full Text Available Crimea’s secession from Ukraine and its annexation to the Russian Federation invoked Kosovo precedent, in its declaration of independence, as an argument for secession. The territorial referendum in the Autonomous Republic of Crimea, only five days after the declaration of independence, was an attempt to justify the secession based on the right to selfdetermination of the people of Crimea. It is overwhelmingly considered illegal and its outcome has not been accepted and recognized by states, regional and international organizations. The comparative elements of statehood and secession between Kosovo and Crimea are reflected through analyzing the declarations of independence, international recognition and Russia’s role as a third-state factor in external selfdetermination. Essential distinctions are highlighted. Kosovo is widely acknowledged and accepted a sui generis case. Its declaration of independence came as result of a long monitored comprehensive process; not to legitimize the right for self-determination but as the final option for stability and peace in the region. Crimea seceded in violation of international law through the use of force. While Kosovo is a democratic, multi-ethnic new state and recognized by 107 states, the secession of Crimea and its annexation to the Russian Federation is considered illegal and endangers the existing international order.

  1. Bell's Palsy: Symptoms Preceding and Accompanying the Facial Paresis

    Science.gov (United States)

    Mancini, Patrizia; Minni, Antonio; Prosperini, Luca; De Seta, Elio; Attanasio, Giuseppe; Covelli, Edoardo; De Carlo, Andrea; Filipo, Roberto

    2014-01-01

    This individual prospective cohort study aims to report and analyze the symptoms preceding and accompanying the facial paresis in Bell's palsy (BP). Two hundred sixty-nine patients affected by BP with a maximum delay of 48 hours from the onset were enrolled in the study. The evolution of the facial paresis expressed as House-Brackmann grade in the first 10 days and its correlation with symptoms were analyzed. At the onset, 136 patients presented postauricular pain, 114 were affected by dry eye, and 94 reported dysgeusia. Dry mouth was present in 54 patients (19.7%), facial pain, hyperlacrimation, aural fullness, and hyperacusis represented a smaller percentage of the reported symptoms. After 10 days, 39.9% of the group had a severe paresis while 10.2% reached a complete recovery. Dry mouth at the onset was correlated with severe grade of palsy and was prognostic for poor recovery in the early period. These outcomes lead to the deduction that the nervus intermedius plays an important role in the presentation of the BP and it might be responsible for most of the accompanying symptomatology of the paresis. Our findings could be of important interest to early address a BP patient to further examinations and subsequent therapy. PMID:25544960

  2. Precedents For Authorization Of Contents Using Dose Rate Measurements

    International Nuclear Information System (INIS)

    Abramczyk, G.; Bellamy, S.; Nathan, S.; Loftin, B.

    2012-01-01

    For the transportation of Radioactive Material (RAM) packages, the requirements for the maximum allowed dose rate at the package surface and in its vicinity are given in Title 10 of the Code of Federal Regulations, Section 71.47. The regulations are based on the acceptable dose rates to which the public, workers, and the environment may be exposed. As such, the regulations specify dose rates, rather than quantity of radioactive isotopes and require monitoring to confirm the requirements are met. 10CFR71.47 requires that each package of radioactive materials offered for transportation must be designed and prepared for shipment so that under conditions normally incident to transportation the radiation level does not exceed 2 mSv/h (200 mrem/h) at any point on the external Surface of the package, and the transport index does not exceed 10. Before shipment, the dose rate of the package is determined by measurement, ensuring that it conforms to the regulatory limits, regardless of any analyses. This is the requirement for all certified packagings. This paper discusses the requirements for establishing the dose rates when shipping RAM packages and the precedents for meeting these requirements by measurement.

  3. HIGH RATES OF EVOLUTION PRECEDED THE ORIGIN OF BIRDS

    Science.gov (United States)

    Puttick, Mark N; Thomas, Gavin H; Benton, Michael J; Polly, P David

    2014-01-01

    The origin of birds (Aves) is one of the great evolutionary transitions. Fossils show that many unique morphological features of modern birds, such as feathers, reduction in body size, and the semilunate carpal, long preceded the origin of clade Aves, but some may be unique to Aves, such as relative elongation of the forelimb. We study the evolution of body size and forelimb length across the phylogeny of coelurosaurian theropods and Mesozoic Aves. Using recently developed phylogenetic comparative methods, we find an increase in rates of body size and body size dependent forelimb evolution leading to small body size relative to forelimb length in Paraves, the wider clade comprising Aves and Deinonychosauria. The high evolutionary rates arose primarily from a reduction in body size, as there were no increased rates of forelimb evolution. In line with a recent study, we find evidence that Aves appear to have a unique relationship between body size and forelimb dimensions. Traits associated with Aves evolved before their origin, at high rates, and support the notion that numerous lineages of paravians were experimenting with different modes of flight through the Late Jurassic and Early Cretaceous. PMID:24471891

  4. Activities preceding a decline in the paratuberculosis test prevalence

    DEFF Research Database (Denmark)

    Nielsen, Søren Saxmose; Toft, Nils

    . A challenge in evaluation of activities in a national programme it is essentially a sample size of one without a control group. Therefore, the apparent effect of activities on programme level can only be descriptive. Our objective was to describe the decline in the test-prevalence along with the activities...... preceding this decline. The cohort of herds enrolled in 2006-2007 had an average estimated within-herd test-prevalence of 10% at start. By January 2014 this had declined to 2%. The test-prevalence in the cohort of herds enrolled in 2008-2010 started at approximately 6% and by January 2014 was reduced...... to about 3%. In addition to these data, a “sampling error” in August 2011 resulted in the availability of a sample of 99 herds that were not enrolled in the programme. They had a median test-prevalence of 5.5% compared to 3.1% in 268 herds from the 2006-2007 cohort tested in the same month. This sample...

  5. Activities preceding a decline in the paratuberculosis test prevalence

    DEFF Research Database (Denmark)

    Nielsen, Søren Saxmose; Toft, Nils

    A voluntary control programme on Mycobacterium avium subsp. paratuberculosis (MAP) was initiated in Denmark in 2006 and has since 2007 included 25-28% of the dairy herds and 35-40% of the dairy cows. The programme was complemented with activities aimed to reduce the MAP infection prevalence. A ch...... for a “continuous” flow of diagnostic test information four times annually in each herd. This information can be used for detection and management of infectious animals and for prevalence monitoring........ A challenge in evaluation of activities in a national programme it is essentially a sample size of one without a control group. Therefore, the apparent effect of activities on programme level can only be descriptive. Our objective was to describe the decline in the test-prevalence along with the activities...... preceding this decline. The cohort of herds enrolled in 2006-2007 had an average estimated within-herd test-prevalence of 10% at start. By January 2014 this had declined to 2%. The test-prevalence in the cohort of herds enrolled in 2008-2010 started at approximately 6% and by January 2014 was reduced...

  6. Oral Hygiene Behaviors and Caries Experience in Northwest PRECEDENT Patients

    Science.gov (United States)

    Rothen, Marilynn; Cunha-Cruz, Joana; Zhou, Lingmei; Mancl, Lloyd; Jones, Jackie S.; Berg, Joel

    2014-01-01

    Objectives To investigate the association between oral hygiene behaviors (toothbrushing, water rinsing after brushing, interproximal cleaning, and adjunctive use of fluoride products) and recent caries (past 24 months) in a random sample of patients in Northwest PRECEDENT practices. Methods Practitioner-members of Northwest PRECEDENT dental Practice-based Research Network (PBRN) conducted a longitudinal study on caries risk assessment. At baseline patients completed a questionnaire on oral self-care, snacking, health, and socio-demographics. A dental exam recorded readily-visible heavy plaque and DMFT; chart review captured new caries and treatments in the previous 24 months. Bivariate and multiple GEE log-linear regression models stratified by age groups were used to relate oral hygiene behaviors to the primary outcome of mean dental caries in the past 24 months on data from 1400 patients in 63 practices. The primary exposure of interest was fluoride toothbrushing frequency. Results Fluoride toothbrushing once per day or more by patients 9-17 was significantly associated with a 50% lower mean caries rate compared to fluoride toothbrushing less than once per day, after adjustment for age, gender, race, education, income, between-meal carbohydrate snacks, sugar-added beverages, alcohol consumption, smoking, BMI, exercise, stimulated salivary pH, number of teeth, and all other oral hygiene behaviors captured [Rate Ratio (RR)=0.5; 95% confidence interval (CI)=0.3-0.8]. After adjustment, for patients 18-64 fluoride toothbrushing two or more times per day was significantly associated with a 40% lower recent mean caries rate (RR=0.6; 95%CI=0.4-0.9); in patients 65+, twice a day or more fluoride toothbrushing was not associated with lower caries rates (RR=1.1; 95%CI=0.7-1.8). Of the other oral hygiene variables, after adjustment, patients 18-64 who rinsed with water after brushing had a 40% lower mean caries rate compared to no rinsing (RR=0.6; 95%CI=0.4-0.9) and the

  7. Oral hygiene behaviors and caries experience in Northwest PRECEDENT patients.

    Science.gov (United States)

    Rothen, Marilynn; Cunha-Cruz, Joana; Zhou, Lingmei; Mancl, Lloyd; Jones, Jackie S; Berg, Joel

    2014-12-01

    To investigate the association between oral hygiene behaviors (toothbrushing, water rinsing after brushing, interproximal cleaning, and adjunctive use of fluoride products) and recent caries (past 24 months) in a random sample of patients in Northwest PRECEDENT practices. Practitioner-members of Northwest PRECEDENT, a dental practice-based research network, conducted a longitudinal study on caries risk assessment. At baseline, patients completed a questionnaire on oral self-care, snacking, health, and socio-demographics. A dental examination recorded readily visible heavy plaque and decayed, missing, and filled teeth; chart review captured new caries and treatments in the previous 24 months. Bivariate and multiple generalized estimating equations (GEE) log-linear regression models stratified by age-groups were used to relate oral hygiene behaviors to the primary outcome of mean dental caries in the past 24 months on data from 1400 patients in 63 practices. The primary exposure of interest was fluoride toothbrushing frequency. Fluoride toothbrushing once per day or twice or more per day by patients 9-17 was significantly associated with a 50% lower mean caries rate compared with fluoride toothbrushing less than once per day, after adjustment for covariates [rate ratios (RR) = 0.5; 95% confidence intervals (CI) = 0.3-0.8]. After adjustment, for patients 18-64, fluoride toothbrushing two or more times per day was significantly associated with a 40% lower recent mean caries rate (RR = 0.6; 95% CI = 0.4-0.9); in patients 65+, twice a day or more fluoride toothbrushing was not associated with lower caries rates (RR = 1.1; 95% CI = 0.7-1.8). Of the other oral hygiene variables, after adjustment, patients 18-64 who rinsed with water after brushing had a 40% lower mean caries rate compared with no rinsing (RR = 0.6; 95% CI = 0.4-0.9) and the presence of readily visible heavy plaque was significantly associated with an increase in the mean caries rate for

  8. VEGF-mediated inflammation precedes angiogenesis in adult brain.

    Science.gov (United States)

    Croll, Susan D; Ransohoff, Richard M; Cai, Ning; Zhang, Qing; Martin, Francis J; Wei, Tao; Kasselman, Lora J; Kintner, Jennifer; Murphy, Andrew J; Yancopoulos, George D; Wiegand, Stanley J

    2004-06-01

    Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis when infused continuously into adult rat brain tissue. In addition, VEGF has been shown to enhance permeability in brain vasculature. Adult rats were continuously infused with mouse VEGF into neocortex for up to 7 days. We studied the development of VEGF-induced vasculature in rat neocortex and evaluated the temporal expression of a wide variety of markers for inflammation and vascular leak in relation to the angiogenic response using immunohistochemistry and Western blot analysis. We report here that VEGF-mediated inflammation in brain is characterized by upregulation of ICAM-1 and the chemokine MIP-1alpha, as well as a preferential extravasation of monocytes. VEGF causes a dramatic breakdown of the blood-brain barrier, which is characterized by decreased investment of the vasculature with astroglial endfeet. Perivascular cells, in contrast, increase around the newly formed cerebrovasculature. In addition, breakdown of the blood-brain barrier, leukocyte extravasation, and extracellular matrix deposition occur before vascular proliferation. Furthermore, administration of low doses of VEGF induces permeability and inflammation without appreciable vascular proliferation.

  9. Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions.

    Science.gov (United States)

    Lee, Sun Ha; Moon, Sung Jin; Paeng, Jisun; Kang, Hye-Young; Nam, Bo Young; Kim, Seonghun; Kim, Chan Ho; Lee, Mi Jung; Oh, Hyung Jung; Park, Jung Tak; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2015-08-01

    Podocyte hypertrophy and apoptosis are two hallmarks of diabetic glomeruli, but the sequence in which these processes occur remains a matter of debate. Here we investigated the effects of inhibiting hypertrophy on apoptosis, and vice versa, in both podocytes and glomeruli, under diabetic conditions. Hypertrophy and apoptosis were inhibited using an epidermal growth factor receptor inhibitor (PKI 166) and a pan-caspase inhibitor (zAsp-DCB), respectively. We observed significant increases in the protein expression of p27, p21, phospho-eukaryotic elongation factor 4E-binding protein 1, and phospho-p70 S6 ribosomal protein kinase, in both cultured podocytes exposed to high-glucose (HG) medium, and streptozotocin-induced diabetes mellitus (DM) rat glomeruli. These increases were significantly inhibited by PKI 166, but not by zAsp-DCB. In addition, the amount of protein per cell, the relative cell size, and the glomerular volume were all significantly increased under diabetic conditions, and these changes were also blocked by treatment with PKI 166, but not zAsp-DCB. Increased protein expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, together with increased Bax/Bcl-2 ratios, were also observed in HG-stimulated podocytes and DM glomeruli. Treatment with either zAsp-DCB or PKI 166 resulted in a significant attenuation of these effects. Both PKI 166 and zAsp-DCB also inhibited the increase in number of apoptotic cells, as assessed by Hoechst 33342 staining and TUNEL assay. Under diabetic conditions, inhibition of podocyte hypertrophy results in attenuated apoptosis, whereas blocking apoptosis has no effect on podocyte hypertrophy, suggesting that podocyte hypertrophy precedes apoptosis.

  10. Pentobarbital anesthesia alters neural responses in the precedence effect.

    Science.gov (United States)

    Song, Penglong; Wang, Ningyu; Wang, Hui; Xie, Yan; Jia, Jun; Li, Huijun

    2011-07-01

    The precedence effect (PE) is thought to be beneficial for proper localization and perception of sounds. The majority of recent physiological studies focus on the neural discharges correlated with PE in the inferior colliculus (IC). Pentobarbital anesthesia is widely used in physiological studies. However, little is known of the effect of pentobarbital on the discharge of neurons in PE. Neuronal responses in the IC from 23 male SD rats were recorded by standard extracellular recording techniques following presentation of 4 ms white noise bursts, presented from either or both of two loud speakers, at different interstimulus delays (ISDs). The neural responses were recorded for off-line analysis before or after intraperitoneal administration of pentobarbital at a loading or maintenance dose. Data were assessed by one-way repeated measures analysis of variance and pairwise comparisons. When the ipsilateral stimuli were leading, pentobarbital at a loading dose significantly increased normalized response to lagging stimuli during recovery from anesthesia. However, it was not the case when the contralateral stimuli were leading. At a maintenance dose, the normalized response to lagging stimuli were significantly reduced, independent of whether contralateral or ipsilateral stimuli were leading. These data show that pentobarbital have no effect on the normalized response of leading stimuli but can prolong the recovery time of lagging stimuli to paired sources produced PE illusions, which was gradually attenuated during recovery from anesthesia. Thus, extracellular recording immediately after administration of pentobarbital should be avoided in physiological studies of neural correlates of PE. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.

    Science.gov (United States)

    Sapone, Anna; de Magistris, Laura; Pietzak, Michelle; Clemente, Maria G; Tripathi, Amit; Cucca, Francesco; Lampis, Rosanna; Kryszak, Deborah; Cartenì, Maria; Generoso, Maddalena; Iafusco, Dario; Prisco, Francesco; Laghi, Francesca; Riegler, Gabriele; Carratu, Romano; Counts, Debra; Fasano, Alessio

    2006-05-01

    Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.

  12. Judicial precedent in the Nigerian legal system and a case for its ...

    African Journals Online (AJOL)

    It is noted that International Court of Justice is not bound to follow judicial precedence in its decisions. The statute of the International Court of Justice expressly foreclosed the adoption of precedence in decisions of the court. This is an exclusion that impacts negatively on the cause of justice in international judicial forum like ...

  13. Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes

    Directory of Open Access Journals (Sweden)

    Philpott Michael P

    2010-02-01

    Full Text Available Abstract Background The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus. This indicates that upregulation of FOXM1 may be an early molecular signal required for aberrant cell cycle and cancer initiation. Results The present study investigated the putative early mechanism of UVB and FOXM1 in skin cancer initiation. We have demonstrated that UVB dose-dependently increased FOXM1 protein levels through protein stabilisation and accumulation rather than de novo mRNA expression in human epidermal keratinocytes. FOXM1 upregulation in primary human keratinocytes triggered pro-apoptotic/DNA-damage checkpoint response genes such as p21, p38 MAPK, p53 and PARP, however, without causing significant cell cycle arrest or cell death. Using a high-resolution Affymetrix genome-wide single nucleotide polymorphism (SNP mapping technique, we provided the evidence that FOXM1 upregulation in epidermal keratinocytes is sufficient to induce genomic instability, in the form of loss of heterozygosity (LOH and copy number variations (CNV. FOXM1-induced genomic instability was significantly enhanced and accumulated with increasing cell passage and this instability was increased even further upon exposure to UVB resulting in whole chromosomal gain (7p21.3-7q36.3 and segmental LOH (6q25.1-6q25.3. Conclusion We hypothesise that prolonged and repeated UVB exposure selects for skin cells bearing stable FOXM1 protein causes aberrant cell cycle checkpoint thereby allowing ectopic cell cycle entry and subsequent genomic instability. The aberrant

  14. Fluoxetin Upregulates Connexin 43 Expression in Astrocyte

    Directory of Open Access Journals (Sweden)

    Hossein Mostafavi

    2014-02-01

    Full Text Available Introduction: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS. Molecular target therapy studies in MS have revealed that connexin-43 (Cx43 and Aquaporin-4 (AQP4 contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte.  Methods: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 &mug/ml with or without adenyl cyclase (AC and protein kinase A (PKA inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated.  Results: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed.  Discussion: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches.

  15. The New Civil Procedure Code And The Binding Precedents: Reflections In Search Of An Adequate Application

    Directory of Open Access Journals (Sweden)

    Ellen Carina Mattias Sartori

    2016-12-01

    Full Text Available The new Civil Procedure Code revered the binding precedents as a way of shield the constitutionals principles of isonomy and legal security, as well as jurisdiction unit. The absence of a juridical culture based on precedents in Brazil, however, brings out several imprecisions that put on threat the objectives of the new Code. The article, thus, reflects about some application and flexibility precedent´s techniques, developed over the years in the countries that adopted the common law, that would be essential for the new code to reach the intention to establish a fast, effective, fair and equal jurisdictional activity.

  16. An improved car-following model accounting for the preceding car's taillight

    Science.gov (United States)

    Zhang, Jian; Tang, Tie-Qiao; Yu, Shao-Wei

    2018-02-01

    During the deceleration process, the preceding car's taillight may have influences on its following car's driving behavior. In this paper, we propose an extended car-following model with consideration of the preceding car's taillight. Two typical situations are used to simulate each car's movement and study the effects of the preceding car's taillight on the driving behavior. Meanwhile, sensitivity analysis of the model parameter is in detail discussed. The numerical results show that the proposed model can improve the stability of traffic flow and the traffic safety can be enhanced without a decrease of efficiency especially when cars pass through a signalized intersection.

  17. Exact and Heuristic Algorithms for Routing AGV on Path with Precedence Constraints

    Directory of Open Access Journals (Sweden)

    Liang Xu

    2016-01-01

    Full Text Available A new problem arises when an automated guided vehicle (AGV is dispatched to visit a set of customers, which are usually located along a fixed wire transmitting signal to navigate the AGV. An optimal visiting sequence is desired with the objective of minimizing the total travelling distance (or time. When precedence constraints are restricted on customers, the problem is referred to as traveling salesman problem on path with precedence constraints (TSPP-PC. Whether or not it is NP-complete has no answer in the literature. In this paper, we design dynamic programming for the TSPP-PC, which is the first polynomial-time exact algorithm when the number of precedence constraints is a constant. For the problem with number of precedence constraints, part of the input can be arbitrarily large, so we provide an efficient heuristic based on the exact algorithm.

  18. Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer.

    Science.gov (United States)

    Chen, Ru; Pan, Sheng; Lai, Keith; Lai, Lisa A; Crispin, David A; Bronner, Mary P; Brentnall, Teresa A

    2014-12-07

    To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer. Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer. Immunohistochemical analysis was used to evaluate TRAP1 expression on tissue microarrays containing colonic tissues from 42 UC progressors (patients with cancer or dysplasia) and 38 non-progressors (dysplasia/cancer free patients). Statistical analyses of the TRAP1 immunohistochemistry staining were performed using GraphPad Prism. Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test. Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls. TRAP1 was up-regulated in the colon tissues from UC progressors, but not in the colon tissues from UC non-progressors. Moreover, up-regulation of TRAP1 preceded the neoplastic changes: it was present in both the dysplastic and non-dysplastic tissues of UC progressors. When TRAP1 staining in rectal tissue was used as a diagnostic marker, it could distinguish progressors from non-progressors with 59% sensitivity and 80% specificity. Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues, which could be related to the increased oxidation present in the colonic mucosa from UC progressors. We then investigated the cellular proteome changes underlying oxidative stress, and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis. These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1, which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from

  19. The Arab-Israeli Conflict: The War of Attrition and Preparations Preceding the October 1973 War

    Science.gov (United States)

    1986-06-06

    CO 00 o CO < I O < THE ARAB -ISRAELI CONFLICT! THE WAR OF ATTRITION AND PREPARATIONS PRECEDING THE OCTOBER 1973 WAR A thesis presented...SECURITY CLASSIFICATION OF THIS PAGE THE ARAB -ISRAELI CONFLICT: THE WAR OF ATTRITION AND PREPARATIONS PRECEDING THE OCTOBER 1973 WAR A thesis...APPROVAL PA6E Name o-f Candidate: Major Jerry R. Thornberry Title o-f Thesis: The Arab -Israeli Conflict - The War o-f Attrition and Preparations

  20. Apollon/Bruce is upregulated by Humanin.

    Science.gov (United States)

    Hashimoto, Yuichi; Takeshita, Yuji; Naito, Mikihiko; Uchino, Hiroyuki; Matsuoka, Masaaki

    2014-12-01

    Humanin, a short bioactive peptide, inhibits a variety of cell deaths. Humanin-mediated inhibition of neuronal cell death, caused by an Alzheimer's disease (AD)-linked mutant gene occurs via binding of Humanin to its heterotrimeric Humanin receptor (htHNR), which results in the activation of the Janus-associated kinases (JAKs) and signal transducer and activator and transcription 3 (STAT3) signaling pathway. A previous study demonstrated that the Humanin-induced activation of the htHNR/JAK2/STAT3 signaling pathway leads to increased expression of SH3 domain-binding protein 5 (SH3BP5), which is an essential effector of Humanin's anti-cell death activity in some cultured neuronal cells. However, it remains unknown whether SH3BP5 is the sole effector of the Humanin signaling pathway via htHNR/JAKs/STAT3. Here we show that the Humanin signaling pathway via htHNR/JAKs/STAT3 increased the expression levels of mRNA and protein of Apollon/Bruce, an unusual member of the inhibitors of apoptosis proteins, and that overexpression of Apollon/Bruce inhibits neuronal death, caused by a London-type familial AD-linked mutant (V642I) of amyloid β precursor protein. Overall, the results indicate that expression of Apollon/Bruce is upregulated by Humanin, and Apollon/Bruce could be an effector of Humanin in a context-dependent manner.

  1. Upregulation of Leukotriene Receptors in Gastric Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Venerito, Marino [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Kuester, Doerthe [Institute of Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Harms, Caroline [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Schubert, Daniel [Department of General, Visceral and Vascular Surgery, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg 39120 (Germany); Wex, Thomas, E-mail: thomas.wex@med.ovgu.de; Malfertheiner, Peter [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany)

    2011-08-08

    Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis.

  2. No evidence of conpopulation sperm precedence between allopatric populations of house mice.

    Directory of Open Access Journals (Sweden)

    Renée C Firman

    Full Text Available Investigations into the evolution of reproductive barriers have traditionally focused on closely related species, and the prevalence of conspecific sperm precedence. The effectiveness of conspecific sperm precedence at limiting gene exchange between species suggests that gametic isolation is an important component of reproductive isolation. However, there is a paucity of tests for evidence of sperm precedence during the earlier stages of divergence, for example among isolated populations. Here, we sourced individuals from two allopatric populations of house mice (Mus domesticus and performed competitive in vitro fertilisation assays to test for conpopulation sperm precedence specifically at the gametic level. We found that ova population origin did not influence the outcome of the sperm competitions, and thus provide no evidence of conpopulation or heteropopulation sperm precedence. Instead, we found that males from a population that had evolved under a high level of postcopulatory sexual selection consistently outcompeted males from a population that had evolved under a relatively lower level of postcopulatory sexual selection. We standardised the number of motile sperm of each competitor across the replicate assays. Our data therefore show that competitive fertilizing success was directly attributable to differences in sperm fertilizing competence.

  3. Study on Determination of Preceding Vehicle Motion State at the Traffic Lights Intersection

    Directory of Open Access Journals (Sweden)

    Cailin Wu

    2014-10-01

    Full Text Available In order to enhance the security of automotive safety systems and reduce traffic accidents in traffic lights intersection, In view of this, it is proposed to apply the distance measurement technology of binocular vision ranging in determination of preceding vehicle motion state at the traffic lights intersection, We study the determination of preceding vehicle motion state at the traffic lights intersection based on binocular vision. The system, which is divided into four steps, adopts the theory combining the binocular stereo vision principle and the triangulation principle. First of all, from different angles, image information with preceding vehicles and traffic lights, collected by two CCD cameras, is processed and positioned. Next, two pairs of corresponding feature matching points is obtained by using the stereo matching method. Furthermore, the distance between the cameras and the preceding vehicle, and the distance between the cameras and the traffic lights are determined, according to the camera calibration technique, the parallax disparity principle and the triangulation principle. Finally, the determination about the motion state of traffic lights intersection is determined according to the distance difference principle. Experimental results show that the design, with high measurement accuracy and application value, realize the determination of preceding vehicle’s motion state at traffic lights intersection.

  4. Use of oral antihypertensive medication preceding blood pressure elevation in hospitalized patients

    Directory of Open Access Journals (Sweden)

    Macedo Cristiano Ricardo Bastos de

    2001-01-01

    Full Text Available OBJECTIVE: To evaluate the frequency of oral antihypertensive medication preceding the increase in blood pressure in patients in a university hospital, the drug of choice, and the maintained use of antihypertensive medication. METHODS: Data from January to June 1997 from the University Hospital Professor Edgard Santos Pharmacy concerning the prescriptions of all inpatients were used. Variables included in the analysis were: antihypertensive medication prescription preceding increase in blood pressure, type of antihypertensive medication, gender, clinical or surgical wards, and the presence of maintained antihypertensive medication. RESULTS: The hospital admitted 2,532 patients, 1,468 in surgical wards and 818 in medical wards. Antihypertensive medication prescription preceding pressure increase was observed in 578 patients (22.8%. Nifedipine was used in 553 (95.7% and captopril in 25 (4.3%. In 50.7% of patients, prescription of antihypertensive medication was not associated with maintained antihypertensive medication. Prescription of antihypertensive drugs preceding elevation of blood pressure was significantly (p<0.001 more frequent on the surgical floor (27.5%; 405/1468 than on the medical floor (14.3%; 117/818. The frequency of prescription of antihypertensive drugs preceding elevation of blood pressure without maintained antihypertensive drugs and the ratio between the number of prescriptions of nifedipine and captopril were greater in surgical wards. CONCLUSION: The use of antihypertensive medication, preceding elevation of blood pressure (22.8% observed in admitted patients is not supported by scientific evidence. The high frequency of this practice may be even greater in nonuniversity hospitals.

  5. Developing Targeted Health Service Interventions Using the PRECEDE-PROCEED Model: Two Australian Case Studies

    Directory of Open Access Journals (Sweden)

    Jane L. Phillips

    2012-01-01

    Full Text Available Aims and Objectives. This paper provides an overview of the applicability of the PRECEDE-PROCEED Model to the development of targeted nursing led chronic illness interventions. Background. Changing health care practice is a complex and dynamic process that requires consideration of social, political, economic, and organisational factors. An understanding of the characteristics of the target population, health professionals, and organizations plus identification of the determinants for change are also required. Synthesizing this data to guide the development of an effective intervention is a challenging process. The PRECEDE-PROCEED Model has been used in global health care settings to guide the identification, planning, implementation, and evaluation of various health improvement initiatives. Design. Using a reflective case study approach, this paper examines the applicability of the PRECEDE-PROCEED Model to the development of targeted chronic care improvement interventions for two distinct Australian populations: a rapidly expanding and aging rural population with unmet palliative care needs and a disadvantaged urban community at higher risk of cardiovascular disease. Results. The PRECEDE-PROCEED Model approach demonstrated utility across diverse health settings in a systematic planning process. In environments characterized by increasing health care needs, limited resources, and growing community expectations, adopting planning tools such as PRECEDE-PROCEED Model at a local level can facilitate the development of the most effective interventions. Relevance to Clinical Practice. The PRECEDE-PROCEED Model is a strong theoretical model that guides the development of realistic nursing led interventions with the best chance of being successful in existing health care environments.

  6. Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q.

    LENUS (Irish Health Repository)

    Kelly, Kevin

    2008-12-01

    Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.

  7. Infrastructura i necessitat ambiental: els precedents de l'eix viari dels Túnels de Vallvidriera

    OpenAIRE

    Gabarró i Sust, Xavier

    1992-01-01

    A partir dels precedents de l'eix viari dels túnels de Vallvidrera, s'assaja sobre la problemàtica que origina l'impacte ambiental, tema del qual hi ha encara una certa manca d'informació i d'experiència arreu, pel fet que és un aspecte nou que encara no s'ha generalitzat a l'obra pública. L'obertura de l'eix viari esmentat va representar un precedent interessant quant a la possibilitat de fer compatibles al màxim les necessitats d'infrastructures amb el respecte al medi natural.

  8. The Preceding Voltage Pulse and Separation Welding Mechanism of Electrical Contacts

    DEFF Research Database (Denmark)

    Yang, Xiao Cheng; Huang, Jiang; Li, Zhen Biao

    2016-01-01

    , and changes in a contact gap and heights of pips with increases in operation cycles were observed through charge-coupled device cameras. The resultant test results show that welding in separation is accompanied with a preceding voltage pulse which represents arc rather than contact bounce arc....

  9. Last mated male sperm precedence in doubly mated females is not ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 92; Issue 2. Last mated male sperm precedence in doubly mated females is not ubiquitous: evidence from sperm competition in laboratory populations of Drosophila nasuta nasuta and Drosophila nasuta albomicans. B. Shruthi S. R. Ramesh. Research Note Volume 92 Issue 2 ...

  10. Bilateral orbital granulocytic sarcoma (chloroma) preceding the blast phase of acute myelogenous leukemia: CT findings

    International Nuclear Information System (INIS)

    Bulas, R.B.; Laine, F.J.; Das Narla, L.

    1995-01-01

    We report the CT findings of a case of bilateral intraorbital granulocytic sarcoma which preceded the blast phase of acute myelogenous leukemia (AML) and led to its diagnosis. An awareness of granulocytic sarcoma and its CT appearance may expedite the diagnosis of AML or prompt close monitoring of those cases of granulocytic sarcoma antedating the appearance of AML. (orig.)

  11. Use and adaptation of precedents in architectural design. Toward an evolutionary design model

    NARCIS (Netherlands)

    Moraes Zarzar, K.

    2003-01-01

    For centuries, architects have re-used design precedents in the conception of new design solutions. Whether explicitly - as in the case of Le Corbusier, James Stirling and Jo Coenen - or implicitly - as with J.J.P. Oud, Aldo van Eyk, and Santiago Calatrava - this practice has led to very

  12. Brachial plexitis preceding encephalomyelitis in a patient with West Nile virus infection.

    Science.gov (United States)

    Scholz, Sonja; Kaas, Bonnie; Simpkins, Alexis; Lyons, Jennifer; Venkatesan, Arun; Probasco, John

    2013-12-05

    We describe the case of a 54-year-old woman with West Nile virus infection presenting with painful brachial plexitis and radiculitis that preceded the more typically associated symptoms of meningoencephalitis. Physicians should be aware that West Nile virus infection can present with painful brachial plexitis.

  13. 7 CFR 1779.63 - Conditions precedent to issuance of the Loan Note Guarantee.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Conditions precedent to issuance of the Loan Note Guarantee. 1779.63 Section 1779.63 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) WATER AND WASTE DISPOSAL PROGRAMS...

  14. Energy-aware stochastic scheduler for batch of precedence-constrained jobs on heterogeneous computing system

    International Nuclear Information System (INIS)

    Sajid, Mohammad; Raza, Zahid

    2017-01-01

    The problem of optimal scheduling of precedence-constrained jobs as well as finding the Pareto-optimal sets for multi objective scheduling problem have been proven to be nondeterministic polynomial time (NP)-complete. The growing consumption of energy has compelled the researchers to consider energy consumption as an important parameter along with other parameters in multi-objective scheduling problem. Accordingly, many energy-aware precedence-constraints scheduling algorithms have been reported in the literature. Most of the algorithms have a limitation of treating this problem as a single objective optimization problem modelling with deterministic execution times rather than stochastic execution times. This work proposes energy-aware stochastic scheduler to schedule the batch of precedence-constrained jobs on dynamic voltage frequency scaling-enabled processors in order to optimize the energy consumption and the turnaround time. The execution and inter-communication times are stochastic which are drawn from independent probability distributions. A novel encoding for batch of precedence-constrained jobs, stochastic turnaround time and energy models are also proposed. Experimental results show that, compared with other algorithms, the proposed scheduler offers reduced turnaround time and reduced energy consumption. - Highlights: • This paper reports stochastic scheduler for energy management of data centres. • Novel encoding, turnaround time and energy consumption models are proposed. • Clark's equations are used to compute the turnaround time and energy consumption. • The proposed scheduler offers reduced turnaround time as well as energy consumption.

  15. Reconciling findings of emotion-induced memory enhancement and impairment of preceding items.

    Science.gov (United States)

    Knight, Marisa; Mather, Mara

    2009-12-01

    A large body of work has revealed that people remember emotionally arousing information better than neutral information. However, previous research has revealed contradictory effects of emotional events on memory for neutral events that precede or follow them: In some studies, emotionally arousing items have impaired memory for immediately preceding or following items, and in others arousing items enhanced memory for preceding items. By demonstrating both emotion-induced enhancement and impairment, Experiments 1 and 2 clarified the conditions under which these effects are likely to occur. The results suggest that emotion-induced enhancement is most likely to occur for neutral items that (a) precede (and so are poised to predict the onset of) emotionally arousing items, (b) have high attentional weights at encoding, and (c) are tested after a delay period of a week rather than within the same experimental session. In contrast, emotion-induced impairment is most likely to occur for neutral items near the onset of emotional arousal that are overshadowed by highly activated competing items during encoding.

  16. Investigating the build-up of precedence effect using reflection masking

    DEFF Research Database (Denmark)

    Hartcher-O'Brien, Jessica; Buchholz, Jörg

    2006-01-01

    The auditory processing level involved in the build-up of precedence [Freyman et al., J. Acoust. Soc. Am. 90, 874–884 (1991)] has been investigated here by employing reflection masked threshold (RMT) techniques. Given that RMT techniques are generally assumed to address lower levels of the auditory...

  17. Sinan and Palladio: A comparative morphological analysis of two sacred precedents

    Directory of Open Access Journals (Sweden)

    Buthayna Eilouti

    2017-06-01

    Full Text Available An exploratory study on the design schemes underlying two architectural precedents is presented and discussed. The study compares the formalistic compositions of two prominent precedents on multiple levels. These levels include the morphological, semantic, and pragmatic layers. The morphological aspects of these layers are emphasized. The study aims to identify the commonalities and differences between two cases of classical sacred architecture in terms of their morphometric and morphosyntactic structures. These cases are represented by Palladio׳s II Redentore Church and Sinan׳s Süleymaniye Mosque designs. The scope of the analysis focuses on the syntax and mathematics of the floor plans, and the facade and section of each case are referenced occasionally. Within this scope, the proportional system that regulates the compositions and eidonomy of the precedents are scrutinized. Findings resulting from the comparative analysis are reported and then discussed. The study shows that the two ostensibly different precedents share obscurely many commonalities, which are greater than what their initial appearances suggest.

  18. In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication

    NARCIS (Netherlands)

    Baltus, Andrew E.; Menke, Douglas B.; Hu, Yueh-Chiang; Goodheart, Mary L.; Carpenter, Anne E.; de Rooij, Dirk G.; Page, David C.

    2006-01-01

    The transition from mitosis to meiosis is a defining juncture in the life cycle of sexually reproducing organisms. In yeast, the decision to enter meiosis is made before the single round of DNA replication that precedes the two meiotic divisions. We present genetic evidence of an analogous decision

  19. Strategy Precedes Operational Effectiveness: Aligning High Graduation Rankings with Competitive Graduation Grade Point Averages

    Science.gov (United States)

    Apprey, Maurice; Bassett, Kimberley C.; Preston-Grimes, Patrice; Lewis, Dion W.; Wood, Beverly

    2014-01-01

    Two pivotal and interconnected claims are addressed in this article. First, strategy precedes program effectiveness. Second, graduation rates and rankings are insufficient in any account of academic progress for African American students. In this article, graduation is regarded as the floor and not the ceiling, as it were. The ideal situation in…

  20. High Health Care Utilization Preceding Diagnosis of Systemic Lupus Erythematosus in Youth.

    Science.gov (United States)

    Chang, Joyce C; Mandell, David S; Knight, Andrea M

    2017-12-01

    Childhood-onset systemic lupus erythematosus (SLE) is associated with high risk for organ damage, which may be mitigated by early diagnosis and treatment. We characterized health care utilization for youth in the year preceding SLE diagnosis compared to controls. Using Clinformatics ™ DataMart (OptumInsight, Eden Prairie, MN) de-identified administrative data from 2000 to 2013, we identified 682 youth ages 10-24 years with new-onset SLE (≥3 International Classification of Diseases, Ninth Revision (ICD-9) codes for SLE 710.0, each >30 days apart), and 1,364 age and sex-matched healthy controls. We compared the incidence of ambulatory, emergency, and inpatient visits 12 months before SLE diagnosis, and frequency of primary diagnoses. We examined subject characteristics associated with utilization preceding SLE diagnosis. Youth with SLE had significantly more visits in the year preceding diagnosis than controls across ambulatory (incidence rate ratio (IRR) 2.48, p<0.001), emergency (IRR 3.42, p<0.001) and inpatient settings (IRR 3.02, p<0.001). The most frequent acute care diagnoses and median days to SLE diagnosis were: venous thromboembolism (313, interquartile range (IQR) 18-356), thrombocytopenia (278, IQR 39-354), chest pain (73, IQR 29.5-168), fever (52, IQR 17-166), and acute kidney failure (14, IQR 5-168). Having a psychiatric diagnosis prior to SLE diagnosis was strongly associated with increased utilization across all settings. Youth with SLE have high health care utilization throughout the year preceding SLE diagnosis. Examining variable diagnostic trajectories of youth presenting for acute care preceding SLE diagnosis, and increased attention to psychiatric morbidity may help improve care for youth with new-onset SLE. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Aortic and carotid arterial stiffness and epigenetic regulator gene expression changes precede blood pressure rise in stroke-prone Dahl salt-sensitive hypertensive rats.

    Science.gov (United States)

    Herrera, Victoria L; Decano, Julius L; Giordano, Nicholas; Moran, Ann Marie; Ruiz-Opazo, Nelson

    2014-01-01

    Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV), precedes hypertension and is an independent predictor of hypertension end organ diseases including stroke, cardiovascular disease and chronic kidney disease. Risk factor studies for arterial stiffness implicate age, hypertension and sodium. However, causal mechanisms linking risk factor to arterial stiffness remain to be elucidated. Here, we studied the causal relationship of arterial stiffness and hypertension in the Na-induced, stroke-prone Dahl salt-sensitive (S) hypertensive rat model, and analyzed putative molecular mechanisms. Stroke-prone and non-stroke-prone male and female rats were studied at 3- and 6-weeks of age for arterial stiffness (PWV, strain), blood pressure, vessel wall histology, and gene expression changes. Studies showed that increased left carotid and aortic arterial stiffness preceded hypertension, pulse pressure widening, and structural wall changes at the 6-week time-point. Instead, differential gene induction was detected implicating molecular-functional changes in extracellular matrix (ECM) structural constituents, modifiers, cell adhesion, and matricellular proteins, as well as in endothelial function, apoptosis balance, and epigenetic regulators. Immunostaining testing histone modifiers Ep300, HDAC3, and PRMT5 levels confirmed carotid artery-upregulation in all three layers: endothelial, smooth muscle and adventitial cells. Our study recapitulates observations in humans that given salt-sensitivity, increased Na-intake induced arterial stiffness before hypertension, increased pulse pressure, and structural vessel wall changes. Differential gene expression changes associated with arterial stiffness suggest a molecular mechanism linking sodium to full-vessel wall response affecting gene-networks involved in vascular ECM structure-function, apoptosis balance, and epigenetic regulation.

  2. Aortic and carotid arterial stiffness and epigenetic regulator gene expression changes precede blood pressure rise in stroke-prone Dahl salt-sensitive hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV, precedes hypertension and is an independent predictor of hypertension end organ diseases including stroke, cardiovascular disease and chronic kidney disease. Risk factor studies for arterial stiffness implicate age, hypertension and sodium. However, causal mechanisms linking risk factor to arterial stiffness remain to be elucidated. Here, we studied the causal relationship of arterial stiffness and hypertension in the Na-induced, stroke-prone Dahl salt-sensitive (S hypertensive rat model, and analyzed putative molecular mechanisms. Stroke-prone and non-stroke-prone male and female rats were studied at 3- and 6-weeks of age for arterial stiffness (PWV, strain, blood pressure, vessel wall histology, and gene expression changes. Studies showed that increased left carotid and aortic arterial stiffness preceded hypertension, pulse pressure widening, and structural wall changes at the 6-week time-point. Instead, differential gene induction was detected implicating molecular-functional changes in extracellular matrix (ECM structural constituents, modifiers, cell adhesion, and matricellular proteins, as well as in endothelial function, apoptosis balance, and epigenetic regulators. Immunostaining testing histone modifiers Ep300, HDAC3, and PRMT5 levels confirmed carotid artery-upregulation in all three layers: endothelial, smooth muscle and adventitial cells. Our study recapitulates observations in humans that given salt-sensitivity, increased Na-intake induced arterial stiffness before hypertension, increased pulse pressure, and structural vessel wall changes. Differential gene expression changes associated with arterial stiffness suggest a molecular mechanism linking sodium to full-vessel wall response affecting gene-networks involved in vascular ECM structure-function, apoptosis balance, and epigenetic regulation.

  3. Validity and QOL of neck dissection preceding radiation therapy for hypopharyngeal cancer

    International Nuclear Information System (INIS)

    Uemura, Hirokazu; Yoshino, Kunitoshi; Fujii, Takashi; Suzuki, Motoyuki

    2009-01-01

    Thirty-one cases of hypopharyngeal cancer with neck dissection preceding radiation and 16 cases of hypopharyngeal cancer with neck dissection for locoregional recurrences after radiation were reviewed in order to make comparative evaluations of difficulty in surgical operation, postoperative complications, laryngeal preservation rate, and cause specific 5-year survival rate retrospectively. And quality of life (QOL) after neck dissection was additionally evaluated through the questionnaire. Since neck dissection preceding radiation for hypopharyngeal cancer may be superior to neck dissection for radiation failure, with easy surgical approach an non-lymphoid tissue preservation, that modality can be a reasonable choice of treatment for patients with nodal lesions, which are probably difficult to treat with radiation alone. Even though further investigation on QOL questionnaire is necessary, this modality can make a contribution to the neck and shoulder condition after neck dissection. (author)

  4. Global precedence effects account for individual differences in both face and object recognition performance

    DEFF Research Database (Denmark)

    Gerlach, Christian; Starrfelt, Randi

    2018-01-01

    There has been an increase in studies adopting an individual difference approach to examine visual cognition and in particular in studies trying to relate face recognition performance with measures of holistic processing (the face composite effect and the part-whole effect). In the present study we...... examine whether global precedence effects, measured by means of non-face stimuli in Navon’s paradigm, can also account for individual differences in face recognition and, if so, whether the effect is of similar magnitude for faces and objects. We find evidence that global precedence effects facilitate...... both face and object recognition, and to a similar extent. Our results suggest that both face and object recognition are characterized by a coarse-to-fine temporal dynamic, where global shape information is derived prior to local shape information, and that the efficiency of face and object recognition...

  5. Will the judgment in the Hague trial constitute a precedent in international law

    Directory of Open Access Journals (Sweden)

    Bojanić Petar

    2006-01-01

    Full Text Available On the great crime (mala in se; scelus infandum and sovereignty In this text we are attempting to think the International Criminal Tribunal for the former Yugoslavia together, and always with its necessary connection to the International Court of Justice and International Criminal Court. By paraphrasing the title of another work, the long forgotten Hans Kelsen text from 1947 (today usually used by detractors of the Tribunal "Will the Judgment in the Nuremberg Trial constitute a Precedent in International Law?", I wish to distinguish between the two Tribunals (as well as The Treaty of Versaille,and in so doing treat international law as legislative history or judicial precedents (and their recognition.

  6. Legal precedents regarding use and defensibility of risk assessment in Federal transportation of SNF and HLW

    International Nuclear Information System (INIS)

    Bentz, E.J. Jr.; Bentz, C.B.; O'Hora, T.D.; Chen, S.Y.

    1997-01-01

    Risk assessment has become an increasingly important and essential tool in support of Federal decision-making regarding the handling, storage, disposal, and transportation of spent nuclear fuel (SNF) and high-level radioactive waste (HLW). This paper analyzes the current statutory and regulatory framework and related legal precedents with regard to SNF and HLW transportation. The authors identify key scientific and technical issues regarding the use and defensibility of risk assessment in Federal decision-making regarding anticipated shipments

  7. Designing a community engagement strategy for Limerick Smarter travel using focus groups and precedent studies

    OpenAIRE

    Cullinane, Kathleen Clair

    2012-01-01

    peer-reviewed This research aims to create a rational basis for designing and implementing a plan for Limerick Smarter Travel. This plan will pay particular attention to community engagement. This research establishes a rationale for a community engagement strategy. Precedent studies also provide direct guidance for this rationale. The objective of the plan is to develop a local culture of Smarter Travel in Limerick communities using best international practice, and thereby achieving behav...

  8. Complex Admixture Preceded and Followed the Extinction of Wisent in the Wild

    OpenAIRE

    W?cek, Karolina; Hartmann, Stefanie; Paijmans, Johanna L. A.; Taron, Ulrike; Xenikoudakis, Georgios; Cahill, James A.; Heintzman, Peter D.; Shapiro, Beth; Baryshnikov, Gennady; Bunevich, Aleksei N.; Crees, Jennifer J.; Dobosz, Roland; Manaserian, Ninna; Okarma, Henryk; Tokarska, Ma?gorzata

    2016-01-01

    © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. Retracing complex population processes that precede extreme bottlenecks may be impossible using data from living individuals. The wisent (Bison bonasus), Europe's largest terrestrial mammal, exemplifies such a population history, having gone extinct in the wild but subsequently restored by captive breeding efforts. Using low coverage genomic data from modern and historical ind...

  9. Sleeping Pattern of Medical Students Preceding Viva Examination and Their Performance

    OpenAIRE

    Mukhtar Ansari

    2016-01-01

    Introduction: Sleep is an important determinant of keeping healthy physically and mentally. Deviation in sleep is a common problem among students during examinations. The purpose of this study is to determine students’ sleep pattern during night preceding viva examination and its correlation with performance. Methods: This was a cross-sectional prospective study conducted between January and February 2014 among 1st and 2nd year MBBS students of National Medical College, Birgunj...

  10. Medical records documentation of constipation preceding Parkinson disease: A case-control study.

    Science.gov (United States)

    Savica, R; Carlin, J M; Grossardt, B R; Bower, J H; Ahlskog, J E; Maraganore, D M; Bharucha, A E; Rocca, W A

    2009-11-24

    Parkinson disease (PD) may affect the autonomic nervous system and may cause constipation; however, few studies have explored constipation preceding the motor onset of PD. We investigated constipation preceding PD using a case-control study design in a population-based sample. Using the medical records-linkage system of the Rochester Epidemiology Project, we identified 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to ascertain the occurrence of constipation preceding the onset of PD (or index year). Constipation preceding PD or the index year was more common in cases than in controls (odds ratio [OR] 2.48; 95% confidence interval [CI] 1.49 to 4.11; p = 0.0005). This association remained significant after adjusting for smoking and coffee consumption (ever vs never), and after excluding constipation possibly induced by drugs. In addition, the association remained significant in analyses restricted to constipation documented 20 or more years before the onset of motor symptoms of PD. Although the association was stronger in women than in men and in patients with PD with rest tremor compared with patients with PD without rest tremor, these differences were not significant. Our findings suggest that constipation occurring as early as 20 or more years before the onset of motor symptoms is associated with an increased risk of Parkinson disease.

  11. Organizational precedents for ownership and management of decentralized renewable-energy systems

    Energy Technology Data Exchange (ETDEWEB)

    Meunier, R.; Silversmith, J.A.

    1981-03-01

    Three existing organizational types that meet the decentralization criteria of local consumer ownership and control - cooperatives, Rural Electric Cooperatives, and municipal utilities - are examined. These three organizational precedents are analyzed in terms of their histories, structures, legal powers, sources of capital, and social and political aspects. Examples of related experiments with renewable energy technologies are given, and inferences are drawn regarding the organizations' suitability as vehicles for future implementation of decentralized renewable energy systems.

  12. A Legal Analysis of the Precedents of Medical Disputes in the Cosmetic Surgery Field

    OpenAIRE

    Bo Young Park; Min Ji Kim; So Ra Kang; Seung Eun Hong

    2016-01-01

    Background Disputes regarding medical malpractice occur between practitioners and patients. As patients have become increasingly aware regarding medical care, an increase in the unexpected side effects of procedures has been observed, thereby leading to an increase in disputes regarding medical malpractice. In this study, we reviewed trends in precedents involving cosmetic surgery-related medical disputes, with the goal of helping to prevent unnecessary disputes in the future. Methods We cond...

  13. Substantial Equivalence Standards in Tobacco Governance: Statutory Clarity and Regulatory Precedent for the FSPTCA.

    Science.gov (United States)

    Carpenter, Daniel; Connolly, Gregory N; Lempert, Lauren Kass

    2017-08-01

    The Family Smoking Prevention and Tobacco Control Act (FSPTCA) of 2009 creates the first national system of premarket regulation of tobacco products in American history. The FDA must now review and give marketing authorization to all new tobacco products, based on a public health standard, before they can be legally marketed. Yet the law also contains an alternative pathway for market entry-the substantial equivalence (SE) clause-by which novel and altered tobacco products can be marketed by demonstrating their substantial equivalence to existing products. Over 99 percent of tobacco product applications sent to the FDA under the new law have used this mechanism, and loose application of the SE mechanism carries the risk of undoing the FDA's gatekeeping power under the law. We review the statutory and regulatory precedent for SE, examining the FSPTCA itself as well as regulatory precedent from drug and device regulation (from which the term substantial equivalence and much of the associated statutory language was derived). Our review of standards and scientific precedent demonstrates that exacting scrutiny under the public health standard should govern all SE reviews and that clinical data incorporating social scientific evidence should be routinely required for SE claims by tobacco product sponsors. Copyright © 2017 by Duke University Press.

  14. Sleeping Pattern of Medical Students Preceding Viva Examination and Their Performance.

    Science.gov (United States)

    Ansari, M

    2015-01-01

    Sleep is an important determinant of keeping healthy physically and mentally. Deviation in sleep is a common problem among students during examinations. The purpose of this study is to determine students' sleep pattern during night preceding viva examination and its correlation with performance. This was a cross-sectional prospective study conducted between January and February 2014 among 1st and 2nd year MBBS students of National Medical College, Birgunj, Nepal who appeared in University's final practical examinations. Based on simple random sampling approach, each of the 280 participants was allowed to pick out five pieces of lottery papers and they were asked the five questions resembling the number in the list of questions. Among the total 280 students, 74.6% were from India and 25.4% were from Nepal, and majorities (63%) of them were males. Fifty two percent of the students either could not sleep at all or slept just for 1 to 1.5 hours while 12% slept for 5 to 6.5 hours. Two-third (66%) of the students was able enough to achieve one to two scores, and only 1.8% could succeed to get the maximum score of five. The correlation between hours of sleep preceding examination and the score achieved was positively (r=0.701) and statistically significantly correlated (pstudents either not to sleep or sleep only for few hours preceding viva examination that result in poor performance in examinations.

  15. Two sources of meaning in infant communication: preceding action contexts and act-accompanying characteristics.

    Science.gov (United States)

    Liszkowski, Ulf

    2014-09-19

    How do infants communicate before they have acquired a language? This paper supports the hypothesis that infants possess social-cognitive skills that run deeper than language alone, enabling them to understand others and make themselves understood. I suggested that infants, like adults, use two sources of extralinguistic information to communicate meaningfully and react to and express communicative intentions appropriately. In support, a review of relevant experiments demonstrates, first, that infants use information from preceding shared activities to tailor their comprehension and production of communication. Second, a series of novel findings from our laboratory shows that in the absence of distinguishing information from preceding routines or activities, infants use accompanying characteristics (such as prosody and posture) that mark communicative intentions to extract and transmit meaning. Findings reveal that before infants begin to speak they communicate in meaningful ways by binding preceding and simultaneous multisensory information to a communicative act. These skills are not only a precursor to language, but also an outcome of social-cognitive development and social experience in the first year of life. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  16. The value of auditing negative lower GI investigations preceding a final diagnosis of colorectal cancer.

    Science.gov (United States)

    Somasekar, A; James, L; Stephenson, B M; Thompson, I W; Vellacott, K D; Allison, M C

    2009-09-01

    To review all preceding 'negative' large bowel investigations in patients with a final diagnosis of colorectal cancer, and to examine whether delayed diagnosis was associated with worse outcome. Details were gathered on all patients with a new diagnosis of colorectal adenocarcinoma presenting over 4.5 years. For each patient the hospital's clinical workstation and radiology and endoscopy databases were interrogated for all flexible sigmoidoscopies, colonoscopies and barium enemas during the 5 years prior to diagnosis. Among the 570 patients, 28 (5%) had undergone colonoscopy and/or flexible sigmoidoscopy that had not shown colorectal cancer during the 5 years preceding final diagnosis, and a further 28 (5%) had undergone 'negative' barium enemas. Polyp surveillance might have missed four lesions destined to become malignant. Correspondingly there were three patients undergoing IBD surveillance found to have CRC, having had a negative complete colonoscopy within the preceding 5 years. Among patients undergoing de novo colonoscopy for diagnosis the true miss rate was only one patient per year. At August 2007, 29 (58%) of those with delayed diagnosis were still alive, compared with 216 (42%) of those diagnosed during initial investigation (chi2 = 5.04, P auditing the quality assurance of lower gastrointestinal diagnostic services. Despite the delay, late diagnosis was found to be associated with improved survival and a lower likelihood of metastatic disease.

  17. Quiet Periods in Edge Turbulence Preceding the L-H Transition in NSTX

    Energy Technology Data Exchange (ETDEWEB)

    Zweben, S; Hager, R; Hallatschek, K; Kaye, S M; Munsat, T; Poli, F M; Roquemore, A L; Sechrest, Y

    2010-04-26

    This paper describes the first observations in NSTX of ‘quiet periods’ in the edge turbulence preceding the L-H transition, as diagnosed by the GPI diagnostic near the outer midplane separatrix. During these quiet periods the GPI Dα light emission pattern was transiently similar to that seen during Hmode, i.e. with a relatively small fraction of the GPI light emission located outside the separatrix. These quiet periods had a frequency of ~3 kHz for at least 30 msec before the L-H transition, and were correlated with changes in the direction of the local poloidal velocity. The GPI turbulence images were also analyzed to obtain an estimate for the dimensionless poloidal shearing S =(dVp/dr)(Lr/Lp)τ. The values of S were strongly modulated by the quiet periods, but not otherwise varying for at least 30 msec preceding the L-H transition. Since neither the quiet periods nor the shear flow increased significantly immediately preceding the L-H transition, neither of these appears to be the trigger for this transition, at least for these cases in NSTX.

  18. Quiet Periods in Edge Turbulence Preceding the L-H Transition in NSTX

    International Nuclear Information System (INIS)

    Zweben, S.; Maqueda, R.J.; Hager, R.; Hallatschek, K.; Kaye, S.M.; Munsat, T.; Poli, F.M.; Roquemore, A.L.; Sechrest, Y.; Stotler, D.P.

    2010-01-01

    This paper describes the first observations in NSTX of 'quiet periods' in the edge turbulence preceding the L-H transition, as diagnosed by the GPI diagnostic near the outer midplane separatrix. During these quiet periods the GPI D light emission pattern was transiently similar to that seen during Hmode, i.e. with a relatively small fraction of the GPI light emission located outside the separatrix. These quiet periods had a frequency of ∼3 kHz for at least 30 msec before the L-H transition, and were correlated with changes in the direction of the local poloidal velocity. The GPI turbulence images were also analyzed to obtain an estimate for the dimensionless poloidal shearing S =(dVp/dr)(Lr/Lp). The values of S were strongly modulated by the quiet periods, but not otherwise varying for at least 30 msec preceding the L-H transition. Since neither the quiet periods nor the shear flow increased significantly immediately preceding the L-H transition, neither of these appears to be the trigger for this transition, at least for these cases in NSTX.

  19. Factors preceding CRM readiness in small- and medium-sized tourism enterprises

    Directory of Open Access Journals (Sweden)

    Dinesh Vallabh

    2015-07-01

    Full Text Available Orientation: Customer relationship management (CRM is important to organisations striving for competitive advantage through building relationships with their customers. Research purpose: This study identified the factors preceding CRM and assessed selected South African small- and medium-sized tourism enterprises’ (SMTEs readiness for CRM. Motivation: CRM is likely to enhance SMTEs’ competitiveness. However, successful adoption and implementation of CRM is unlikely unless the organisation is ready for it. Research design, approach and method: A quantitative research approach and survey questionnaire yielded primary data from 332 respondent organisations selected by systematic sampling. Exploratory factor analysis was used to identify the latent factors preceding CRM readiness. Organisational CRM readiness was assessed based on CRM maturity in terms of data collection, use and sharing throughout the organisation. Main findings: Respondent-organisations performed well on the four factors preceding CRM readiness − business strategy, customer strategy, touch points and competencies, skills and technology and also on data collections and use, but not on data sharing. Practical/Managerial implications: CRM practice is believed to assist organisations in tailoring products and services to customers’ needs, providing customer satisfaction, enhancing customer retention and ultimately improving the organisation’s competitiveness and profitability. CRM might fail if SMTEs do not have CRM-enabling conditions in place and a CRM readiness audit should therefore be performed. Contribution: The study contributes to a largely under-researched area concerning CRM in SMTEs by providing an improved understanding of the factors that will enable SMTEs to engage in CRM activities.

  20. Measuring Algorithm for the Distance to a Preceding Vehicle on Curve Road Using On-Board Monocular Camera

    Science.gov (United States)

    Yu, Guizhen; Zhou, Bin; Wang, Yunpeng; Wun, Xinkai; Wang, Pengcheng

    2015-12-01

    Due to more severe challenges of traffic safety problems, the Advanced Driver Assistance Systems (ADAS) has received widespread attention. Measuring the distance to a preceding vehicle is important for ADAS. However, the existing algorithm focuses more on straight road sections than on curve measurements. In this paper, we present a novel measuring algorithm for the distance to a preceding vehicle on a curve road using on-board monocular camera. Firstly, the characteristics of driving on the curve road is analyzed and the recognition of the preceding vehicle road area is proposed. Then, the vehicle detection and distance measuring algorithms are investigated. We have verified these algorithms on real road driving. The experimental results show that this method proposed in the paper can detect the preceding vehicle on curve roads and accurately calculate the longitudinal distance and horizontal distance to the preceding vehicle.

  1. Upregulation of Interleukin-33 in obstructive renal injury

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Wei-Yu, E-mail: wychen624@cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chang, Ya-Jen [Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (China); Su, Chia-Hao [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Tsai, Tzu-Hsien [Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chen, Shang-Der [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan (China); Hsing, Chung-Hsi [Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan (China); Yang, Jenq-Lin, E-mail: jyang@adm.cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China)

    2016-05-13

    Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases. -- Highlights: •Interleukin (IL)-33 was upregulated in obstructed kidneys. •Interstitial myofibroblasts expressed IL-33 after UUO-induced renal injury. •Deficiency of IL33 reduced interstitial fibrosis and promoted tubular cell proliferation.

  2. Upregulation of gamma-glutamyl-transpeptidase activity and uric ...

    African Journals Online (AJOL)

    Upregulation of gamma-glutamyl-transpeptidase activity and uric acid level in mixed chemical exposure: implications for mutagenic and preneoplastic events. ... The objective of the study was to determine a possible relationship between GGT, uric acid and the angiogenic agent copper (Cu) in mixed chemical exposure.

  3. IL-33 is upregulated in colonocytes of ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Bjerrum, Jacob Tveiten; Coskun, Mehmet

    2010-01-01

    , airway inflammation and arthritis in animal models. We now report IL-33 to be produced by colonic epithelial cells in humans and it is highly upregulated in ulcerative colitis (UC). Little mRNA expression was found in control subjects (N=9), whereas patients with UC in remission (N=7) and active UC (N=9...

  4. Nutraceutical up-regulation of serotonin paradoxically induces compulsive behavior

    Science.gov (United States)

    The role of diet in either the etiology or treatment of complex mental disorder is highly controversial in psychiatry. However, physiological mechanisms by which diet can influence brain chemistry – particularly that of serotonin – are well established. Here we show that dietary up-regulation of br...

  5. Antibody-bound amyloid precursor protein upregulates ornithine decarboxylase expression

    DEFF Research Database (Denmark)

    Nilsson, Tatjana; Malkiewicz, Katarzyna; Gabrielsson, Maria

    2006-01-01

    on the protein level. APP knockdown by RNAi verified that upregulation of ODC was APP-mediated. This APP signalling event did not require gamma-secretase cleavage, as it was independent of the presence of presenilin-1 or -2. The induced ODC expression was rapid and biphasic, resembling growth-factor stimulated...

  6. Up-regulation of corticotropin releasing hormone is associated with ...

    African Journals Online (AJOL)

    releasing hormone binding protein and up-regulation of IL-. 33 and IL-8 expression in psoriasis. Fei Su, Yun Xia, Meng Huang, Liang Zhang, Liuqing Chen*. Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei Province, PR China. *For correspondence: Email: chlq35@126.com; Tel/Fax: +86 27 8533 2621.

  7. Sleeping Pattern of Medical Students Preceding Viva Examination and Their Performance

    Directory of Open Access Journals (Sweden)

    Mukhtar Ansari

    2016-10-01

    Full Text Available Introduction: Sleep is an important determinant of keeping healthy physically and mentally. Deviation in sleep is a common problem among students during examinations. The purpose of this study is to determine students’ sleep pattern during night preceding viva examination and its correlation with performance.  Methods: This was a cross-sectional prospective study conducted between January and February 2014 among 1st and 2nd year MBBS students of National Medical College, Birgunj, Nepal who appeared in University’s  nal practical examinations. Based on simple random sampling approach, each of the 280 participants was allowed to pick out ve pieces of lottery papers and they were asked the ve questions resembling the number in the list of questions.  Results: Among the total 280 students, 74.6% were from India and 25.4% were from Nepal, and majorities (63% of them were males. Fifty two percent of the students either could not sleep at all or slept just for 1 to 1.5 hours while 12% slept for 5 to 6.5 hours. Two-third (66% of the students was able enough to achieve one to two scores, and only 1.8% could succeed to get the maximum score of ve. The correlation between hours of sleep preceding examination and the score achieved was positively (r=0.701 and statistically signi cantly correlated (p<0.001. Conclusions: There is a trend among the medical students either not to sleep or sleep only for few hours preceding viva examination that result in poor performance in examinations.  Keywords: medical; Nepal; performance; sleep deprivation; students.

  8. ECG changes on continuous telemetry preceding in-hospital cardiac arrests.

    Science.gov (United States)

    Do, Duc H; Hayase, Justin; Tiecher, Ricardo Dahmer; Bai, Yong; Hu, Xiao; Boyle, Noel G

    2015-01-01

    About 200,000 patients suffer from in-hospital cardiac arrest (IHCA) annually. Identification of at-risk patients is key to improving outcomes. The use of continuous ECG monitoring in identifying patients at risk for developing IHCA has not been studied. To describe the profile and timing of ECG changes prior to IHCA. Retrospective, observational. Single 520-bed tertiary care hospital. IHCA in adults between April 2010 and March 2012 with at least 3 hours of continuous telemetry data immediately prior to IHCA. We evaluated up to 24 hours of telemetry data preceding IHCA for changes in PR, QRS, ST segment, arrhythmias, and QTc in ventricular tachycardia cases. We determined mechanism and likely clinical cause of the arrest by chart and telemetry review. We studied 81 IHCA patients, in whom the mechanism was ventricular tachycardia/fibrillation in 14 (18%), bradyasystolic in 21 (26%), and pulseless electrical activity (PEA) in 46 (56%). Preceding ECG changes were ST segment changes (31% of cases), atrial tachyarrhythmias (21%), bradyarrhythmias (28%), P wave axis change (21%),QRS prolongation (19%), PR prolongation (17%), isorhythmic dissociation (14%), nonsustained ventricular tachycardia (6%), and PR shortening (5%). At least one of these was present in 77% of all cases, and in 89% of IHCA caused by respiratory or multiorgan failure. Bradyarrhythmias were primarily seen with IHCA in the setting of respiratory or multiorgan failure, and PR and QRS prolongation with IHCA and concomitant multiorgan failure. This is a retrospective study with a limited number of cases; each patient serves as their own control, and a separate control population has not yet been studied. ECG changes are commonly seen preceding IHCA, and have a pathophysiologic basis. Automated detection methods for ECG changes could potentially be used to better identify patients at risk for IHCA. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Education based on precede-proceed on quality of life in elderly.

    Science.gov (United States)

    Mazloomymahmoodabad, Saeed; Masoudy, Gholamreza; Fallahzadeh, Hosain; Jalili, Zahra

    2014-07-29

    One of the most important challenges in public health is to improve the quality of life in elders. Aging may cause various disorders such as disabilities, high risk conditions and some chronic disease. In this study the effect of educational intervention based on precede-proceed on quality of life in elders was examined. This semi experimental study was carried out on 128 elders over 60 years in Zahedan that were randomly selected by multi-stage sampling method and divided in to control and intervention groups. Data collection tool was a triploid questionnaire that included demographic data, questions of precede-proceed constructs and SF-36 questionnaire. The validity and reliability of questionnaire confirmed by experts and Cranach's Alpha coefficient (76%). After primary data collecting, educational intervention was performed and after nine months data was collected again and analyzed in spss.16 soft-ware using descriptive and analytical statistics. The results showed that mean score of quality of life in participants was low and more than 61% of them had a mean score less than 50%. After intervention the mean score of quality of life only in experimental group significantly increased from 47.72 to 58.90. Behavior and self-rated health were the strongest predictors for quality of life in this study. Implementation educational intervention based on precedes-proceed model can improve quality of life in elders. Elderly women and older elderly individuals compared with elderly men and younger elderly should be considering as an important risk factor for reducing HRQOL.

  10. Behaviour of coconut mites preceding take-off to passive aerial dispersal.

    Science.gov (United States)

    Melo, J W S; Lima, D B; Sabelis, M W; Pallini, A; Gondim, M G C

    2014-12-01

    For more than three decades the coconut mite Aceria guerreronis Keifer is one of the most important pests of coconut palms and has recently spread to many coconut production areas worldwide. Colonization of coconut palms is thought to arise from mites dispersing aerially after take-off from other plants within the same plantation or other plantations. The underlying dispersal behaviour of the mite at take-off, in the airborne state and after landing is largely unknown and this is essential to understand how they spread from tree to tree. In this article we studied whether take-off to aerial dispersal of coconut mites is preceded by characteristic behaviour, whether there is a correlation between the body position preceding aerial dispersal and the direction of the wind, and whether the substrate (outer surface of coconut bracts or epidermis) and the wind speed matter to the decision to take-off. We found that take-off can sometimes be preceded by a raised body stance, but more frequently take-off occurs while the mite is walking or resting on its substrate. Coconut mites that become airborne assumed a body stance that had no relation to the wind direction. Take-off was suppressed on a substrate providing food to coconut mites, but occurred significantly more frequently on the outer surface of coconut bracts than on the surface of the fruit. For both substrates, take-off frequency increased with wind speed. We conclude that coconut mites have at least some degree of control over take-off for aerial dispersal and that there is as yet no reason to infer that a raised body stance is necessary to become airborne.

  11. Development of a Rheumatoid Arthritis Education Program using the PRECEDE_PROCEED Model

    Directory of Open Access Journals (Sweden)

    Kaveh Bahmanpour

    2011-12-01

    Full Text Available Background: In order to help rheumatoid arthritis (RA patients in carrying out and attaining relevant self-care behaviors and adaptation to the physical limitations of this disease and, conse-quently, promoting their level of health status, an education program based on the PRECEDE component of the PRECEDE–PROCEED model targeting patients with RA was developed. This paper describes the planning of a RA Patient Education Program (RAPEP designed to promote their quality of life.Methods: The development of the program began with a comprehensive review of the literature. This included a review of the signs and symptoms of RA, accompanying functional disabilities, previous educational programs and the effect of the disease on the patient’s quality of life. Be-sides, in order to help inform RAPEP program development, and organize the survey according to the factors identified in the PRECEDE model a cross-sectional survey was applied on a non-prob-ability sample of 181 outpatients in Yazd, center of Iran.Results: The quality of life (QOL problem identified was the considerable low role functioning, health perception and physical functioning due to chronic pain. One of the most significant modi-fiable behavioral factors impacting pain and functional limitations was self-care behaviors in RA patients. Higher level of knowledge, attitude, self-efficacy, enabling factors and social support is associated with better self-care behavior.Conclusions: The PRECEDE component of the PRECEDE–PROCEED model provided a com-prehensive conceptual framework for the development of RAPEP aiming at RA patients in Yazd. Further research to evaluate this educational program is suggested.

  12. Gestalt perception and the decline of global precedence in older subjects.

    Science.gov (United States)

    Staudinger, Markus R; Fink, Gereon R; Mackay, Clare E; Lux, Silke

    2011-01-01

    Our visual world is hierarchically organized. Hierarchical processing is frequently investigated using Navon figures (large letters made up of smaller ones). In young adults, many studies reported faster reaction times (RT) to target letters presented at the global level [i.e., global precedence (GP)]. Furthermore, an age-related decline of this GP has been reported. We tested whether deficits in perceptual grouping via Gestalt laws (Gestalt principles of Proximity and Continuity) might contribute to this decline. In a directed attention task with valid and invalid cues, 20 young (mean age 22) and 20 older (mean age 57) male subjects had to indicate whether a target letter appeared at the global or local level of a Navon figure. The number of local letters forming the global figure was modulated in 5 steps. As expected, during valid trials, young adults showed a GP that linearly increased with increasing numbers of local letters (i.e., GP enhancement). This suggests that GP is related to perceptual grouping via Gestalt laws. By contrast, the group of older subjects demonstrated no precedence effect in RT and a non-significant trend toward GP in error rates (ER). No GP enhancement with an increasing number of local elements was observed. Exploratory analysis revealed that individual insensitivity to the modulation of matrix density, as revealed by a lack of global RT acceleration, was restricted to subjects that showed an overall local precedence (LP). Because older subjects tended to more frequently display an insensitivity to matrix modulation and an LP, we conclude that deficient Gestalt detection as indicated by non-enhanced global RT might contribute to the RT-related decline of GP with age. Copyright © 2010 Elsevier Srl. All rights reserved.

  13. Natural Magnetic Fields Preceding the Loma Prieta Earthquake that Damaged San Francisco in October 1989

    Science.gov (United States)

    Campbell, W. H.

    2005-05-01

    Available records of the magnetic indices Dst and ap together with USGS standard observatory recordings of the 1-min fields are examined for the time preceding the Loma Prieta earthquake that severely damaged the San Francisco area in October, 1989. The results indicate that a 1990 report claiming the existence of a ULF geomagnetic field precursor signal foretelling a nearby earthquake is very likely false. The observatory study shows that the ULF signal was not local but rather widespread throughout the western United States and therefore expected to be of solar-terrestrial disturbance origin. The two planetary activity indices support this conclusion.

  14. Natural magnetic disturbance fields, not precursors, preceding the Loma Prieta earthquake

    Science.gov (United States)

    Campbell, Wallace H.

    2009-05-01

    Available records of the magnetic indices Dst and ap together with standard observatory recordings of 1-min field levels were examined for the period preceding the earthquake of October 1989, centered near Loma Prieta, California. The magnetic records showed that the Fraser-Smith et al. (1990) report claiming the existence of a 100-s (ultralow frequency) geomagnetic field precursor signal at Corralitos, California, foretelling a nearby earthquake is not valid. My study shows that the Stanford ULF signal was not local but rather widespread throughout the western United States and, therefore, expected to be due to a coincidental geomagnetic solar-terrestrial disturbance field.

  15. Mutation of the p53 gene precedes aneuploid clonal divergence in colorectal carcinoma.

    OpenAIRE

    Carder, P. J.; Cripps, K. J.; Morris, R.; Collins, S.; White, S.; Bird, C. C.; Wyllie, A. H.

    1995-01-01

    To establish whether p53 mutation precedes or follows clonal divergence in human colorectal carcinomas, 17 tumours were analysed at multiple sites (2-5 each) for single-strand conformation polymorphisms (SSCP) within exons 5-8 of the p53 gene. A previous study had demonstrated subclones of differing DNA ploidy in these tumours, but all showed immunocytochemical evidence for p53 stabilisation, using the monoclonal antibody PAb 1801. Mutations within exons 5-8 of p53 were identified by the pres...

  16. Onset of Bonding Plasmon Hybridization Preceded by Gap Modes in Dielectric Splitting of Metal Disks

    DEFF Research Database (Denmark)

    Frederiksen, Maj; Bochenkov, Vladimir; Ogaki, Ryosuke

    2013-01-01

    Dielectric splitting of nanoscale disks was studied experimentally and via finite-difference time-domain (FDTD) simulations through systematic introduction of multiple ultrathin dielectric layers. Tunable, hybridized dark bonding modes were seen with first-order gap modes preceding the appearance...... of bonding dipole−dipole disk modes. The observed bright dipolar mode did not show the energy shift expected from plasmon hybridization but activated dark higher order gap modes. Introducing lateral asymmetry was shown to remodel the field distribution resulting in 3D asymmetry that reoriented the dipole...

  17. An Adaptive Evolutionary Algorithm for Traveling Salesman Problem with Precedence Constraints

    Directory of Open Access Journals (Sweden)

    Jinmo Sung

    2014-01-01

    Full Text Available Traveling sales man problem with precedence constraints is one of the most notorious problems in terms of the efficiency of its solution approach, even though it has very wide range of industrial applications. We propose a new evolutionary algorithm to efficiently obtain good solutions by improving the search process. Our genetic operators guarantee the feasibility of solutions over the generations of population, which significantly improves the computational efficiency even when it is combined with our flexible adaptive searching strategy. The efficiency of the algorithm is investigated by computational experiments.

  18. Characteristics of Precedent : The Case Law of the European Court of Justice in Three Dimensions

    OpenAIRE

    Derlén, Mattias; Lindholm, Johan

    2015-01-01

    The case law of the Court of Justice of the European Union (CJEU) is one of the most important sources of European Union law. However, case law’s role in EU law is not uniform. By empirically studying how the Court uses its own case law as a source of law, we explore the correlation between, on the one hand, the characteristics of a CJEU case— type of action, actors involved, and area of law—and, on the other hand, the judgment’s “embeddedness” in previous case law and value as a precedent in...

  19. Process And Progress: Binding Precedents In The Civil Law And Common Law Traditions

    Directory of Open Access Journals (Sweden)

    Benedito Cerezzo Pereira Filho

    2016-12-01

    Full Text Available The present work investigates the consolidation of the stare decisis doctrine in common law, as the basis for understanding the phenomenon of deprecedentarization of trials recently introduced to the Brazilian legal framework, in order to evaluate its developmental potential. The main argument hereby presented wishes to demonstrate that the binding precedent microsystem, once established to create calculability and allow planning, may be theoretically essential for the development of a country and for the effectiveness of justice, through the foundation of the principles of legal security and equality, to allow the delivery of effective decisions.

  20. Solving a large-scale precedence constrained scheduling problem with elastic jobs using tabu search

    DEFF Research Database (Denmark)

    Pedersen, C.R.; Rasmussen, R.V.; Andersen, Kim Allan

    2007-01-01

    This paper presents a solution method for minimizing makespan of a practical large-scale scheduling problem with elastic jobs. The jobs are processed on three servers and restricted by precedence constraints, time windows and capacity limitations. We derive a new method for approximating the server...... exploitation of the elastic jobs and solve the problem using a tabu search procedure. Finding an initial feasible solution is in general -complete, but the tabu search procedure includes a specialized heuristic for solving this problem. The solution method has proven to be very efficient and leads...

  1. Vanishing bile duct syndrome and immunodeficiency preceding the diagnosis of Hodgkin lymphoma.

    Science.gov (United States)

    Yeh, P; Lokan, J; Anantharajah, A; Grigg, A

    2014-12-01

    Vanishing bile duct syndrome (VBDS) in association with Hodgkin lymphoma (HL) is well described but not well understood. We report an unusual case of a 75-year-old patient presenting with biopsy-proven VBDS and immunodeficiency, without identifiable cause, which showed a waxing and waning course, culminating in the development of HL 18 months later. To our knowledge, this is the first adult case in which VBDS preceded the diagnosis of HL by such a long period. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

  2. Situational Factors of Influencing Drivers to Give Precedence to Jaywalking Pedestrians at Signalized Crosswalk

    Directory of Open Access Journals (Sweden)

    Xiaobei Jiang

    2011-12-01

    Full Text Available A large number of fatalities are caused by the vehicle-pedestrian accidents. Under a potential conflict between the vehicle and jaywalking pedestrian, giving precedence to the pedestrian will be a proper decision taken by the driver to avoid collision. Field traffic data has been collected by video recording and image processing at two signalized crosswalks. Vehicle speed performance in the single vehicle-pedestrian encounter and platoon vehicle-pedestrian encounter were analyzed for understanding the driver behavior in the conflict process. Binary logic model was proposed to estimate the drivers' giving precedence influenced by the situational factors and the model was validated to predict the drivers' choices accurately. The vehicle speed, pedestrian speed, pedestrian lateral distance and the vehicle longitudinal distance to the conflict point were proved to affect the drivers' choices in platoon driving. The research results would hopefully be helpful to the design of intelligent vehicles and pedestrian protection systems by the knowledge-based decision making process.

  3. Motor dysfunction as research domain in the period preceding manifest schizophrenia: A systematic review.

    Science.gov (United States)

    Hirjak, Dusan; Meyer-Lindenberg, Andreas; Kubera, Katharina M; Thomann, Philipp A; Wolf, Robert C

    2018-02-20

    Schizophrenia is a severe behavioral syndrome of neurodevelopmental nature marked by primary or genuine motor abnormalities (GMA), which refer to spontaneous and medication-independent motor phenomena. Since motor dysfunction thus might be a consequence of events occurring during early childhood and adolescence, GMA can be detected in the period preceding manifest schizophrenia. However, the question whether motor system dysfunction might be a promising motor intermediate phenotype for schizophrenia remains unanswered. In this review, we systematically evaluate the evidence on GMA in healthy persons, individuals with schizotypal personality traits, persons at ultra-high risk for psychosis, and unaffected first-degree relatives of schizophrenia patients. What becomes evident is a continuum of GMA expression, which appears to be linked to abnormalities of cerebello-thalamo-cortical, fronto-parietal, and cortico-subcortical motor circuits. According to current evidence, motor dysfunction is a key aspect of the neurodevelopmental risk factor model of schizophrenia. Insights provided by this research will help promoting the RDoC Motor System construct and expand the clinical relevance of the motor domain in the period preceding manifest schizophrenia. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures.

    Science.gov (United States)

    Lhatoo, Samden D; Nei, Maromi; Raghavan, Manoj; Sperling, Michael; Zonjy, Bilal; Lacuey, Nuria; Devinsky, Orrin

    2016-07-01

    To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it. We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death. Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic-clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS). SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection-based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  5. The Chicken or the Egg: Examining Temporal Precedence Among Attitudes, Injunctive Norms, and College Student Drinking.

    Science.gov (United States)

    Lewis, Melissa A; Litt, Dana M; Neighbors, Clayton

    2015-07-01

    The present study was designed to test for projection, conformity, or reciprocal associations among attitudes, injunctive norms, and drinking. Assuming that these constructs are not independent, we proposed three possible trajectories. A conformity model would suggest that injunctive norms should temporally precede drinking or attitudes. Alternatively, a projection model would suggest that attitudes or alcohol use would precede injunctive norms. Furthermore, by examining the processes over three time points, the current study would also examine whether both conformity and projection processes were at work, indicating reciprocal relationships. participants included 249 college students (63.1% female), who participated as a control group in a larger intervention trial. Structural equation modeling was used to examine cross-sectional and prospective associations among injunctive norms, attitudes, and drinking across each of the three time points. Findings demonstrated three significant cross-lagged associations. Injunctive norms at Time 1 was significantly associated with drinking at Time 2 (conformity), and both attitudes and drinking at Time 2 were significantly associated with injunctive norms at Time 3 (projection). The pattern of cross-lagged associations suggested one meaningful indirect pathway, from Time 1 injunctive norms to Time 2 drinking to Time 3 injunctive norms (reciprocal association). The present study suggests that both the conformity and the projection processes seem to be important and evident for college student drinking when considering injunctive norms and drinking over time. Interventions that focus on both conformity and projection may be particularly effective at reducing longer-term alcohol use.

  6. A Legal Analysis of the Precedents of Medical Disputes in the Cosmetic Surgery Field.

    Science.gov (United States)

    Park, Bo Young; Kim, Min Ji; Kang, So Ra; Hong, Seung Eun

    2016-05-01

    Disputes regarding medical malpractice occur between practitioners and patients. As patients have become increasingly aware regarding medical care, an increase in the unexpected side effects of procedures has been observed, thereby leading to an increase in disputes regarding medical malpractice. In this study, we reviewed trends in precedents involving cosmetic surgery-related medical disputes, with the goal of helping to prevent unnecessary disputes in the future. We conducted a search of the judgments made in South Korean courts between 2000 and 2013 that were related to the field of plastic surgery. A total of 54 judgments were analyzed, and the selected precedents were reviewed and classified according to the kind of negligence involved. The claim amounts ranged from under 8 million KRW (6,991 USD) to 750 million KRW (629,995 USD). The most common ratio of the judgment amount to the claim amount was 20%-30%. The judgments were classified according to the following categories: violation of the duty of explanation in 17 cases (29%), violation of the duty of care in 10 cases (17%), violation of both duties in 20 cases (35%), and no violation of duty in six cases (10%). Cosmetic surgery-related suits require different approaches than general malpractice suits. The Supreme Court requires plastic surgeons to determine the type, timing, methods, and scope of their treatments when considering possible results. Therefore, practitioners should be educated on their rights and responsibilities to enable them to cope with any possible medical dispute that may arise.

  7. Stressful life events preceding the onset of depression in Asian patients with major depressive disorder.

    Science.gov (United States)

    Park, Subin; Hatim, Ahmad; Si, Tian-Mei; Jeon, Hong Jin; Srisurapanont, Manit; Bautista, Dianne; Liu, Shen-ing; Chua, Hong Choon; Hong, Jin Pyo

    2015-12-01

    Previous studies have identified the significant role of stressful life events in the onset of depressive episodes. However, there is a paucity of cross-national studies on stressful life events that precede depression. We aimed to compare types of stressful life events associated with the onset of depressive episodes in patients with major depressive disorder (MDD) in five Asian countries. A total of 507 outpatients with MDD were recruited in China (n = 114), South Korea (n = 101), Malaysia (n = 90), Thailand (n = 103) and Taiwan (n = 99). All patients were assessed with the Mini-International Neuropsychiatric Interview and the List of Threatening Experiences. The prevalence of each type of stressful life events was calculated and compared between each country. The type of stressful life event that preceded the onset of a depressive episode differed between patients in China and Taiwan and those in South Korea, Malaysia and Thailand. Patients in China and Taiwan were less likely to report interpersonal relationship problems and occupational/financial problems than patients in South Korea, Malaysia and Thailand. Understanding the nature and basis of culturally determined susceptibilities to specific stressful life events is critical for establishing a policy of depression prevention and providing effective counseling services for depressed patients. © The Author(s) 2015.

  8. Upregulated Genes In Sporadic, Idiopathic Pulmonary Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Yacoub Magdi H

    2006-01-01

    Full Text Available Abstract Background To elucidate further the pathogenesis of sporadic, idiopathic pulmonary arterial hypertension (IPAH and identify potential therapeutic avenues, differential gene expression in IPAH was examined by suppression subtractive hybridisation (SSH. Methods Peripheral lung samples were obtained immediately after removal from patients undergoing lung transplant for IPAH without familial disease, and control tissues consisted of similarly sampled pieces of donor lungs not utilised during transplantation. Pools of lung mRNA from IPAH cases containing plexiform lesions and normal donor lungs were used to generate the tester and driver cDNA libraries, respectively. A subtracted IPAH cDNA library was made by SSH. Clones isolated from this subtracted library were examined for up regulated expression in IPAH using dot blot arrays of positive colony PCR products using both pooled cDNA libraries as probes. Clones verified as being upregulated were sequenced. For two genes the increase in expression was verified by northern blotting and data analysed using Student's unpaired two-tailed t-test. Results We present preliminary findings concerning candidate genes upregulated in IPAH. Twenty-seven upregulated genes were identified out of 192 clones examined. Upregulation in individual cases of IPAH was shown by northern blot for tissue inhibitor of metalloproteinase-3 and decorin (P Conclusion Four of the up regulated genes, magic roundabout, hevin, thrombomodulin and sucrose non-fermenting protein-related kinase-1 are expressed specifically by endothelial cells and one, muscleblind-1, by muscle cells, suggesting that they may be associated with plexiform lesions and hypertrophic arterial wall remodelling, respectively.

  9. PPARGC1A is upregulated and facilitates lung cancer metastasis.

    Science.gov (United States)

    Li, Jin-Dong; Feng, Qing-Chuan; Qi, Yu; Cui, Guanghui; Zhao, Song

    2017-10-15

    Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial-mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis. Copyright © 2017. Published by Elsevier Inc.

  10. Electric current precedes emergence of a lateral root in higher plants.

    Science.gov (United States)

    Hamada, S; Ezaki, S; Hayashi, K; Toko, K; Yamafuji, K

    1992-10-01

    Stable electrochemical patterns appear spontaneously around roots of higher plants and are closely related to growth. An electric potential pattern accompanied by lateral root emergence was measured along the surface of the primary root of adzuki bean (Phaseolus angularis) over 21 h using a microelectrode manipulated by a newly developed apparatus. The electric potential became lower at the point where a lateral root emerged. This change preceded the emergence of the lateral root by about 10 h. A theory is presented for calculating two-dimensional patterns of electric potential and electric current density around the primary root (and a lateral root) using only data on the one-dimensional electric potential measured near the surface of the primary root. The development of the lateral root inside the primary root is associated with the influx of electric current of about 0.7 muA.cm(-2) at the surface.

  11. A Hybrid Genetic Algorithm to Minimize Total Tardiness for Unrelated Parallel Machine Scheduling with Precedence Constraints

    Directory of Open Access Journals (Sweden)

    Chunfeng Liu

    2013-01-01

    Full Text Available The paper presents a novel hybrid genetic algorithm (HGA for a deterministic scheduling problem where multiple jobs with arbitrary precedence constraints are processed on multiple unrelated parallel machines. The objective is to minimize total tardiness, since delays of the jobs may lead to punishment cost or cancellation of orders by the clients in many situations. A priority rule-based heuristic algorithm, which schedules a prior job on a prior machine according to the priority rule at each iteration, is suggested and embedded to the HGA for initial feasible schedules that can be improved in further stages. Computational experiments are conducted to show that the proposed HGA performs well with respect to accuracy and efficiency of solution for small-sized problems and gets better results than the conventional genetic algorithm within the same runtime for large-sized problems.

  12. General practice consultations, diagnostic investigations, and prescriptions in the year preceding a lung cancer diagnosis

    DEFF Research Database (Denmark)

    Guldbrandt, Louise M; Møller, Henrik; Jakobsen, Erik

    2017-01-01

    Patterns of general practice utilization in the period before lung cancer (LC) diagnosis may provide new knowledge to ensure timelier and earlier diagnosis of LC. This study aimed to explore the prediagnostic activity in general practice in the year preceding LC diagnosis. The activity was compared...... = 340,170). During months 12 to 1 prior to diagnosis, 92.6% of LC patients and 88.4% of comparison subjects had one or more contacts with general practice. 13.0% of LC patients and 3.3% of comparison subjects had two or more X-rays. 20.8% of LC patients and 8.5% of comparison subjects had two or more...... first-time antibiotics prescriptions. The incidence rate ratio for having a contact to general practice was similar for LC patients with localized disease compared to LC patients with metastatic disease. LC patients with COPD had more frequent contacts, lung functions tests, X-rays, and prescriptions...

  13. Brain Musics: History, Precedents, and Commentary on Whalley, Mavros and Furniss

    Directory of Open Access Journals (Sweden)

    Miguel Ortiz

    2015-05-01

    Full Text Available Whalley, Mavros and Furniss explore questions of agency, control and interaction, as well as the embodied nature of musical performance in relation to the use of human-computer interaction through the work Clasp Together (beta for small ensemble and live electronics. The underlying concept of the piece focuses on direct mapping of a human neural network (embodied by a performer within the ensemble to an artificial neural network running on a computer. With our commentary, we contextualize the work within the field of Music Neuroscience. Specifically, we point at precedents in EEG-based musical practice as well as ongoing research in the field. We hope to more clearly situate Clasp Together (beta in the broad area of Brain Computer Musical Interfaces and discuss the challenges and opportunities that these technologies offer for composers.

  14. Body size shifts and early warning signals precede the historic collapse of whale stocks.

    Science.gov (United States)

    Clements, Christopher F; Blanchard, Julia L; Nash, Kirsty L; Hindell, Mark A; Ozgul, Arpat

    2017-06-22

    Predicting population declines is a key challenge in the face of global environmental change. Abundance-based early warning signals have been shown to precede population collapses; however, such signals are sensitive to the low reliability of abundance estimates. Here, using historical data on whales harvested during the 20th century, we demonstrate that early warning signals can be present not only in the abundance data, but also in the more reliable body size data of wild populations. We show that during the period of commercial whaling, the mean body size of caught whales declined dramatically (by up to 4 m over a 70-year period), leading to early warning signals being detectable up to 40 years before the global collapse of whale stocks. Combining abundance and body size data can reduce the length of the time series required to predict collapse, and decrease the chances of false positive early warning signals.

  15. The chemistry that preceded life's origin: a study guide from meteorites.

    Science.gov (United States)

    Pizzarello, Sandra

    2007-04-01

    Carbonaceous meteorites are rare fragments of asteroids that contain organic carbon of diverse composition, various complexity, and whose lineage can in several instances be traced back to pre-solar environments. Their analyses offer a unique glimpse into the chemistry of the solar system that preceded life and may have been available to its emergence on the early Earth. While the heterogeneity of the organic materials of meteorites is indicative of random synthetic processes for their formation, some of their components have identical counterparts in the biosphere, and a group of meteoritic amino acids were found to display chiral asymmetry, a property known since the time of Pasteur to be inextricably linked to life's processes. The ability of these amino acids to act as asymmetric catalysts, as well as indications that molecular asymmetry in meteorites may not be limited to these compounds, encourage the suggestion of possible involvement of meteoritic material in the induction of selective traits in molecular evolution.

  16. Intense foreshocks and a slow slip event preceded the 2014 Iquique Mw 8.1 earthquake.

    Science.gov (United States)

    Ruiz, S; Metois, M; Fuenzalida, A; Ruiz, J; Leyton, F; Grandin, R; Vigny, C; Madariaga, R; Campos, J

    2014-09-05

    The subduction zone in northern Chile is a well-identified seismic gap that last ruptured in 1877. The moment magnitude (Mw) 8.1 Iquique earthquake of 1 April 2014 broke a highly coupled portion of this gap. To understand the seismicity preceding this event, we studied the location and mechanisms of the foreshocks and computed Global Positioning System (GPS) time series at stations located on shore. Seismicity off the coast of Iquique started to increase in January 2014. After 16 March, several Mw > 6 events occurred near the low-coupled zone. These events migrated northward for ~50 kilometers until the 1 April earthquake occurred. On 16 March, on-shore continuous GPS stations detected a westward motion that we model as a slow slip event situated in the same area where the mainshock occurred. Copyright © 2014, American Association for the Advancement of Science.

  17. From Function to Context to Form: Precedents and Focus Shifts in the Form Creation Process

    DEFF Research Database (Denmark)

    Restrepo-Giraldo, John Dairo

    2005-01-01

    In design, the form creation process involves imagining, seeing and drawing. Translating the vague and imprecise initial ideas into sketches requires significant ability, and in this process, images of existing products (precedents) are a welcomed aid. Searching for them, however, is difficult......, because it requires either exhaustive browsing or verbalization of the ideas to be able to use search engines. This paper presents an approach that uses images as query seeds instead of keywords called Query by Example (QBE). This approach is tested through an empirical study. It shows that the approach...... is a significant step into helping designers satisfy their visual information needs. It also shows that, as designers change their focus from function to context to form, their way of expressing their information needs changes. It concludes suggesting ways of improving both current systems and the QBE software...

  18. Horizontal Gene Transfer of Pectinases from Bacteria Preceded the Diversification of Stick and Leaf Insects.

    Science.gov (United States)

    Shelomi, Matan; Danchin, Etienne G J; Heckel, David; Wipfler, Benjamin; Bradler, Sven; Zhou, Xin; Pauchet, Yannick

    2016-05-23

    Genes acquired by horizontal transfer are increasingly being found in animal genomes. Understanding their origin and evolution requires knowledge about the phylogenetic relationships from both source and recipient organisms. We used RNASeq data and respective assembled transcript libraries to trace the evolutionary history of polygalacturonase (pectinase) genes in stick insects (Phasmatodea). By mapping the distribution of pectinase genes on a Polyneoptera phylogeny, we identified the transfer of pectinase genes from known phasmatodean gut microbes into the genome of an early euphasmatodean ancestor that took place between 60 and 100 million years ago. This transfer preceded the rapid diversification of the suborder, enabling symbiont-free pectinase production that would increase the insects' digestive efficiency and reduce dependence on microbes. Bacteria-to-insect gene transfer was thought to be uncommon, however the increasing availability of large-scale genomic data may change this prevailing notion.

  19. Energy crisis precedes global metabolic failure in a novel Caenorhabditis elegans Alzheimer Disease model.

    Science.gov (United States)

    Fong, Sheng; Teo, Emelyne; Ng, Li Fang; Chen, Ce-Belle; Lakshmanan, Lakshmi Narayanan; Tsoi, Sau Yee; Moore, Philip Keith; Inoue, Takao; Halliwell, Barry; Gruber, Jan

    2016-09-22

    Alzheimer Disease (AD) is a progressive neurological disorder characterized by the deposition of amyloid beta (Aβ), predominantly the Aβ 1-42 form, in the brain. Mitochondrial dysfunction and impaired energy metabolism are important components of AD pathogenesis. However, the causal and temporal relationships between them and AD pathology remain unclear. Using a novel C. elegans AD strain with constitutive neuronal Aβ 1-42 expression that displays neuromuscular defects and age-dependent behavioural dysfunction reminiscent of AD, we have shown that mitochondrial bioenergetic deficit is an early event in AD pathogenesis, preceding dysfunction of mitochondrial electron transfer chain (ETC) complexes and the onset of global metabolic failure. These results are consistent with an emerging view that AD may be a metabolic neurodegenerative disease, and also confirm that Aβ-driven metabolic and mitochondrial effects can be reproduced in organisms separated by large evolutionary distances.

  20. Mixed Emotional Experience Is Associated with and Precedes Improvements in Psychological Well-Being

    Science.gov (United States)

    2012-01-01

    Background The relationships between positive and negative emotional experience and physical and psychological well-being have been well-documented. The present study examines the prospective positive relationship between concurrent positive and negative emotional experience and psychological well-being in the context of psychotherapy. Methods 47 adults undergoing psychotherapy completed measures of psychological well-being and wrote private narratives that were coded by trained raters for emotional content. Results The specific concurrent experience of happiness and sadness was associated with improvements in psychological well-being above and beyond the impact of the passage of time, personality traits, or the independent effects of happiness and sadness. Changes in mixed emotional experience preceded improvements in well-being. Conclusions Experiencing happiness alongside sadness in psychotherapy may be a harbinger of improvement in psychological well-being. PMID:22539987

  1. The market for precedent: shifting visions of the role of clinical negligence claims and trials.

    Science.gov (United States)

    Mulcahy, Linda

    2014-01-01

    This article considers the interface between the standard setting activity of the NHS Litigation Authority, and the courts and uses the clinical negligence action as a prism through which to examine it. It is suggested that despite its many disadvantages, the clinical negligence action remains an important safety valve when internal regulatory systems fail or are insufficiently transparent to gain full legitimacy. More specifically, it explores the ways in which attitudes about the usefulness of the data contained in claims against the NHS have changed in the aftermath of a number of high profile inquiries which have focused on issues of poor performance. The article concludes that while much greater use is now been made of the data contained in claims when setting standards, strategies for prompting judicial precedent as an alternative way of mobilising standard setting behaviour remain under developed. © The Author 2014. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction

    DEFF Research Database (Denmark)

    Stanyer, Lee; Jørgensen, Wenche; Hori, Osamu

    2008-01-01

    shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non......-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)). This susceptibility was more pronounced with regard to ATP-stimulated activity, which was inhibited by 75% in the presence of a bolus addition of 1mM ONOO(-), whereas basal unstimulated...... activity was inhibited by 45%. Treatment of mitochondria with a range of peroxynitrite concentrations (10-1000 microM) revealed that a decline in Lon protease activity preceded electron transport chain (ETC) dysfunction (complex I, II-III and IV) and that ATP-stimulated activity was approximately fivefold...

  3. Static Scheduling of Periodic Hardware Tasks with Precedence and Deadline Constraints on Reconfigurable Hardware Devices

    Directory of Open Access Journals (Sweden)

    Ikbel Belaid

    2011-01-01

    Full Text Available Task graph scheduling for reconfigurable hardware devices can be defined as finding a schedule for a set of periodic tasks with precedence, dependence, and deadline constraints as well as their optimal allocations on the available heterogeneous hardware resources. This paper proposes a new methodology comprising three main stages. Using these three main stages, dynamic partial reconfiguration and mixed integer programming, pipelined scheduling and efficient placement are achieved and enable parallel computing of the task graph on the reconfigurable devices by optimizing placement/scheduling quality. Experiments on an application of heterogeneous hardware tasks demonstrate an improvement of resource utilization of 12.45% of the available reconfigurable resources corresponding to a resource gain of 17.3% compared to a static design. The configuration overhead is reduced to 2% of the total running time. Due to pipelined scheduling, the task graph spanning is minimized by 4% compared to sequential execution of the graph.

  4. Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis.

    Science.gov (United States)

    Gu, Liangcai; Wang, Bo; Kulkarni, Amol; Gehret, Jennifer J; Lloyd, Kayla R; Gerwick, Lena; Gerwick, William H; Wipf, Peter; Håkansson, Kristina; Smith, Janet L; Sherman, David H

    2009-11-11

    Biosynthetic innovation in natural product systems is driven by the recruitment of new genes and enzymes into these complex pathways. Here, an unprecedented decarboxylative chain termination mechanism is described for the polyketide synthase of curacin A, an anticancer lead compound isolated from the marine cyanobacterium Lyngbya majuscula. The unusual chain termination module containing adjacent sulfotransferase (ST) and thioesterase (TE) catalytic domains embedded in CurM was biochemically characterized. The TE was proved to catalyze a hydrolytic chain release of the polyketide chain elongation intermediate. Moreover, a selective ST-mediated sulfonation of the (R)-beta-hydroxyl group was found to precede TE-mediated hydrolysis, triggering a successive decarboxylative elimination and resulting in the formation of a rare terminal olefin in the final metabolite.

  5. Terrorist attacks escalate in frequency and fatalities preceding highly lethal attacks.

    Science.gov (United States)

    Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G; Schimel, Jeff; Webber, David

    2014-01-01

    Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates--both in the number of people killed per attack and in the frequency of attacks--leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack.

  6. Brain slow waves preceding time-locked visuo-motor performance.

    Science.gov (United States)

    Konttinen, N; Lyytinen, H

    1993-06-01

    According to previous findings (Konttinen and Lyytinen, 1992), the slow brain negativity preceding the trigger pull in rifle-shooting tends to be decreased in successful shots among experienced marksmen, whereas no such pattern is found among inexperienced subjects. This effect was interpreted as resulting mainly from optimal arousal. However, another explanation is examined here. The aim of the experiment was to investigate slow electrocortical changes associated with motor regulation and visual aiming related to shooting performance. Four variations on a shooting task were used, in which the visual and motor components were contrasted. Motor activity related to gun stabilization was found to be associated with slow-wave positivity, whereas visual aiming was manifested as slow negativity. The results offer some basis for interpreting the individual slow brain wave patterns that predict shooting performance.

  7. Patterns of life events preceding the suicide in rural young Chinese: a case control study.

    Science.gov (United States)

    Zhang, Jie; Ma, Zhenyu

    2012-10-01

    Previous studies on the Chinese suicide found some life events prior to the suicide different from those in the West, but there is a lack of summary of the Chinese life event patterns to better understand the effects of the social structure on Chinese suicide. We tried to identify the life events that precede the Chinese rural youth suicides and compare them with what are found in the West, so as to find the patterns that are particularly true in the Chinese culture contexts. Suicide cases were investigated with a psychological autopsy study in rural China, and local community living controls were also interviewed with the same protocol. We collapsed 64 negative life events into six categories: (1) Marriage/Love, (2) Family/Home, (3) Work/Business, (4) Health/Hospital, (5) Law/Legal, (6) Friend/Relationship. About 92.3% of the suicides studied had experienced at least one type of negative life events. The three most common negative life events categories in the past one year were Family/Home (60.7%), Health/Hospital (53.8%) and Marriage/Love (51.3%) in the rural young suicide victims. Among the negative life events, those related to family relations, love affairs, and marital issues were most likely to precede a suicide of rural suicides in China, and it is especially true of rural young women. Family is an important social institution in rural China for suicide prevention efforts. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Preparatory process preceding the 2014 eruption of Mount Ontake volcano, Japan: insights from precise leveling measurements

    Science.gov (United States)

    Murase, Masayuki; Kimata, Fumiaki; Yamanaka, Yoshiko; Horikawa, Shinichiro; Matsuhiro, Kenjiro; Matsushima, Takeshi; Mori, Hitoshi; Ohkura, Takahiro; Yoshikawa, Shin; Miyajima, Rikio; Inoue, Hiroyuki; Mishima, Taketoshi; Sonoda, Tadaomi; Uchida, Kazunari; Yamamoto, Keigo; Nakamichi, Harushisa

    2016-01-01

    Preparatory activity preceding the 2014 eruption of Mount Ontake volcano was estimated from vertical deformation detected using a precise leveling survey. Notable uplift (2006-2009) and subsidence (2009-2014) were detected on the eastern flank of the volcano. We estimated pressure source models based on the vertical deformation and used these to infer preparatory process preceding the 2014 eruption. Our results suggest that the subsidence experienced between 2009 and 2014 (including the period of the 2014 eruption) occurred as a result of a sill-like tensile crack with a depth of 2.5 km. This tensile crack might inflate prior to the eruption and deflate during the 2014 activity. A two-tensile-crack model was used to explain uplift from 2006 to 2009. The geometry of the shallow crack was assumed to be the same as the sill-like tensile crack. The deep crack was estimated to be 2 km in length, 4.5 km in width, and 3 km in depth. Distinct uplifts began on the volcano flanks in 2006 and were followed by seismic activities and a small phreatic eruption in 2007. From the partially surveyed leveling data in August 2013, uplift might continue until August 2013 without seismic activity in the summit area. Based on the uplift from 2006 to 2013, magma ascended rapidly beneath the summit area in December 2006, and deep and shallow tensile cracks were expanded between 2006 and 2013. The presence of expanded cracks between 2007 and 2013 has not been inferred by previous studies. A phreatic eruption occurred on 27 September 2014, and, following this activity, the shallow crack may have deflated.

  9. Impairment of adolescent hippocampal plasticity in a mouse model for Alzheimer's disease precedes disease phenotype.

    Directory of Open Access Journals (Sweden)

    Daniela Hartl

    Full Text Available The amyloid precursor protein (APP was assumed to be an important neuron-morphoregulatory protein and plays a central role in Alzheimer's disease (AD pathology. In the study presented here, we analyzed the APP-transgenic mouse model APP23 using 2-dimensional gel electrophoresis technology in combination with DIGE and mass spectrometry. We investigated cortex and hippocampus of transgenic and wildtype mice at 1, 2, 7 and 15 months of age. Furthermore, cortices of 16 days old embryos were analyzed. When comparing the protein patterns of APP23 with wildtype mice, we detected a relatively large number of altered protein spots at all age stages and brain regions examined which largely preceded the occurrence of amyloid plaques. Interestingly, in hippocampus of adolescent, two-month old mice, a considerable peak in the number of protein changes was observed. Moreover, when protein patterns were compared longitudinally between age stages, we found that a large number of proteins were altered in wildtype mice. Those alterations were largely absent in hippocampus of APP23 mice at two months of age although not in other stages compared. Apparently, the large difference in the hippocampal protein patterns between two-month old APP23 and wildtype mice was caused by the absence of distinct developmental changes in the hippocampal proteome of APP23 mice. In summary, the absence of developmental proteome alterations as well as a down-regulation of proteins related to plasticity suggest the disturption of a normally occurring peak of hippocampal plasticity during adolescence in APP23 mice. Our findings are in line with the observation that AD is preceded by a clinically silent period of several years to decades. We also demonstrate that it is of utmost importance to analyze different brain regions and different age stages to obtain information about disease-causing mechanisms.

  10. Diseases that precede disability among latter-stage elderly individuals in Japan.

    Science.gov (United States)

    Naruse, Takashi; Sakai, Mahiro; Matsumoto, Hiroshige; Nagata, Satoko

    2015-08-01

    Understanding causes of disability among elderly individuals is an important public health issue, particularly because of the increasing rate of disabled elderly individuals and the social costs in a rapidly aging society. Accordingly, we aimed to describe the diseases that precede disability and investigate the types of diseases that are related to severe disability among Japanese elderly individuals aged over 75 years. Using claim data from the latter-stage elderly healthcare system and long-term care insurance system, we identified 76,265 elderly individuals over 75 years old who did not qualify as disabled on April 1, 2011. Among them, 3,715 elderly individuals who had been newly qualified as disabled between April 1, 2011 and March 31, 2012 were selected. Disease codes from the medical claim data in the 6 months prior to disability were collected. All descriptions were developed separately for six groups divided by gender and disability level (low, middle, and high). The results of the ordinal logistic analysis including sex and age revealed that men tended to have significantly higher levels of disability (β = 0.417, p disability level groups. In low-level disability groups, cancer in men (12.8%) and arthropathy and fracture in women (11.9% and 13.5%, respectively) were as common as cerebrovascular disorder (12.2% and 9.7%, in men and women, respectively). Stroke was the most common disease for all genders and disability levels. The diseases preceding low-level disability differed by gender. This study demonstrated the need to consider arthropathy and fracture as well as CVD in order to prevent disability.

  11. A Legal Analysis of the Precedents of Medical Disputes in the Cosmetic Surgery Field

    Directory of Open Access Journals (Sweden)

    Bo Young Park

    2016-05-01

    Full Text Available BackgroundDisputes regarding medical malpractice occur between practitioners and patients. As patients have become increasingly aware regarding medical care, an increase in the unexpected side effects of procedures has been observed, thereby leading to an increase in disputes regarding medical malpractice. In this study, we reviewed trends in precedents involving cosmetic surgery-related medical disputes, with the goal of helping to prevent unnecessary disputes in the future.MethodsWe conducted a search of the judgments made in South Korean courts between 2000 and 2013 that were related to the field of plastic surgery. A total of 54 judgments were analyzed, and the selected precedents were reviewed and classified according to the kind of negligence involved.ResultsThe claim amounts ranged from under 8 million KRW (6,991 USD to 750 million KRW (629,995 USD. The most common ratio of the judgment amount to the claim amount was 20%–30%. The judgments were classified according to the following categories: violation of the duty of explanation in 17 cases (29%, violation of the duty of care in 10 cases (17%, violation of both duties in 20 cases (35%, and no violation of duty in six cases (10%.ConclusionsCosmetic surgery-related suits require different approaches than general malpractice suits. The Supreme Court requires plastic surgeons to determine the type, timing, methods, and scope of their treatments when considering possible results. Therefore, practitioners should be educated on their rights and responsibilities to enable them to cope with any possible medical dispute that may arise.

  12. Behaviour patterns preceding a railway suicide: explorative study of German Federal Police officers' experiences.

    Science.gov (United States)

    Lukaschek, Karoline; Baumert, Jens; Ladwig, Karl-Heinz

    2011-08-04

    Constant high-level numbers of railway suicides indicate that prevention strategies against railway suicides are urgently needed. The main question of the present study was whether pre-crash railway suicide behaviour can be identified, using German Federal Police officers experience with suicidal events in railway related environments. To collect information on pre-crash railway suicide behaviour, a questionnaire was used and made available on the German Federal Police intranet. A total of 202 subjects (mean age: 41 years, sex: 84.9% male) were included in the analysis. Multivariate logistic regression analyses were performed to predict the prevention of suicide (first model) or demand for counselling (second model) as outcomes. Sex, age, years of service, number of experienced suicides, suicides personally observed, information on suicides obtained from witnesses and finally either counselling/debriefing (first model) or whether officers had prevented a suicide (second model) were used as predictors. A considerable proportion of police officers reported behavioural patterns preceding a suicide. Half of them observed the dropping or leaving behind of personal belongings or the avoidance of eye contact, more than a third erratic gesture, mimic or movement. Erratic communication patterns and general confusion were each reported by about one quarter. One fifth indicated the influence of alcohol. Less frequently observed behaviour was aimlessly wandering (14.3%) and out of the ordinary clothing (4%). About one third of all railway suicide victims committed suicide in stations. Of those, 70% had chosen an eminent spot. The multivariate logistic regression model using prevented suicides as the outcome identified the number of suicides experienced, counselling/debriefing and having personally observed a suicide as variables with significant impact. The model using counselling/debriefing as the outcome identified age and having prevented a suicide as variables with a

  13. Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation.

    Science.gov (United States)

    Quispe, Ruth Liliám; Canto, Rômulo Faria Santos; Jaramillo, Michael Lorenz; Barbosa, Flavio Augusto Rocha; Braga, Antônio Luiz; de Bem, Andreza Fabro; Farina, Marcelo

    2018-02-12

    Recent studies have shown that probucol (PB), a hipocholesterolemic agent with antioxidant and anti-inflammatory properties, presents neuroprotective properties. On the other hand, adverse effects have limited PB's clinical application. Thus, the search for PB derivatives with no or less adverse effects has been a topic of research. In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicity induced by tert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48 h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondrial dysfunction. Of note, RC513 significantly increased glutathione peroxidase (GPx) activity and mRNA expression of GPx1, a key enzyme involved in peroxide detoxification. The use of mercaptosuccinic acid, an inhibitor of GPx, significantly decreased the protective activity of RC513 against tBuOOH-induced cytotoxicity in HT22 cells, highlighting the importance of GPx upregulation in the observed protection. In summary, the results showed a significant protective activity of a novel PB derivative against tBuOOH-induced oxidative stress and mitochondrial dysfunction, which was related to the upregulation of GPx. Our results point to RC513 as a promising neuroprotective molecule, even though studies concerning potential beneficial effects and safety aspects of RC513 under in vivo conditions are well warranted.

  14. Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

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    Adriana M Zimnicka

    Full Text Available Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX, a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2 also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC. In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

  15. Acupuncture upregulates G protein coupled activity in SAMP8 mice.

    Science.gov (United States)

    Luo, Benhua; Zhao, Lan; Zhang, Xuezhu; Kan, Bohong; Liu, Yunhe; Jia, Yujie; Han, Jingxian; Yu, Jianchun

    2017-08-01

    Transmembrane and intracellular signal transduction of G protein is closely related to the pathophysiology of Alzheimer's disease (AD). To explore the effects of Sanjiao acupuncture on G protein signal transduction pathways in the pathogenesis of AD. 36 senescence-accelerated (SAM) prone 8 mice were divided into three groups that remained untreated (SAMP8, n=12) or received Sanjiao acupuncture (SAMP8+SA, n=12) or control acupuncture (SAMP8+CA, n=12). An additional control group of SAM resistant 1 mice was included (SAMR1 group, n=12). Morris water maze tests were used to investigate learning and memory abilities. Immunoprecipitation and Western blotting were used to study expression of G protein subunits and their activities in the cortex/hippocampus. Behavioural analysis showed that acupuncture attenuated the severe cognitive deficits observed in untreated/CA-treated SAMP8 mice. The findings of the G protein activation assays via immunoprecipitation and Western blots were that the physiologically coupled activation rate (PCAR) and maximal coupled activation rate (MCAR) of Gα s and Gα i were decreased in the cortex of SAMP8 vs SAMR1 mice. Sanjiao acupuncture induced an upregulation in the PCAR of Gα s and Gα i . In the hippocampus of untreated SAMP8 mice, the PCAR of Gα s and MCAR of both Gα s and Gα i declined, and Sanjiao acupuncture was associated with an upregulation in the MCAR of Gα s and Gα i . There were no significant differences in Gα s and Gα i expression between the groups. Sanjiao acupuncture attenuates cognitive deficits in a mouse model of AD via upregulation of G protein activity and stabilisation of the cellular signal. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  16. Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Jeong, Jieun; Wi, Anjin; Park, Whoashig [Jeollanamdo Forest Resources Research Institute, Naju 520-833 (Korea, Republic of); Han, Ho-jae [College of Veterinary Medicine, Seoul National University, Seoul 151-741 (Korea, Republic of); Park, Soo-hyun, E-mail: parksh@chonnam.ac.kr [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of)

    2015-06-05

    Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation.

  17. Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

    International Nuclear Information System (INIS)

    Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee; Jeong, Jieun; Wi, Anjin; Park, Whoashig; Han, Ho-jae; Park, Soo-hyun

    2015-01-01

    Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

  18. The association between preceding drought occurrence and heat waves in the Mediterranean

    Science.gov (United States)

    Russo, Ana; Gouveia, Célia M.; Ramos, Alexandre M.; Páscoa, Patricia; Trigo, Ricardo M.

    2017-04-01

    A large number of weather driven extreme events has occurred worldwide in the last decade, namely in Europe that has been struck by record breaking extreme events with unprecedented socio-economic impacts, including the mega-heatwaves of 2003 in Europe and 2010 in Russia, and the large droughts in southwestern Europe in 2005 and 2012. The last IPCC report on extreme events points that a changing climate can lead to changes in the frequency, intensity, spatial extent, duration, and timing of weather and climate extremes. These, combined with larger exposure, can result in unprecedented risk to humans and ecosystems. In this context it is becoming increasingly relevant to improve the early identification and predictability of such events, as they negatively affect several socio-economic activities. Moreover, recent diagnostic and modelling experiments have confirmed that hot extremes are often preceded by surface moisture deficits in some regions throughout the world. In this study we analyze if the occurrence of hot extreme months is enhanced by the occurrence of preceding drought events throughout the Mediterranean area. In order to achieve this purpose, the number of hot days in the regions' hottest month will be associated with a drought indicator. The evolution and characterization of drought was analyzed using both the Standardized Precipitation Evaporation Index (SPEI) and the Standardized Precipitation Index (SPI), as obtained from CRU TS3.23 database for the period 1950-2014. We have used both SPI and SPEI for different time scales between 3 and 9 months with a spatial resolution of 0.5°. The number of hot days and nights per month (NHD and NHN) was determined using the ECAD-EOBS daily dataset for the same period and spatial resolution (dataset v14). The NHD and NHN were computed, respectively, as the number of days with a maximum or minimum temperature exceeding the 90th percentile. Results show that the most frequent hottest months for the Mediterranean

  19. Rethinking 'flexibilities' in the international drug control system-Potential, precedents and models for reforms.

    Science.gov (United States)

    Collins, John

    2017-01-24

    Much international drug policy debate centres on, what policies are permissible under the international drug treaties, whether member states are openly 'breaching' these treaties by changing national regulatory frameworks and shifting priorities away from a 'war on drugs' approach, and what 'flexibility' exists for policy reform and experimentation at national and local levels. Orthodox interpretations hold that the current system is a US-led 'prohibition regime' that was constructed in an extremely repressive and restrictive manner with almost no flexibility for significant national deviations. This paper challenges these orthodox interpretive frameworks and suggests no absolute and clear dichotomy between strict adherence and 'breaches' of the international treaties. This paper uses historical analysis to highlight the flaws in orthodox policy analyses, which assume a uniform interpretation, implementation and set of policy trajectories towards a 'prohibition regime' in the 20th century. It challenges some existing legal interpretations of the treaties through recourse to historical precedents of flexible interpretation and policy prioritisation. It then examines the legal justifications currently being formulated by member states to explain a shift towards policies which, until recently, have been viewed as outside the permissible scope of the conventions. It then examines a functionalist framework for understanding the likely contours of drug diplomacy in the post-UN General Assembly Special Session (UNGASS) 2016 era. The paper highlights that, contrary to current policy discourses, the international control system has always been implemented in a 'flexible' manner. It demonstrates that drug control goals were repeatedly subsumed to security, development, political stability and population welfare imperatives, or what we might now refer to under the umbrella of 'development issues.' The paper further demonstrates that policy prioritisation, inherent treaty

  20. Use of caries prevention services in the Northwest PRECEDENT dental network.

    Science.gov (United States)

    Ferracane, J; Hilton, T; Korpak, A; Gillette, J; McIntyre, P Speed; Berg, J

    2011-02-01

    This cross-sectional study assessed the use of caries preventive services by Northwest PRECEDENT dental network practitioners and compared the caries experience of patients who received such services in the past 12 months with those who had not. An oral health survey was conducted on approximately 20 patients seen by each of 97 private practice dental practitioners in the network. Eligible patients (total of 1877 aged 3-92) were randomly assessed for the occurrence of one or more new caries lesions as well as having received the following preventive services within the past 12 months: fluoride varnish or gel, sealant in molar or premolar, and prophylaxis. Patients were stratified by gender and age (1-17 years old, 18-64 years old, and 65+ years old). Logistic regression was used to investigate the association between the practitioner characteristics and the use of preventive services, as well as the preventive services and the presence of a new caries lesion in the past 12 months. The percent of patients in age category 1-17 years old/18-64 years old/65+ years old receiving each preventive treatment varied as follows: 95%/85%/81% for prophylaxis, 87%/24%/22% for fluoride, and 27%/2%/0% for sealant. There was a very limited association between the use of a specific preventive service and practitioner gender, and no significant association between use of services and practice location (rural, urban or suburban). There was a significant association between greater use of sealants for dentists with 0-15 years of practice experience as compared with those having more than 25 years of experience. For the 1-17-year-old age group, boys had about 1.7 times the odds of having a new lesion than girls in the past 12 months, and patients receiving a sealant had 1.9 times the odds of having a new caries lesion. In the 18-64-year-old group, receiving a prophylaxis in the past 12 months was significantly associated with lower odds for having a new lesion (odds ratio = 0.57). This

  1. Behaviour patterns preceding a railway suicide: Explorative study of German Federal Police officers' experiences

    Directory of Open Access Journals (Sweden)

    Ladwig Karl-Heinz

    2011-08-01

    Full Text Available Abstract Background Constant high-level numbers of railway suicides indicate that prevention strategies against railway suicides are urgently needed. The main question of the present study was whether pre-crash railway suicide behaviour can be identified, using German Federal Police officers experience with suicidal events in railway related environments. Methods To collect information on pre-crash railway suicide behaviour, a questionnaire was used and made available on the German Federal Police intranet. A total of 202 subjects (mean age: 41 years, sex: 84.9% male were included in the analysis. Multivariate logistic regression analyses were performed to predict the prevention of suicide (first model or demand for counselling (second model as outcomes. Sex, age, years of service, number of experienced suicides, suicides personally observed, information on suicides obtained from witnesses and finally either counselling/debriefing (first model or whether officers had prevented a suicide (second model were used as predictors. Results A considerable proportion of police officers reported behavioural patterns preceding a suicide. Half of them observed the dropping or leaving behind of personal belongings or the avoidance of eye contact, more than a third erratic gesture, mimic or movement. Erratic communication patterns and general confusion were each reported by about one quarter. One fifth indicated the influence of alcohol. Less frequently observed behaviour was aimlessly wandering (14.3% and out of the ordinary clothing (4%. About one third of all railway suicide victims committed suicide in stations. Of those, 70% had chosen an eminent spot. The multivariate logistic regression model using prevented suicides as the outcome identified the number of suicides experienced, counselling/debriefing and having personally observed a suicide as variables with significant impact. The model using counselling/debriefing as the outcome identified age and

  2. Hypoxia upregulates neutrophil degranulation and potential for tissue injury

    Science.gov (United States)

    Hoenderdos, Kim; Lodge, Katharine M; Hirst, Robert A; Chen, Cheng; Palazzo, Stefano G C; Emerenciana, Annette; Summers, Charlotte; Angyal, Adri; Porter, Linsey; Juss, Jatinder K; O'Callaghan, Christopher; Chilvers, Edwin R

    2016-01-01

    Background The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. Methods and results Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. Conclusion Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion. PMID:27581620

  3. Involvement of Prohibitin Upregulation in Abrin-Triggered Apoptosis

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    Yu-Huei Liu

    2012-01-01

    Full Text Available Abrin (ABR, a protein purified from the seeds of Abrus precatorius, induces apoptosis in various types of cancer cells. However, the detailed mechanism remains largely uncharacterized. By using a cDNA microarray platform, we determined that prohibitin (PHB, a tumor suppressor protein, is significantly upregulated in ABR-triggered apoptosis. ABR-induced upregulation of PHB is mediated by the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK pathway, as demonstrated by chemical inhibitors. In addition, ABR significantly induced the expression of Bax as well as the activation of caspase-3 and poly(ADP-ribose polymerase (PARP in Jurkat T cells, whereas the reduction of PHB by specific RNA interference delayed ABR-triggered apoptosis through the proapoptotic genes examined. Moreover, our results also indicated that nuclear translocation of the PHB-p53 complex may play a role in the transcription of Bax. Collectively, our data show that PHB plays a role in ABR-induced apoptosis, which may be helpful for the development of diagnostic or therapeutic agents.

  4. Upregulation of Relaxin after Experimental Subarachnoid Hemorrhage in Rabbits

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    Yuichiro Kikkawa

    2014-01-01

    Full Text Available Background. Although relaxin causes vasodilatation in systemic arteries, little is known about its role in cerebral arteries. We investigated the expression and role of relaxin in basilar arteries after subarachnoid hemorrhage (SAH in rabbits. Methods. Microarray analysis with rabbit basilar artery RNA was performed. Messenger RNA expression of relaxin-1 and relaxin/insulin-like family peptide receptor 1 (RXFP1 was investigated with quantitative RT-PCR. RXFP1 expression in the basilar artery was investigated with immunohistochemistry. Relaxin concentrations in cerebrospinal fluid (CSF and serum were investigated with an enzyme-linked immunosorbent assay. Using human brain vascular smooth muscle cells (HBVSMC preincubated with relaxin, myosin light chain phosphorylation (MLC was investigated with immunoblotting after endothelin-1 stimulation. Results. After SAH, RXFP1 mRNA and protein were significantly downregulated on day 3, whereas relaxin-1 mRNA was significantly upregulated on day 7. The relaxin concentration in CSF was significantly elevated on days 5 and 7. Pretreatment with relaxin reduced sustained MLC phosphorylation induced by endothelin-1 in HBVSMC. Conclusion. Upregulation of relaxin and downregulation of RXFP1 after SAH may participate in development of cerebral vasospasm. Downregulation of RXFP1 may induce a functional decrease in relaxin activity during vasospasm. Understanding the role of relaxin may provide further insight into the mechanisms of cerebral vasospasm.

  5. Hyperbaric oxygen upregulates cochlear constitutive nitric oxide synthase

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    Kao Ming-Ching

    2011-02-01

    Full Text Available Abstract Background Hyperbaric oxygen therapy (HBOT is a known adjuvant for treating ischemia-related inner ear diseases. Controversies still exist in the role of HBOT in cochlear diseases. Few studies to date have investigated the cellular changes that occur in inner ears after HBOT. Nitric oxide, which is synthesized by nitric oxide synthase (NOS, is an important signaling molecule in cochlear physiology and pathology. Here we investigated the effects of hyperbaric oxygen on eardrum morphology, cochlear function and expression of NOS isoforms in cochlear substructures after repetitive HBOT in guinea pigs. Results Minor changes in the eardrum were observed after repetitive HBOT, which did not result in a significant hearing threshold shift by tone burst auditory brainstem responses. A differential effect of HBOT on the expression of NOS isoforms was identified. Upregulation of constitutive NOS (nNOS and eNOS was found in the substructures of the cochlea after HBOT, but inducible NOS was not found in normal or HBOT animals, as shown by immunohistochemistry. There was no obvious DNA fragmentation present in this HBOT animal model. Conclusions The present evidence indicates that the customary HBOT protocol may increase constitutive NOS expression but such upregulation did not cause cell death in the treated cochlea. The cochlear morphology and auditory function are consequently not changed through the protocol.

  6. Expression and in vitro upregulation of MHCII in koala lymphocytes.

    Science.gov (United States)

    Lau, Quintin; Canfield, Paul J; Higgins, Damien P

    2012-06-15

    Understanding and measuring immune activity of the koala (Phascolarctos cinereus), is important to studies of the epidemiology and impact of the widespread chlamydial and koala retroviral (KoRV) infections that occur in this iconic but increasingly threatened species. To explore the interaction of disease and immunity, and to assess the potential for use of class II major histocompatibility complex (MHCII) upregulation as an indicator of lymphocyte activation in in vitro immune assays, we have investigated the expression of MHCII in koala lymphocytes by flow cytometry. MHCII expression was upregulated in mitogen stimulated B lymphocytes in vitro but no such increase was detected in vivo in free-living koalas with active inflammation. In assessing phenotypic baseline data of captive koalas, we have identified that MHCII is expressed predominantly on circulating B lymphocytes (85.7 ± 2.4%) but on very few T lymphocytes (3.4 ± 1.9%), even following activation, and suggest that the latter finding might be compensated by the greater absolute numbers of peripheral blood B lymphocytes in this species relative to many eutherian species. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Progesterone Upregulates Gene Expression in Normal Human Thyroid Follicular Cells

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    Ana Paula Santin Bertoni

    2015-01-01

    Full Text Available Thyroid cancer and thyroid nodules are more prevalent in women than men, so female sex hormones may have an etiological role in these conditions. There are no data about direct effects of progesterone on thyroid cells, so the aim of the present study was to evaluate progesterone effects in the sodium-iodide symporter NIS, thyroglobulin TG, thyroperoxidase TPO, and KI-67 genes expression, in normal thyroid follicular cells, derived from human tissue. NIS, TG, TPO, and KI-67 mRNA expression increased significantly after TSH 20 μUI/mL, respectively: 2.08 times, P<0.0001; 2.39 times, P=0.01; 1.58 times, P=0.0003; and 1.87 times, P<0.0001. In thyroid cells treated with 20 μUI/mL TSH plus 10 nM progesterone, RNA expression of NIS, TG, and KI-67 genes increased, respectively: 1.78 times, P<0.0001; 1.75 times, P=0.037; and 1.95 times, P<0.0001, and TPO mRNA expression also increased, though not significantly (1.77 times, P=0.069. These effects were abolished by mifepristone, an antagonist of progesterone receptor, suggesting that genes involved in thyroid cell function and proliferation are upregulated by progesterone. This work provides evidence that progesterone has a direct effect on thyroid cells, upregulating genes involved in thyroid function and growth.

  8. How are topics born? Understanding the research dynamics preceding the emergence of new areas

    Directory of Open Access Journals (Sweden)

    Angelo A. Salatino

    2017-06-01

    Full Text Available The ability to promptly recognise new research trends is strategic for many stakeholders, including universities, institutional funding bodies, academic publishers and companies. While the literature describes several approaches which aim to identify the emergence of new research topics early in their lifecycle, these rely on the assumption that the topic in question is already associated with a number of publications and consistently referred to by a community of researchers. Hence, detecting the emergence of a new research area at an embryonic stage, i.e., before the topic has been consistently labelled by a community of researchers and associated with a number of publications, is still an open challenge. In this paper, we begin to address this challenge by performing a study of the dynamics preceding the creation of new topics. This study indicates that the emergence of a new topic is anticipated by a significant increase in the pace of collaboration between relevant research areas, which can be seen as the ‘parents’ of the new topic. These initial findings (i confirm our hypothesis that it is possible in principle to detect the emergence of a new topic at the embryonic stage, (ii provide new empirical evidence supporting relevant theories in Philosophy of Science, and also (iii suggest that new topics tend to emerge in an environment in which weakly interconnected research areas begin to cross-fertilise.

  9. The first film presentation of REM sleep behavior disorder precedes its scientific debut by 35 years

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    Janković Slavko M.

    2006-01-01

    Full Text Available The perplexing and tantalizing disease of rapid eye movement (REM sleep behavior disorder (RBD is characterized by peculiar, potentially dangerous behavior during REM sleep. It was described both in animals and humans. RBD in mammals was first described by Jouvet and Delorme in 1965, based on an experimental model induced by lesion in pontine region of cats [1]. In 1972, Passouant et al. described sleep with eye movements and persistent tonic muscle activity induced by tricyclic antidepressant medication [2], and Tachibana et al., in 1975, the preservation of muscle tone during REM sleep in the acute psychosis induced by alcohol and meprobamate abuse [3]. However, the first formal description of RBD in humans as new parasomnia was made by Schenck et al in 1986 [4-7]. Subsequently, in 1990, the International Classification of Sleep Disorders definitely recognized RBD as new parasomnia [8]. To our knowledge, arts and literature do not mention RBD. Except for the quotation, made by Schenck et al [6] in 2002, of Don Quixote de la Mancha whose behavior in sleep strongly suggested that Miguel de Servantes actually described RBD, no other artistic work has portrayed this disorder. Only recently we become aware of the cinematic presentation of RBD which by decades precedes the first scientific description. The first presentation of RBD on film was made prior to the era of advanced electroencephalography and polysomnography, and even before the discovery of REM sleep by Aserinsky and Kleitman in 1953. [9]. The artistic and intuitive presentation of RBD was produced in Technicolor in a famous film "Cinderella" created by Walt Disney in 1950, some 35 years prior to its original publication in the journal "Sleep" [2]. Since there is an earlier version of the film initially produced in 1920, presumably containing this similar scene, we can only speculate that the first cinematic presentation of RBD might precede its scientific debut by 65 years. In a scene

  10. Complex Admixture Preceded and Followed the Extinction of Wisent in the Wild.

    Science.gov (United States)

    Wecek, Karolina; Hartmann, Stefanie; Paijmans, Johanna L A; Taron, Ulrike; Xenikoudakis, Georgios; Cahill, James A; Heintzman, Peter D; Shapiro, Beth; Baryshnikov, Gennady; Bunevich, Aleksei N; Crees, Jennifer J; Dobosz, Roland; Manaserian, Ninna; Okarma, Henryk; Tokarska, Malgorzata; Turvey, Samuel T; Wójcik, Jan M; Zyla, Waldemar; Szymura, Jacek M; Hofreiter, Michael; Barlow, Axel

    2017-03-01

    Retracing complex population processes that precede extreme bottlenecks may be impossible using data from living individuals. The wisent (Bison bonasus), Europe's largest terrestrial mammal, exemplifies such a population history, having gone extinct in the wild but subsequently restored by captive breeding efforts. Using low coverage genomic data from modern and historical individuals, we investigate population processes occurring before and after this extinction. Analysis of aligned genomes supports the division of wisent into two previously recognized subspecies, but almost half of the genomic alignment contradicts this population history as a result of incomplete lineage sorting and admixture. Admixture between subspecies populations occurred prior to extinction and subsequently during the captive breeding program. Admixture with the Bos cattle lineage is also widespread but results from ancient events rather than recent hybridization with domestics. Our study demonstrates the huge potential of historical genomes for both studying evolutionary histories and for guiding conservation strategies. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. Menstrual irregularities and lactation failure may precede thyroid dysfunction or goitre.

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    Joshi J

    1993-07-01

    Full Text Available Menstrual and reproductive history of 178 women referred to the thyroid clinic was compared with 49 healthy controls. Cases were classified as euthyroid, hypothyroid or hyperthyroid after clinical examination and after serum T3, T4, TSH measurements. Reproductive history was related chronologically to symptoms and signs of thyroid dysfunction. Only 31.8% of hypothyroid and 35.3% of hyperthyroid women had normal menstrual pattern in contrast with 56.3% of Euthyroid and 87.8% of healthy controls (p < 0.001. Reproductive failure (infertility, pregnancy wastage, failure of lactation occurred in 37.5% of hypothyroid and 36.5% of hyperthyroid cases against 16.3% of euthyroid and 16.7% of healthy controls (p < 0.05. Interestingly, in 45% of cases with menstrual abnormality, the anomaly was antecedent to other clinical features by a variable period of two months to ten years. Reproductive failure and lactation failure also preceded thyroid dysfunction or goitre. Reproductive dysfunction may therefore be considered as one of the presenting symptoms of thyroid disorders in women, keeping in mind both menstrual irregularities and lactation failure may also arise from other common or idiopathic origins. Especially in women with menstrual irregularities in the perimenopausal age if thyroid dysfunction is detected, pharmacotherapy may be a superior alternative to surgical interventions like hysterectomy.

  12. Nocturnal leg cramps and prescription use that precedes them: a sequence symmetry analysis.

    Science.gov (United States)

    Garrison, Scott R; Dormuth, Colin R; Morrow, Richard L; Carney, Greg A; Khan, Karim M

    2012-01-23

    The use of diuretics, statins, and inhaled long-acting β2-agonists (LABAs) is linked to muscle cramps but largely by anecdotal evidence. This study sought population-level data to better evaluate these associations. Linked health care databases containing prescribing information (December 1, 2000, to November 30, 2008) about 4.2 million residents of British Columbia, Canada, were evaluated using sequence symmetry analysis to determine in adults 50 years or older whether new quinine prescriptions (initiations of cramp treatment) increase in the year following diuretic, statin, or LABA starts. The statistic of interest was the sequence ratio: the number of quinine starts in the year following index drug introduction compared with the number of quinine starts in the preceding year (adjusted for age and time trends in population prescribing). Adjusted sequence ratios (95% CIs) for the 3 drug classes were 1.47 (1.33-1.63 [P Cramp treatment was substantially more likely in the year following introduction of LABAs, potassium-sparing diuretics, or thiazidelike diuretics, and 60.3% of quinine users (individuals experiencing cramp) received at least 1 of these medications during a 13-year period. In contrast, statin and loop diuretic associations were small. Physicians should be mindful that the use of these medications may worsen symptoms in patients experiencing nocturnal leg cramps.

  13. Using the PRECEDE Model in Understanding Determinants of Quality of Life Among Iranian Male Addicts

    Science.gov (United States)

    Matin, Behzad Karami; Jalilian, Farzad; Alavijeh, Mehdi Mirzaei; Ashtarian, Hossein; Mahboubi, Mohammad; Afsar, Ali

    2014-01-01

    Quality of Life (QOL) in opiate-addicted patients who are receiving methadone maintenance therapy is one of the important issues to be considered in the treatment of addiction. To determine a needs assessment using the PRECEDE model to find out factors related to QOL among Iranian male opiate addicts. This cross-sectional study was conducted in Kermanshah, Iran in 2013. A total of 762 male opiate addicts, who were referred to addiction treatment centers for receiving methadone maintenance treatment, were randomly selected to participate voluntarily in the study. SF-12, predisposing factors, enabling factors, reinforcement factors, and methadone maintenance treatment intention were used to find the related factors. Data were analyzed by the SPSS software (ver. 21.0) using the t-test, one-way analysis of variance (ANOVA), bivariate correlations, and linear regression at 95% significant level. Linear regression analysis showed the determinant variable accounted for 17% of the variation in QOL. Our findings suggest, providing social support for addicts could be beneficial results for the increasing quality of life among them. PMID:25363110

  14. Smoking, alcohol, and coffee consumption preceding Parkinson's disease: a case-control study.

    Science.gov (United States)

    Benedetti, M D; Bower, J H; Maraganore, D M; McDonnell, S K; Peterson, B J; Ahlskog, J E; Schaid, D J; Rocca, W A

    2000-11-14

    To study the association of PD with preceding smoking, alcohol, and coffee consumption using a case-control design. The authors used the medical records linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, during the years 1976 to 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control subject. The authors reviewed the complete medical records of cases and control subjects to abstract exposure information. For coffee consumption, the authors found an OR of 0.35 (95% CI = 0.16 to 0.78, p = 0.01), a dose-effect trend (p = 0.003), and a later age at PD onset in cases who drank coffee compared with those who never did (median 72 versus 64 years; p = 0.0002). The inverse association with coffee remained significant after adjustment for education, smoking, and alcohol drinking and was restricted to PD cases with onset at age coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered.

  15. Increased anterior cingulate cortex response precedes behavioural adaptation in anorexia nervosa.

    Science.gov (United States)

    Geisler, Daniel; Ritschel, Franziska; King, Joseph A; Bernardoni, Fabio; Seidel, Maria; Boehm, Ilka; Runge, Franziska; Goschke, Thomas; Roessner, Veit; Smolka, Michael N; Ehrlich, Stefan

    2017-02-13

    Patients with anorexia nervosa (AN) are characterised by increased self-control, cognitive rigidity and impairments in set-shifting, but the underlying neural mechanisms are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of behavioural adaptation to changes in reward contingencies in young acutely ill AN patients. Thirty-six adolescent/young adult, non-chronic female AN patients and 36 age-matched healthy females completed a well-established probabilistic reversal learning task during fMRI. We analysed hemodynamic responses in empirically-defined regions of interest during positive feedback and negative feedback not followed/followed by behavioural adaptation and conducted functional connectivity analyses. Although overall task performance was comparable between groups, AN showed increased shifting after receiving negative feedback (lose-shift behaviour) and altered dorsal anterior cingulate cortex (dACC) responses as a function of feedback. Specifically, patients had increased dACC responses (which correlated with perfectionism) and task-related coupling with amygdala preceding behavioural adaption. Given the generally preserved task performance in young AN, elevated dACC responses specifically during behavioural adaption is suggestive of increased monitoring for the need to adjust performance strategies. Higher dACC-amygdala coupling and increased adaptation after negative feedback underlines this interpretation and could be related to intolerance of uncertainty which has been suggested for AN.

  16. Resting-state functional connectivity remains unaffected by preceding exposure to aversive visual stimuli.

    Science.gov (United States)

    Geissmann, Léonie; Gschwind, Leo; Schicktanz, Nathalie; Deuring, Gunnar; Rosburg, Timm; Schwegler, Kyrill; Gerhards, Christiane; Milnik, Annette; Pflueger, Marlon O; Mager, Ralph; de Quervain, Dominique J F; Coynel, David

    2018-02-15

    While much is known about immediate brain activity changes induced by the confrontation with emotional stimuli, the subsequent temporal unfolding of emotions has yet to be explored. To investigate whether exposure to emotionally aversive pictures affects subsequent resting-state networks differently from exposure to neutral pictures, a resting-state fMRI study implementing a two-group repeated-measures design in healthy young adults (N = 34) was conducted. We focused on investigating (i) patterns of amygdala whole-brain and hippocampus connectivity in both a seed-to-voxel and seed-to-seed approach, (ii) whole-brain resting-state networks with an independent component analysis coupled with dual regression, and (iii) the amygdala's fractional amplitude of low frequency fluctuations, all while EEG recording potential fluctuations in vigilance. In spite of the successful emotion induction, as demonstrated by stimuli rating and a memory-facilitating effect of negative emotionality, none of the resting-state measures was differentially affected by picture valence. In conclusion, resting-state networks connectivity as well as the amygdala's low frequency oscillations appear to be unaffected by preceding exposure to widely used emotionally aversive visual stimuli in healthy young adults. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. [The first film presentation of REM sleep behavior disorder precedes its scientific debut by 35 years].

    Science.gov (United States)

    Janković, Slavko M; Sokić, Dragoslav V; Vojvodić, Nikola M; Ristić, Aleksandar J

    2006-01-01

    The perplexing and tantalizing disease of rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by peculiar, potentially dangerous behavior during REM sleep. It was described both in animals and humans. RBD in mammals was first described by Jouvet and Delorme in 1965, based on an experimental model induced by lesion in pontine region of cats. In 1972, Passouant et al. described sleep with eye movements and persistent tonic muscle activity induced by tricyclic antidepressant medication, and Tachibana et al., in 1975, the preservation of muscle tone during REM sleep in the acute psychosis induced by alcohol and meprobamate abuse. wever, the first formal description of RBD in humans as new parasomnia was made by Schenck et al in 1986. Subsequently, in 1990, the International Classification of Sleep Disorders definitely recognized RBD as new parasomnia. To our knowledge, arts and literature do not mention RBD. Except for the quotation, made by Schenck et al [n 2002, of Don Quixote de la Mancha whose behavior in sleep strongly suggested that Miguel de Servantes actually described RBD, no other artistic work has portrayed this disorder. Only recently we become aware of the cinematic presentation of RBD which by decades precedes the first scientific description. The first presentation of RBD on film was made prior to the era of advanced electroencephalography and polysomnography, and even before the discovery of REM sleep by Aserinsky and Kleitman in 1953. The artistic and intuitive presentation of RBD was produced in Technicolor in a famous film "Cinderella" created by Walt Disney in 1950, some 35 years prior to its original publication in the journal "Sleep". Since there is an earlier version of the film initially produced in 1920, presumably containing this similar scene, we can only speculate that the first cinematic presentation of RBD might precede its scientific debut by 65 years. In a scene in a barn, clumsy and goofy dog Bruno is, as dogs

  18. Precedents, Patterns and Puzzles: Feminist Reflections on the First Women Lawyers

    Directory of Open Access Journals (Sweden)

    Mary Jane Mossman

    2016-10-01

    Full Text Available This paper initially examines the historical precedents established by some of the first women who entered the “gentleman’s profession” of law in different jurisdictions, as well as the biographical patterns that shaped some women’s ambitions to enter the legal professions. The paper then uses feminist methods and theories to interpret “puzzles that remain unsolved” about early women lawyers, focusing especially on two issues. One puzzle is the repeated claims on the part of many of these early women lawyers that they were “lawyers”, and not “women lawyers”, even as they experienced exclusionary practices and discrimination on the part of male lawyers and judges—a puzzle that suggests how professional culture required women lawyers to conform to existing patterns in order to succeed. A second puzzle relates to the public voices of early women lawyers, which tended to suppress disappointments, difficulties and discriminatory practices. In this context, feminist theories suggest a need to be attentive to the “silences” in women’s stories, including the stories of the lives of early women lawyers. Moreover, these insights may have continuing relevance for contemporary women lawyers because it is at least arguable that, while there have been changes in women’s experiences, there has been very little transformation in their work status in relation to men.

  19. Sjögren's syndrome: the diagnostic potential of early oral manifestations preceding hyposalivation/xerostomia.

    Science.gov (United States)

    Mignogna, M D; Fedele, S; Lo Russo, L; Lo Muzio, L; Wolff, A

    2005-01-01

    Sjögren's syndrome (SS) is a systemic autoimmune exocrinopathy that affects mainly the salivary and lacrimal glands, leading to progressive reduction in saliva and tear flow. Although the underlying immuno-mediated glandular destruction is thought to develop slowly over several years, a long delay from the start of the symptoms to final diagnosis has been frequently reported. A limited knowledge concerning SS natural history is among the major causes of the actual diagnostic delay. Although very few studies have been focused on the analysis of SS early clinical onset, a series of oral features preceding xerostomia/hyposalivation development in patients eventually diagnosed as having SS have been reported. Sialochemistry alterations, salivary gland swelling, early dental loss and sialorrhea have been observed before the onset of typical signs and symptoms (namely xerostomia and/or hyposalivation), which usually lead to SS clinical presentation and diagnosis. Here we suggest, after evaluating available data, that the traditional 'untouchable' association between SS and xerostomia/hyposalivation might probably be reconsidered, and that astute clinicians should not underestimate the possible presence or development of SS in patients without xerostomia/hyposalivation and presenting these atypical early oral features.

  20. Cognitive declines precede and predict functional declines in aging and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Laura B Zahodne

    Full Text Available To investigate the temporal ordering of cognitive and functional declines separately in older adults with or without Alzheimer's disease (AD.A community-based longitudinal study of aging and dementia in Northern Manhattan (Washington Heights/Hamilton Heights Inwood Columbia Aging Project and a multicenter, clinic-based longitudinal study of prevalent AD at Columbia University Medical Center, Johns Hopkins School of Medicine, Massachusetts General Hospital, and the Hôpital de la Salpêtrière in Paris, France (the Predictors Study.3,443 initially non-demented older adults (612 with eventual incident dementia and 517 patients with AD.Cognitive measures included the modified Mini-Mental State Exam and composite scores of memory and language derived from a standardized neuropsychological battery. Function was measured with the Blessed Dementia Rating Scale, completed by the participant (in the sample of non-demented older adults or an informant (in the sample of prevalent AD patients. Data were analyzed with autoregressive cross-lagged panel analysis.Cognitive scores more consistently predicted subsequent functional abilities than vice versa in non-demented older adults, participants with eventual incident dementia, and patients with prevalent AD.Cognitive declines appear to precede and cause functional declines prior to and following dementia diagnosis. Standardized neuropsychological tests are valid predictors of later functional changes in both non-demented and demented older adults.

  1. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

    Science.gov (United States)

    Sohn, Elliott H; van Dijk, Hille W; Jiao, Chunhua; Kok, Pauline H B; Jeong, Woojin; Demirkaya, Nazli; Garmager, Allison; Wit, Ferdinand; Kucukevcilioglu, Murat; van Velthoven, Mirjam E J; DeVries, J Hans; Mullins, Robert F; Kuehn, Markus H; Schlingemann, Reinier Otto; Sonka, Milan; Verbraak, Frank D; Abràmoff, Michael David

    2016-05-10

    Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

  2. Corneal nerve fibre damage precedes diabetic retinopathy in patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Bitirgen, G; Ozkagnici, A; Malik, R A; Kerimoglu, H

    2014-04-01

    To quantify the morphological alterations in corneal nerve fibres and cells in patients with type 2 diabetes mellitus in relation to the severity of diabetic retinopathy. One hundred and thirty-two eyes of 132 patients with type 2 diabetes and 32 eyes of 32 healthy control subjects were evaluated with in vivo corneal confocal microscopy. Patients with diabetes were classified into three groups: patients without diabetic retinopathy, patients with non-proliferative diabetic retinopathy and patients with proliferative diabetic retinopathy. Anterior and posterior stromal keratocyte, endothelial cell and basal epithelial cell densities and sub-basal nerve fibre structure were evaluated. Significant reductions in basal epithelial cell, anterior stromal keratocyte and endothelial cell densities were observed only in patients with diabetic retinopathy. However, nerve fibre density, nerve branch density and nerve fibre length were reduced in patients without diabetic retinopathy and worsened progressively with increasing severity of retinopathy. Corneal cell pathology occurs in patients with diabetic retinopathy, but corneal nerve fibre damage seems to precede the development of diabetic retinopathy. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

  3. Prediction of activation patterns preceding hallucinations in patients with schizophrenia using machine learning with structured sparsity.

    Science.gov (United States)

    de Pierrefeu, Amicie; Fovet, Thomas; Hadj-Selem, Fouad; Löfstedt, Tommy; Ciuciu, Philippe; Lefebvre, Stephanie; Thomas, Pierre; Lopes, Renaud; Jardri, Renaud; Duchesnay, Edouard

    2018-04-01

    Despite significant progress in the field, the detection of fMRI signal changes during hallucinatory events remains difficult and time-consuming. This article first proposes a machine-learning algorithm to automatically identify resting-state fMRI periods that precede hallucinations versus periods that do not. When applied to whole-brain fMRI data, state-of-the-art classification methods, such as support vector machines (SVM), yield dense solutions that are difficult to interpret. We proposed to extend the existing sparse classification methods by taking the spatial structure of brain images into account with structured sparsity using the total variation penalty. Based on this approach, we obtained reliable classifying performances associated with interpretable predictive patterns, composed of two clearly identifiable clusters in speech-related brain regions. The variation in transition-to-hallucination functional patterns not only from one patient to another but also from one occurrence to the next (e.g., also depending on the sensory modalities involved) appeared to be the major difficulty when developing effective classifiers. Consequently, second, this article aimed to characterize the variability within the prehallucination patterns using an extension of principal component analysis with spatial constraints. The principal components (PCs) and the associated basis patterns shed light on the intrinsic structures of the variability present in the dataset. Such results are promising in the scope of innovative fMRI-guided therapy for drug-resistant hallucinations, such as fMRI-based neurofeedback. © 2018 Wiley Periodicals, Inc.

  4. Tobacco use in silent film: precedents of modern-day substance use portrayals.

    Science.gov (United States)

    St Romain, Theresa; Hawley, Suzanne R; Ablah, Elizabeth; Kabler, Bethany S; Molgaard, Craig A

    2007-12-01

    Much research has been done into tobacco use portrayals in film since the mid-twentieth century, but the earlier years of Hollywood history have been overlooked. Yet the first decades of the twentieth century saw annual per capita cigarette consumption increase from under 100 in 1900 upto 1,500 in 1930. The current study looks at frequency and context (gender, age range, socioeconomic status, type of portrayal) of tobacco use in 20 top-grossing silent films spanning the silent feature era (1915-1928). The sample averaged 23.31 tobacco uses per hour. Tobacco use was most often associated with positive characterizations, working/middle class status, masculinity, and youth. Previous research has verified the influence of the film industry on tobacco consumption in modern years, and this potential connection should not be ignored for the silent film era. Top-grossing silent films set a precedent for positive media portrayals of substance use that have persisted to the present day.

  5. Stromal cell migration precedes hemopoietic repopulation of the bone marrow after irradiation

    International Nuclear Information System (INIS)

    Werts, E.D.; Gibson, D.P.; Knapp, S.A.; DeGowin, R.L.

    1980-01-01

    Circulation of hemopoietic stem cells into an irradiated site has been thoroughly documented, but migration of stromal cells to repair radiation damage has not. We determined the radiosensitivity of mouse bone marrow stroma and evaluated stromal and hemopoietic repopulation in x-irradiated marrow. The D 0 for growth of colonies of marrow stromal cells (MSC) was 215 to 230 rad. Total-body irradiation (TB) obliterated marrow stromal and hemopoietic cells within 3 days. In contrast, 1 day after 1000 rad leg irradiation (LI), MSC rose to 80% of normal, but fell to 34% by 3 days and recovered to 72% by 30 days. However, femoral nucleated cells diminished to 20% by 3 days and recovered to 74% of normal by 30 days. Likewise, differentiated marrow cells and hemopoietic stem cells were initially depleted. With 1000 rad LI followed 3 h later by 1000 rad to the body while shielding the leg, MSC and femoral nucleated cells recovered to values intermediate between 1000 rad TB and 1000 rad LI. We concluded that: (1) the D 0 for MSC was 215 to 230 rad, (2) stromal repopulation preceded hemopoietic recovery, and (3) immigration of stromal cells from an unirradiated sanctuary facilitated hemopoietic repopulation of a heavily irradiated site

  6. Presentations and Preceding factors of Drug Overdose amongst adolescents admitted to a Large Regional Hospital.

    LENUS (Irish Health Repository)

    Maduemem, KE

    2018-04-01

    Suicide is the third most common cause of death among adolescents globally, and poisoning is the leading method of attempted suicide. Survival after self-poisoning or drug overdose (OD) is common, providing an opportunity for secondary prevention. The aim of this study was to highlight pattern of presentations and preceding factors of OD in an adolescent population. We retrospectively evaluated the data of 85 adolescents presenting to a large regional hospital with OD over a 3-year period. The female-to-male ratio was 4.3:1. The median age of adolescents was 15.83 (range: 11.32 – 16.98) years. History of deliberate self-harm (DSH) was documented in 44.7%. Twenty-eight (33%) patients had been under the care of the CAMHS prior to index admission. Acetaminophen was the commonest drug used. Depression was the most common cause of mental illness in the study group. Substance abuse and conduct disorder were significantly commoner in males (p<0.05). Self-poisoning including OD in adolescence is a strong predictor of suicide; understanding the probable triggers can be significant in establishing appropriate prevention strategies.

  7. Signs of maternal vascular dysfunction precede preeclampsia in women with type 1 diabetes

    DEFF Research Database (Denmark)

    Clausen, Peter; Ekbom, Pia; Damm, Peter

    2007-01-01

    Aim This study aims to test the hypothesis that vascular dysfunction is present early in pregnancy in women with type 1 diabetes who subsequently develop preeclampsia. Methods Eighty-three women with type 1 diabetes of more than 10 years duration were followed up prospectively during pregnancy. E......% (5.9–10.5%) vs. 7.2% (5.3–10.9%), P=.008, respectively]. Conclusion This prospective study indicates that signs of maternal vascular dysfunction precede development of preeclampsia in women with type 1 diabetes.......Aim This study aims to test the hypothesis that vascular dysfunction is present early in pregnancy in women with type 1 diabetes who subsequently develop preeclampsia. Methods Eighty-three women with type 1 diabetes of more than 10 years duration were followed up prospectively during pregnancy......±57 µg/l, PWomen who later developed preeclampsia were also characterized by higher UAE, higher BP, and higher HbA1C than women who did not [Gestational Week 11: 194 (3–1104) vs. 7 (0–412) mg/24 h, median (range), P=.0003; 122±12/75±6 vs. 111±11/69±9 mmHg, mean±S.D., P2...

  8. Retinal changes precede visual dysfunction in the complement factor H knockout mouse.

    Directory of Open Access Journals (Sweden)

    Jennifer A E Williams

    Full Text Available We previously reported that aged mice lacking complement factor H (CFH exhibit visual defects and structural changes in the retina. However, it is not known whether this phenotype is age-related or is the consequence of disturbed development. To address this question we investigated the effect of Cfh gene deletion on the retinal phenotype of young and mid-age mice. Cfh(-/- mouse eyes exhibited thickening of the retina and reduced nuclear density, but relatively normal scotopic and photopic electroretinograms. At 12 months there was evidence of subtle astroglial activation in the Cfh(-/- eyes, and significant elevation of the complement regulator, decay-accelerating factor (DAF in Müller cells. In the retinal pigment epithelium (RPE of young control and Cfh(-/- animals mitochondria and melanosomes were oriented basally and apically respectively, whereas the apical positioning of melanosomes was significantly perturbed in the mid-age Cfh(-/- RPE. We conclude that deletion of Cfh in the mouse leads to defects in the retina that precede any marked loss of visual function, but which become progressively more marked as the animals age. These observations are consistent with a lifelong role for CFH in retinal homeostasis.

  9. Up-regulation of reciprocal inhibition by explosive strength training

    DEFF Research Database (Denmark)

    Geertsen, Svend Sparre; Jensen, Jesper Lundbye; Nielsen, Jens Bo

    At the onset of dorsiflexion disynaptic reciprocal inhibition (DRI) of soleus motoneurones is increased in order to prevent activation of the antagonistic plantarflexors. This is caused by descending facilitation of transmission in the DRI pathway. Since the risk of eliciting stretch reflexes...... in the ankle plantarflexors at the onset of dorsiflexion is larger the quicker the movement, we hypothesized that DRI may be up-regulated when subjects are trained to perform dorsiflexion movements as quickly as possible.   For this purpose, 15 healthy human subjects (7 male, 8 female) with an average age...... by 6% before the training and by 22% after the training, which was a statistically significant difference (pregulated in healthy subjects following explosive strength training in order to ensure efficient suppression of the antagonist...

  10. The right to keep and bear arms in the United States: State Courts precedents in the 19th century

    Directory of Open Access Journals (Sweden)

    Shulus A.A.

    2017-03-01

    Full Text Available in the article the author describes activities of State Courts in the 19th century on the admissibility of the right to keep and bear arms. The researcher has analyzed the most important precedents of State Courts and presented the jurisprudence evolution in this sphere.

  11. Magnetic resonance imaging findings of mumps meningoencephalitis with bilateral hippocampal lesions without preceding acute parotitis: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Ah Reum; Lee, Ha Young; Lim, Myung Kwan; Kang, Young Hye; Cho, Soon Gu; Choi, Seong Hye; Baek, Ji Hyeon [Inha University School of Medicine, Incheon (Korea, Republic of)

    2017-04-15

    Meningitis is a common central nervous system (CNS) complication of the mumps, a viral infection, but encephalitis and meningoencephalitis are less common in mumps. We describe magnetic resonance imaging findings of acute mumps meningoencephalitis in a 32-year-old male who showed bilateral hippocampal lesions without preceding parotitis. Although it is rare, hippocampal involvement should be considered a CNS complication of mumps infection.

  12. Effects of actions preceding the jump shot on gaze behavior and shooting performance in elite female basketball players

    NARCIS (Netherlands)

    Oudejans, R.R.D.; Karamat, R.S.; Stolk, M.H.

    2012-01-01

    The aim was to investigate the effects of different actions preceding the jump shot on basketball shooting in expert female basketball players. Participants took two-point jump shots after a dribble or after receiving a pass. The dribble was executed with the dominant or non-dominant hand.

  13. Suicide and general elections in Austria: do preceding regional suicide rate differentials foreshadow subsequent voting behavior swings?

    Science.gov (United States)

    Voracek, Martin; Formann, Anton K; Fülöp, Gerhard; Sonneck, Gernot

    2003-05-01

    Suicide-epidemiological research on short-term effects of elections on national/regional suicide and parasuicide incidence has yielded contradictory evidence. Reversing the cause-effect relationship of this line of research we investigated whether preceding regional suicide rates are related to subsequent election results. For Austria's 121 districts, we regressed averaged standardized suicide rates for the preceding period (1988-1994) on political parties' subsequent electoral gains/losses (1999-to-1995) while controlling for a set of 12 domain-relevant psychosocial/economic indices. Stepwise weighted multiple regression led to a significant model. The 1999-to-1995 electoral gains/losses of two opposition parties, together with the population variation caused by migration balance and by births/deaths balance, accounted for a substantial part (30%) of the variability in preceding district-level suicide rates. Various other social indices failed to contribute further substantial increments to this model. This finding suggests that variations in preceding regional suicide incidence might be mirrored in subsequent changes in voting behavior. A speculative post hoc explanation for the finding is offered: on a community level, suicide's aftermath might produce socially and politically alienated survivors of suicide who co-shape swings towards opposition parties in subsequent general elections. The finding calls for more research on suicide's long-term aftermath. Within-country replicability and cross-national generalizability await further investigation. At present, the factor/mechanism accounting for this finding is neither well-established nor has been directly tested.

  14. Timing, quantity and quality of stressful life events in childhood and preceding the first episode of bipolar disorder.

    Science.gov (United States)

    Horesh, Netta; Apter, Alan; Zalsman, Gil

    2011-11-01

    A large body of evidence supports the importance of genetic risk factors in bipolar disorder (BPD), but less is known about the role of stressful life events (SLE). This study assessed the role of SLE in childhood, adulthood and one year prior to first episodes of both depression and mania in BPD. Three groups of 50 matched subjects each were assessed: patients with BPD, with borderline personality disorder (BLPD) and healthy controls. Structured clinical interviews were used for diagnoses. The Coddington Life Events Schedule and the Israel Psychiatric Epidemiology Research Interview Life Event Scale measured life events and were confirmed with a semi-structured interview for subjective experience for each SLE. In BPD, the total number of SLE was lower during childhood and higher in the year preceding the first depression compared to controls and the proportion of loss-related events in childhood was higher. In the year preceding the first depressive episode, BPD subjects had more total, negative uncontrolled and independent but not positive SLE. In the year preceding the first episode of mania, the total number of uncontrolled, negative SLE were higher in BPD, whereas positive and separation-related SLE were not. After the first episode, BPD subjects had less SLE than controls. Negative and loss-related SLE are common in BPD subjects, occur in the year preceding the first episodes of depression and mania and are less common in childhood or after the onset of the disorder. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. The Effect of an Education Program Utilising PRECEDE Model on the Quality of Life in Patients with Type 2 Diabetes

    Science.gov (United States)

    Taghdisi, M. H.; Borhani, M.; Solhi, M.; Afkari, M. E.; Hosseini, F.

    2012-01-01

    Background and objective: The problems caused by diabetes have direct and indirect impacts on the quality of life of diabetic patients. An increase of these problems means a decrease in a patient's quality of life. This study was conducted to assess the effect of the educational programme based on the precede model in promoting quality of life of…

  16. Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage.

    NARCIS (Netherlands)

    Boogaard, E. van den; Cohn, D.M.; Korevaar, J.C.; Dawood, F.; Vissenberg, R.; Middeldorp, S.; Goddijn, M.; Farquharson, R.G.

    2013-01-01

    Objective: To investigate the relationship between the number and sequence of preceding miscarriages and antiphospholipid syndrome (APS). Design: Retrospective cohort study. Setting: Recurrent miscarriage (RM) clinic. Patient(s): Women who attended the RM clinic from 1988 to 2006. Intervention(s):

  17. First sale doctrine on computer programs in the European Union. reiteration of the precedent or jurisprudential change?

    Directory of Open Access Journals (Sweden)

    Sergio Raúl Cardoso González

    2017-08-01

    Full Text Available Comparative analysis of rulings C-128/11 (UsedSoft of July 3, 2012 and C-166/15 (Ranks and Vasiļevičs of October 12, 2016 by the Court of Justice of the European Union, concerning first sale doctrine on computer programs. Reiteration of the precedent or jurisprudential change?

  18. Upregulation of KCNQ1/KCNE1 K+ channels by Klotho.

    Science.gov (United States)

    Almilaji, Ahmad; Pakladok, Tatsiana; Muñoz, Carlos; Elvira, Bernat; Sopjani, Mentor; Lang, Florian

    2014-01-01

    Klotho is a transmembrane protein expressed primarily in kidney, parathyroid gland, and choroid plexus. The extracellular domain could be cleaved off and released into the systemic circulation. Klotho is in part effective as β-glucuronidase regulating protein stability in the cell membrane. Klotho is a major determinant of aging and life span.Overexpression of Klotho increases and Klotho deficiency decreases life span. Klotho deficiency may further result in hearing loss and cardiac arrhythmia. The present study explored whether Klotho modifies activity and protein abundance of KCNQ1/KCNE1, a K(+) channel required for proper hearing and cardiac repolarization. To this end, cRNA encoding KCNQ1/KCNE1 was injected in Xenopus oocytes with or without additional injection of cRNA encoding Klotho. KCNQ1/KCNE1 expressing oocytes were treated with human recombinant Klotho protein (30 ng/mL) for 24 h. Moreover, oocytes which express both KCNQ1/KCNE1 and Klotho were treated with 10 μM DSA L (D-saccharic acid-1,4-lactone), a β-glucuronidase inhibitor. The KCNQ1/KCNE1 depolarization-induced current (I(Ks)) was determined utilizing dual electrode voltage clamp, while KCNQ1/KCNE1 protein abundance in the cell membrane was visualized utilizing specific antibody binding and quantified by chemiluminescence. KCNQ1/KCNE1 channel activity and KCNQ1/KCNE1 protein abundance were upregulated by coexpression of Klotho. The effect was mimicked by treatment with human recombinant Klotho protein (30 ng/mL) and inhibited by DSA L (10 μM). In conclusion, Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane, an effect at least partially mediated through the β-glucuronidase activity of Klotho protein.

  19. XBP1 Depletion Precedes Ubiquitin Aggregation and Golgi Fragmentation in TDP-43 Transgenic Rats

    Science.gov (United States)

    Tong, Jianbin; Huang, Cao; Bi, Fangfang; Wu, Qinxue; Huang, Bo; Zhou, Hongxia

    2012-01-01

    Protein inclusion is a prominent feature of neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) that is characterized by the presence of ubiquitinated TDP-43 inclusion. Presence of protein inclusions indicates an interruption to protein degradation machinery or the overload of misfolded proteins. In response to the increase in misfolded proteins, cells usually initiate a mechanism called unfolded protein response (UPR) to reduce misfolded proteins in the lumen of endoplasmic reticules. Here we examined the effects of mutant TDP-43 on the UPR in transgenic rats that express mutant human TDP-43 restrictedly in the neurons of the forebrain. Overexpression of mutant TDP-43 in rats caused prominent aggregation of ubiquitin and remarkable fragmentation of Golgi complexes prior to neuronal loss. While ubiquitin aggregates and Golgi fragments were accumulating, neurons expressing mutant TDP-43 failed to upregulate chaperones residing in the endoplasmic reticules and failed to initiate the UPR. Prior to ubiquitin aggregation and Golgi fragmentation, neurons were depleted of X-box binding protein 1 (XBP1), a key player of UPR machinery. While it remains to determine how mutation of TDP-43 leads to the failure of the UPR, our data demonstrate that failure of the UPR is implicated in TDP-43 pathogenesis. PMID:22970712

  20. Changes in the Sexual Relationship and Relationship Adjustment Precede Extradyadic Sexual Involvement.

    Science.gov (United States)

    Scott, Shelby B; Parsons, Aleja; Post, Kristina M; Stanley, Scott M; Markman, Howard J; Rhoades, Galena K

    2017-02-01

    Extradyadic sexual involvement (ESI) is associated with negative consequences for individuals and threatens couple stability. Research on ESI in unmarried samples has been marked by methodological limitations, such as examining only mean levels of sexual satisfaction or frequency to predict later ESI as opposed to changes in various aspects of the sexual relationship over time. The current study compared linear trajectories of four aspects of the sexual relationship-sexual satisfaction, frequency of sex, comfort communicating about sex, and sexual closeness-between individuals in opposite-sex, unmarried relationships who subsequently engaged in ESI (ESI group; n = 183) compared to individuals who did not engage in ESI (non-ESI group; n = 603). Trajectories of relationship adjustment were also evaluated leading up to ESI as well as controlled for in models evaluating the sexual relationship. Results indicated that relationship adjustment declined for individuals preceding ESI, but did not change for the non-ESI group. When controlling for relationship adjustment, comfort communicating about sex decreased for ESI women but increased for ESI men. Some results became nonsignificant after controlling for relationship adjustment, including that sexual satisfaction declined more steeply in the ESI group compared to the non-ESI group, and ESI women significantly decreased in sexual closeness while ESI men demonstrated no significant change. Some mean level differences were also discovered directly before ESI. Conclusions include that changes in a couple's sexual relationship and relationship adjustment are associated with ESI behaviors, providing novel information regarding normative and risk trajectories.

  1. A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma

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    Wijetunga, Neil Ari; Ben-Dayan, Miriam; Tozour, Jessica; Burk, Robert D.; Schlecht, Nicolas F.; Einstein, Mark H.; Greally, John M.

    2016-01-01

    Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors. PMID:27557505

  2. Enhanced canopy growth precedes senescence in 2005 and 2010 Amazonian droughts

    KAUST Repository

    Liu, Yi Y.

    2018-04-09

    preceding drought-induced senescence should be taken into account when interpreting the ecological impacts of Amazonian droughts.

  3. Effect of preceding exercise on cerebral and splanchnic vascular responses to mental task

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    Someya Nami

    2012-06-01

    Full Text Available Abstract Background To investigate the effect of preceding acute exercise on the peripheral vascular response to a mental task, we measured splanchnic and cerebral blood flow responses to performing a mental task after exercise and resting. Methods In the exercise trial, 11 males exercised for 30 min on a cycle ergometer with a workload set at 70% of the age-predicted maximal heart rate for each individual. After a 15-min recovery period, the subjects rested for 5 min for pre-task baseline measurement and then performed mental arithmetic for 5 min followed by 5 min of post-task measurement. In the resting trial, they rested for 45 min and pre-task baseline data was obtained for 5 min. Then mental arithmetic was performed for 5 min followed by post-task measurement. We measured the mean blood velocity in the middle cerebral artery and superior mesenteric artery and the mean arterial pressure. Results Mean arterial pressure and mean blood velocity in the middle cerebral artery were significantly higher than the baseline during mental arithmetic in both exercise and resting trials. Mean blood velocity in the middle cerebral artery during mental arithmetic was greater in the control trial than the exercise trial. Mean blood velocity in the superior mesenteric artery showed no significant change during mental arithmetic from baseline in both trials. Conclusion These results suggest that acute exercise can moderate the increase in cerebral blood flow induced by a mental task.

  4. Identification of Aging-Associated Gene Expression Signatures That Precede Intestinal Tumorigenesis.

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    Yoshihisa Okuchi

    Full Text Available Aging-associated alterations of cellular functions have been implicated in various disorders including cancers. Due to difficulties in identifying aging cells in living tissues, most studies have focused on aging-associated changes in whole tissues or certain cell pools. Thus, it remains unclear what kinds of alterations accumulate in each cell during aging. While analyzing several mouse lines expressing fluorescent proteins (FPs, we found that expression of FPs is gradually silenced in the intestinal epithelium during aging in units of single crypt composed of clonal stem cell progeny. The cells with low FP expression retained the wild-type Apc allele and the tissues composed of them did not exhibit any histological abnormality. Notably, the silencing of FPs was also observed in intestinal adenomas and the surrounding normal mucosae of Apc-mutant mice, and mediated by DNA methylation of the upstream promoter. Our genome-wide analysis then showed that the silencing of FPs reflects specific gene expression alterations during aging, and that these alterations occur in not only mouse adenomas but also human sporadic and hereditary (familial adenomatous polyposis adenomas. Importantly, pharmacological inhibition of DNA methylation, which suppresses adenoma development in Apc-mutant mice, reverted the aging-associated silencing of FPs and gene expression alterations. These results identify aging-associated gene expression signatures that are heterogeneously induced by DNA methylation and precede intestinal tumorigenesis triggered by Apc inactivation, and suggest that pharmacological inhibition of the signature genes could be a novel strategy for the prevention and treatment of intestinal tumors.

  5. A case-control study on cigarette, alcohol, and coffee consumption preceding Parkinson's disease.

    Science.gov (United States)

    Ragonese, P; Salemi, G; Morgante, L; Aridon, P; Epifanio, A; Buffa, D; Scoppa, F; Savettieri, G

    2003-01-01

    To investigate the association between cigarette smoking, alcohol drinking, coffee consumption and Parkinson's disease (PD). We selected subjects affected by idiopathic PD, with a Mini-Mental State Examination of > or =24, and controls matched 1 to 1 with cases by age (+/- 2 years) and sex. Controls were randomly selected from the resident list of the same municipality of residence of the cases. We assessed cigarette smoking, alcohol drinking, and coffee consumption preceding the onset of PD or the corresponding time for controls using a structured questionnaire, which also evaluated the duration and dose of exposure. Using conditional logistic regression analysis, we calculated adjusted OR and 95% CI. We interviewed 150 PD patients and 150 matched controls. Cigarette smoking (ever vs. never smokers OR = 0.66, 95% CI = 0.41-1.05, p = 0.08) did not show a statistically significant association with PD. We observed an inverse association between alcohol drinking (ever vs. never OR = 0.61, 95% CI = 0.39-0.97, p = 0.037) and coffee consumption (ever vs. never OR = 0.16, 95% CI 0.05-0.46, p = 0.0001) and PD. These associations remained significant after adjustment for other covariates: OR for ever vs. never alcohol consumption was 0.62 (95% CI = 0.43-0.89, p = 0.009) and that for coffee drinking 0.19 (95% CI = 0.07-0.52, p = 0.001). Heavy coffee consumption confirmed the inverse association between coffee and PD (more than 81 cup/year vs. none: OR = 0.20, 95% CI = 0.08-0.47, p coffee drinking, alcohol consumption and PD. The multiple inverse association observed may indicate a complex interaction between genetic and environmental factors. Copyright 2003 S. Karger AG, Basel

  6. Observations of increased tropical rainfall preceded by air passage over forests.

    Science.gov (United States)

    Spracklen, D V; Arnold, S R; Taylor, C M

    2012-09-13

    Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.

  7. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

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    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell' Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy); Riccio, Eleonora; Pisani, Antonio [University of Naples Federico II, Department of Public Health, Naples (Italy)

    2017-12-15

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by {sup 123}I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by {sup 123}I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r{sup 2} = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, {sup 123}I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  8. Preliminary analysis of surface temperature anomalies that preceded the two major Emilia 2012 earthquakes (Italy

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    Kai Qin

    2012-10-01

    Full Text Available In the 1980's, from an analysis of satellite images, Russian scientists reported on a short-term thermal infrared radiation enhancement that occurred before some medium-to-large earthquakes in central Asia [Gorny et al. 1988]. Since then, many researchers have been studying earthquake thermal anomalies with satellite remote sensing data [Qiang et al. 1991, Tronin 1996, Tramutoli et al. 2001, Ouzounov and Freund 2004, Saraf and Choudhury 2004, Aliano et al. 2008, Blackett et al. 2011]. Recently, abnormal surface latent heat flux [Dey and Singh 2003, Cervone et al. 2005, Qin et al. 2009, Qin et al. 2011, Qin et al. 2012], outgoing long-wave radiation [Ouzounov et al. 2007] and microwave radiation [Takashi and Tadashi 2010] have also been shown to precede earthquakes. To investigate the possible physical mechanisms of such satellite thermal anomalies, some studies conducted a series of detecting experiments on rock loaded to fracturing [Wu et al. 2000, Freund 2002, Wu et al. 2002, Wu et al. 2006a, Wu et al. 2006b, Freund et al. 2007], and some hypotheses have been proposed. These have included: leaking of pore-gas, and hence the resulting greenhouse effect [Qiang et al. 1995]; activating and recombining of p-holes during rock deformation [Freund 2002]; release of latent heat due to near-surface air ionization [Pulinets et al. 2006], and stress-induced thermal effects due to friction and fluids [Wu and Liu 2009]. […] In this study, the long-term temperature data from both satellite and ground (with greater emphasis on the satellite data have been used to determine whether there were thermal anomalies associated with this Emilia 2012 seismic sequence. In particular, the next section will be dedicated to describing both the data and the method of analysis. In Section 3, we provide the more significant results, which we discuss in Section 4, together with the main conclusions. […

  9. Seagrass proliferation precedes mortality during hypo-salinity events: a stress-induced morphometric response.

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    Catherine J Collier

    Full Text Available Halophytes, such as seagrasses, predominantly form habitats in coastal and estuarine areas. These habitats can be seasonally exposed to hypo-salinity events during watershed runoff exposing them to dramatic salinity shifts and osmotic shock. The manifestation of this osmotic shock on seagrass morphology and phenology was tested in three Indo-Pacific seagrass species, Halophila ovalis, Halodule uninervis and Zostera muelleri, to hypo-salinity ranging from 3 to 36 PSU at 3 PSU increments for 10 weeks. All three species had broad salinity tolerance but demonstrated a moderate hypo-salinity stress response--analogous to a stress induced morphometric response (SIMR. Shoot proliferation occurred at salinities <30 PSU, with the largest increases, up to 400% increase in shoot density, occurring at the sub-lethal salinities <15 PSU, with the specific salinity associated with peak shoot density being variable among species. Resources were not diverted away from leaf growth or shoot development to support the new shoot production. However, at sub-lethal salinities where shoots proliferated, flowering was severely reduced for H. ovalis, the only species to flower during this experiment, demonstrating a diversion of resources away from sexual reproduction to support the investment in new shoots. This SIMR response preceded mortality, which occurred at 3 PSU for H. ovalis and 6 PSU for H. uninervis, while complete mortality was not reached for Z. muelleri. This is the first study to identify a SIMR in seagrasses, being detectable due to the fine resolution of salinity treatments tested. The detection of SIMR demonstrates the need for caution in interpreting in-situ changes in shoot density as shoot proliferation could be interpreted as a healthy or positive plant response to environmental conditions, when in fact it could signal pre-mortality stress.

  10. Dentate gyrus network dysfunctions precede the symptomatic phase in a genetic mouse model of seizures

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    Oana eToader

    2013-08-01

    Full Text Available Neuronal circuit disturbances that lead to hyperexcitability in the cortico-hippocampal network are one of the landmarks of temporal lobe epilepsy. The dentate gyrus (DG network plays an important role in regulating the excitability of the entire hippocampus by filtering and integrating information received via the perforant path. Here, we investigated possible epileptogenic abnormalities in the function of the DG neuronal network in the Synapsin II (Syn II knockout mouse (Syn II-/-, a genetic mouse model of epilepsy. Syn II is a presynaptic protein whose deletion in mice reproducibly leads to generalized seizures starting at the age of two months. We made use of a high-resolution microelectrode array (4096 electrodes and patch-clamp recordings, and found that in acute hippocampal slices of young pre-symptomatic (3-6 weeks-old Syn II-/- mice excitatory synaptic output of the mossy fibers is reduced. Moreover, we showed that the main excitatory neurons present in the polymorphic layer of the DG, hilar mossy cells, display a reduced excitability. We also provide evidence of a predominantly inhibitory regulatory output from mossy cells to granule cells, through feed-forward inhibition, and show that the excitatory-inhibitory ratio is increased in both pre-symptomatic and symptomatic Syn II-/- mice. These results support the key role of the hilar mossy neurons in maintaining the normal excitability of the hippocampal network and show that the late epileptic phenotype of the Syn II-/- mice is preceded by neuronal circuitry dysfunctions. Our data provide new insights into the mechanisms of epileptogenesis in the Syn II-/- mice and open the possibility for early diagnosis and therapeutic interventions.

  11. Severe hyponatremia as the initial sign preceding Guillain-Barré syndrome: a case report

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    Abhishek Wankar

    2014-01-01

    Full Text Available Diagnosis of Guillain-Barrι syndrome (GBS is established clinically and is supported by nerve conduction studies and cerebrospinal fluid examination. Renal function is usually not affected, but recent case reports have established a link between GBS and hyponatremia. A 60-year-old woman presenting with lower back ache since 3 days, became drowsy the next day and developed paraparesis and bulbar symptoms. Her sensorium and power deteriorated progressively over the next 2 days and she was brought to hospital in a drowsy state. She was found to have severe hyponatremia (Na + at 113 and nerve conduction study (NCS was son of AMAN. The patient was started on intravenous immunoglobulin and her sodium levels were corrected, and the patient recovered completely. The occurrence of hyponatremia in patients diagnosed with GBS is well described. However, there have been only two prior case reports in which hyponatremia had been observed before the manifestation of neuromuscular deficits. Our patient case is unique in that severe hyponatremia occurred simultaneously with neurologic symptoms and the diagnosis of GBS. In most cases reported in the literature, hyponatremia was noted after a diagnosis of GBS was established. The mean period of onset of syndrome of inappropriate antidiuretic hormone (SIADH was 8.8 days after the onset of symptoms of GBS. In Conclusion , this presentation raises the possibility that early changes in the autonomic nervous system triggered by GBS might lead to alterations in water and sodium balance that can precede symptomatic changes in the peripheral nervous system. Although rarely, but both GBS and its treatment, intravenous immunoglobulin, should be considered in the differential diagnosis of hyponatremia.

  12. Metabolic Markers or Conditions Preceding Parkinson’s Disease: A Case-Control Study

    Science.gov (United States)

    Savica, Rodolfo; Grossardt, Brandon R.; Ahlskog, J. Eric; Rocca, Walter A.

    2013-01-01

    Background Several metabolic markers or conditions have been explored as possible risk or protective factors for Parkinson’s disease (PD); however, results remain conflicting. We further investigated these associations using a case-control study design. Methods We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (± 1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to abstract information about body mass index (BMI), cholesterol levels, hypertension, and diabetes mellitus preceding the onset of PD (or the index year). Results There were no significant differences between cases and controls for the metabolic markers or conditions investigated. No significant associations were found using 2 cut-offs for BMI levels (BMI ≥ 25 or BMI ≥ 30 kg/m2) and 3 cut-offs for cholesterol levels (> 200, > 250, or > 300 mg/dl). A diagnosis of hypertension or the documented use of anti-hypertensive medications were not significantly associated with the subsequent risk of PD (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.65–1.54; P = .99), nor was a diagnosis of diabetes mellitus or the use of glucose-lowering medications (OR, 0.77; 95% CI, 0.37–1.57; P =.47). Conclusions Our study, based on historical information from a records-linkage system, does not support an association between BMI, cholesterol levels, hypertension, or diabetes mellitus and later development of PD. PMID:22674432

  13. Course sequences in bipolar disorder: depressions preceding or following manias or hypomanias.

    Science.gov (United States)

    Koukopoulos, A; Reginaldi, D; Tondo, L; Visioli, C; Baldessarini, R J

    2013-10-01

    Inferior response to lithium treatment has been reported in bipolar disorder (BD) patients with mania or hypomania following episodes of major depression (DMI) versus preceding depression (MDI), with intervening euthymic periods. However, additional characteristics of BD course-patterns require further assessment. We reviewed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences. Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals. Prevalent sequences included: major depression-hypomania (15.0%), mania-major depression (14.6%), major depression-mania (11.6%), and rapid-cycling (9.6%). Among subjects grouped by course-sequences (based on mania, mixed-states, or hypomania and major or minor depression), depression-before-[hypo]mania (DMI) cases were more likely to be women, diagnosed BD-II, have first-episodes of depressive or anxiety disorder, spend more time ill in depression, and benefit less with long-term mood-stabilizing treatments than with the opposite pattern (MDI). MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments. Meta-analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29% [CI: 18-40%] (p<0.0001). Some data were retrospective and subject to recall bias, and treatment was clinical (non-randomized). The DMI course was strongly associated with first-episode depression or anxiety, excess depressive morbidity, and inferior treatment response, especially for depression. © 2013 Elsevier B.V. All rights reserved.

  14. Sympathetic overactivity precedes metabolic dysfunction in a fructose model of glucose intolerance in mice

    Science.gov (United States)

    Angelis, Katia De; Senador, Danielle D.; Mostarda, Cristiano; Irigoyen, Maria C.

    2012-01-01

    Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease. PMID:22319048

  15. White matter alterations in Parkinson's disease with normal cognition precede grey matter atrophy.

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    Ivan Rektor

    Full Text Available While progressive MRI brain changes characterize advanced Parkinson's disease (PD, little has been discovered about structural alterations in the earliest phase of the disease, i.e. in patients with motor symptoms and with normal cognition. Our study aimed to detect grey matter (GM and white matter (WM changes in PD patients without cognitive impairment.Twenty PD patients and twenty-one healthy controls (HC were tested for attention, executive function, working memory, and visuospatial and language domains. High-resolution T1-weighted and 60 directional diffusion-weighted 3T MRI images were acquired. The cortical, deep GM and WM volumes and density, as well as the diffusion properties of WM, were calculated. Analyses were repeated on data flipped to the side of the disease origin.PD patients did not show any significant differences from HC in cognitive functioning or in brain volumes. Decreased GM intensity was found in the left superior parietal lobe in the right (p<0.02 and left (p<0.01 flipped data. The analysis of original, un-flipped data demonstrated elevated axial diffusivity (p<0.01 in the superior and anterior corona radiata, internal capsule, and external capsule in the left hemisphere of PD relative to HC, while higher mean and radial diffusivity were discovered in the right (p<0.02 and p<0.03, respectively and left (p<0.02 and p<0.02, respectively in the fronto-temporal WM utilizing flipped data.PD patients without cognitive impairment and GM atrophy demonstrated widespread alterations of WM microstructure. Thus, WM impairment in PD might be a sensitive sign preceding the neuronal loss in associated GM regions.

  16. Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development.

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    Dzidic, Majda; Abrahamsson, Thomas R; Artacho, Alejandro; Björkstén, Bengt; Collado, Maria Carmen; Mira, Alex; Jenmalm, Maria C

    2017-03-01

    Although a reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development, IgA responses to the gut microbiota have not yet been studied. We sought to determine the proportions of IgA coating together with the characterization of the dominant bacteria, bound to IgA or not, in infant stool samples in relation to allergy development. A combination of flow cytometric cell sorting and deep sequencing of the 16S rDNA gene was used to characterize the bacterial recognition patterns by IgA in stool samples collected at 1 and 12 months of age from children staying healthy or having allergic symptoms up to 7 years of age. The children with allergic manifestations, particularly asthma, during childhood had a lower proportion of IgA bound to fecal bacteria at 12 months of age compared with healthy children. These alterations cannot be attributed to differences in IgA levels or bacterial load between the 2 groups. Moreover, the bacterial targets of early IgA responses (including coating of the Bacteroides genus), as well as IgA recognition patterns, differed between healthy children and children with allergic manifestations. Altered IgA recognition patterns in children with allergy were observed already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breast-fed children. An aberrant IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development, possibly indicating an impaired mucosal barrier function in allergic children. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling

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    Cecilie Linneberg

    2015-09-01

    Full Text Available In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.

  18. Legal Sentience and the Problem of the Instant: A Critical Assessment of the Temporal Structure of Precedent and its Implications for Legal Authority

    OpenAIRE

    Wargan, Pawel

    2015-01-01

    This paper assesses the authority of precedent from a phenomenological standpoint. Phenomenology distinguishes between two temporal models. One describes time in an idealised form, as a divisible chain of instants or events. The other looks at lived temporality as fluid and indivisible duration. In the system of precedent, we witness an interaction of both models. The legal order is constructed from slices in time that become the building blocks of future judgments. Precedents are binding for...

  19. Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

    Directory of Open Access Journals (Sweden)

    Sarah L. DeVos

    2018-04-01

    Full Text Available Alzheimer's disease (AD is defined by the presence of intraneuronal neurofibrillary tangles (NFTs composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau

  20. Large-scale unloading processes preceding the 2015 Mw 8.4 Illapel, Chile earthquake

    Science.gov (United States)

    Huang, H.; Meng, L.

    2017-12-01

    Foreshocks and/or slow slip are observed to accelerate before some recent large earthquakes. However, it is still controversial regarding the universality of precursory signals and their value in hazard assessment or mitigation. On 16 September 2015, the Mw 8.4 Illapel earthquake ruptured a section of the subduction thrust on the west coast of central Chile. Small earthquakes are important in resolving possible precursors but are often incomplete in routine catalogs. Here, we employ the matched filter technique to recover the undocumented small events in a 4-years period before the Illapel mainshock. We augment the template dataset from Chilean Seismological Center (CSN) with previously found new repeating aftershocks in the study area. We detect a total of 17658 events in the 4-years period before the mainshock, 6.3 times more than the CSN catalog. The magnitudes of detected events are determined according to different magnitude-amplitude relations estimated at different stations. Among the enhanced catalog, 183 repeating earthquakes are identified before the mainshock. Repeating earthquakes are located at both the northern and southern sides of the principal coseismic slip zone. The seismicity and aseismic slip progressively accelerate in a small low-coupling area around the epicenter starting from 140 days before the mainshock. The acceleration leads to a M 5.3 event 36 days before the mainshock, then followed by a relative quiescence in both seismicity and slow slip until the mainshock. This may correspond to a slow aseismic nucleation phase after the slow-slip transient ends. In addition, to the north of the mainshock rupture area, the last aseismic-slip episode occurs within 175-95 days before the mainshock and accumulates the largest amount of slip in the observation period. The simultaneous occurrence of slow slip over a large area indicates a large-scale unloading process preceding the mainshock. In contrast, in a region 70-150 km south of the mainshock

  1. Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling

    Science.gov (United States)

    Stucky, Andres; Bakshi, Kalindi P.; Friedman, Eitan; Wang, Hoau-Yan

    2016-01-01

    Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor—NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-γ1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission. PMID:27494324

  2. Osteopontin upregulates the expression of glucose transporters in osteosarcoma cells.

    Directory of Open Access Journals (Sweden)

    I-Shan Hsieh

    Full Text Available Osteosarcoma is the most common primary malignancy of bone. Even after the traditional standard surgical therapy, metastasis still occurs in a high percentage of patients. Glucose is an important source of metabolic energy for tumor proliferation and survival. Tumors usually overexpress glucose transporters, especially hypoxia-responsive glucose transporter 1 and glucose transporter 3. Osteopontin, hypoxia-responsive glucose transporter 1, and glucose transporter 3 are overexpressed in many types of tumors and have been linked to tumorigenesis and metastasis. In this study, we investigated the regulation of glucose transporters by osteopontin in osteosarcoma. We observed that both glucose transporters and osteopontin were upregulated in hypoxic human osteosarcoma cells. Endogenously released osteopontin regulated the expression of glucose transporter 1 and glucose transporter 3 in osteosarcoma and enhanced glucose uptake into cells via the αvβ3 integrin. Knockdown of osteopontin induced cell death in 20% of osteosarcoma cells. Phloretin, a glucose transporter inhibitor, also caused cell death by treatment alone. The phloretin-induced cell death was significantly enhanced in osteopontin knockdown osteosarcoma cells. Combination of a low dose of phloretin and chemotherapeutic drugs, such as daunomycin, 5-Fu, etoposide, and methotrexate, exhibited synergistic cytotoxic effects in three osteosarcoma cell lines. Inhibition of glucose transporters markedly potentiated the apoptotic sensitivity of chemotherapeutic drugs in osteosarcoma. These results indicate that the combination of a low dose of a glucose transporter inhibitor with cytotoxic drugs may be beneficial for treating osteosarcoma patients.

  3. RhoA Controls Wnt Upregulation on Microstructured Titanium Surfaces

    Directory of Open Access Journals (Sweden)

    Simone Lumetti

    2014-01-01

    Full Text Available Rough topography enhances the activation of Wnt canonical signaling in vitro, and this mediates its effects on cell differentiation. However, the molecular mechanisms underlying topography-dependent control of Wnt signaling are still poorly understood. As the small GTPase RhoA controls cytoskeletal reorganization and actomyosin-induced tensional forces, we hypothesized that RhoA could affect the activation of Wnt signaling in cells on micropatterned titanium surfaces. G-LISA assay revealed that RhoA activation was higher in C2C12 cells on rough (SLA surfaces under basal conditions than on smooth (Polished titanium. Transfection with dominant negative RhoA decreased Wnt activation by normalized TCF-Luc activity on SLA, whilst transfection with constitutively active RhoA increased TCF-Luc activation on Polished titanium. One mM Myosin II inhibitor Blebbistatin increased RhoA activation but decreased Wnt activation on SLA surfaces, indicating that tension-generating structures are required for canonical Wnt modulation on titanium surfaces. Actin inhibitor Cytochalasin markedly enhanced RhoA and TCF-Luc activation on both surfaces and increased the expression of differentiation markers in murine osteoblastic MC3T3 cells. Taken together, these data show that RhoA is upregulated in cells on rough surfaces and it affects the activation of Wnt canonical signaling through Myosin II modulation.

  4. Effects of Preceding Ethanol Intake on Glucose Response to Low-Dose Glucagon in Individuals With Type 1 Diabetes

    DEFF Research Database (Denmark)

    Ranjan, Ajenthen; Nørgaard, Kirsten; Tetzschner, Rikke

    2018-01-01

    OBJECTIVE: This study investigated whether preceding ethanol intake impairs glucose response to low-dose glucagon in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized, crossover, placebo-controlled study in 12 insulin pump-treated individuals (median...... ethanol compared with placebo. The second glucagon bolus had similar responses between visits, but PG remained 1.8 ± 0.7 mmol/L lower after ethanol compared with placebo. CONCLUSIONS: The ability of low-dose glucagon to treat mild hypoglycemia persisted with preceding ethanol intake, although it tended...... to be metabolized, and a subcutaneous (s.c.) insulin bolus was given to induce mild hypoglycemia. When plasma glucose (PG) was ≤3.9 mmol/L, 100 µg glucagon was given s.c., followed by another s.c. 100 µg glucagon 2 h later. Primary end point was incremental peak PG induced by the first glucagon bolus. RESULTS...

  5. Informed Consent as a Litigation Strategy in the Field of Aesthetic Surgery: An Analysis Based on Court Precedents

    OpenAIRE

    Bo Young Park; Jungwoo Kwon; So Ra Kang; Seung Eun Hong

    2016-01-01

    Background In an increasing number of lawsuits doctors lose, despite providing preoperative patient education, because of failure to prove informed consent. We analyzed judicial precedents associated with insufficient informed consent to identify judicial factors and trends related to aesthetic surgery medical litigation. Methods We collected data from civil trials between 1995 and 2015 that were related to aesthetic surgery and resulted in findings of insufficient informed consent. Based on ...

  6. The Legal Doctrine on 'Limitation of Liability' in the Precedent Analysis on Plastic Surgery Medical Malpractice Lawsuits

    OpenAIRE

    Park, Bo Young; Pak, Ji-Hyun; Hong, Seung-Eun; Kang, So Ra

    2015-01-01

    This study intended to review the precedents on plastic surgery medical malpractice lawsuits in lower-court trials, classify the reasons of 'limitation of liability' by type, and suggest a standard in the acknowledgement of limitation of liability ratio. The 30 lower-court's rulings on the cases bearing the medical negligence of the defendants acknowledged the liability ratio of the defendants between 30% and 100%. Ten cases ruled that the defendants were wholly responsible for the negligence...

  7. Food allergy preceded by contact urticaria due to the same food: Involvement of epicutaneous sensitization in food allergy

    OpenAIRE

    Naoko Inomata; Mayumi Nagashima; Amiko Hakuta; Michiko Aihara

    2015-01-01

    Background: There have recently been reports suggesting that sensitization to food allergens may occur outside the intestinal tract, especially through the skin. To clarify the role of epicutaneous sensitization in food allergy, we investigated the clinical characteristics of adult patients with food allergies preceded by contact urticaria due to the same foods. Methods: We investigated clinical characteristics of 15 patients (20–51 years of age; 5 men and 10 women), who had food allergies...

  8. Comprehension of wh-questions precedes their production in typical development and autism spectrum disorders

    Science.gov (United States)

    Goodwin, Anthony; Fein, Deborah; Naigles, Letitia R.

    2011-01-01

    Lay Abstract Children with autism produce few wh-questions, compared to their typically developing peers. It is unclear if this is because of social-pragmatic difficulties, or if they have not yet learned the grammar for asking wh-questions. If children do not know how to use grammatical rules to produce questions, they might simply repeat sentences that they have heard without completely understanding them first. We visited the homes of 15 children with autism and 18 typically developing children with similar language abilities, across a three-year period. At each visit, children watched a video that depicted an apple hitting a flower and keys hitting a book. The children were then shown the items side-by-side on the screen and the audio asked “what hit the flower?” and “what did the keys hit?” We filmed the children’s eye movements and analyzed how long they looked at the named item, compared to when they heard “where is the flower/keys?” At each visit, we also filmed a 30-minute mother-child play session and analyzed the types of questions that the children asked. Children with autism showed comprehension of wh-questions at a later age than typically developing children, but at a similar level of overall language development. Neither group produced wh-questions before they had demonstrated that they understood the underlying grammatical rules. Therefore, children with autism seem to process wh-questions in the same way as their typically developing peers, just at a later age. This paper discusses the implications of our findings for the language development of children with autism. Scientific Abstract Children with autism (ASD) rarely produce wh-questions (e.g., “What hit the book?”) in naturalistic speech. It is unclear if this is due to social-pragmatic difficulties, or if grammatical deficits are also involved. If grammar is impaired, production of wh-questions by rote memorization might precede comprehension of similar forms. In a

  9. Network topology and functional connectivity disturbances precede the onset of Huntington's disease.

    Science.gov (United States)

    Harrington, Deborah L; Rubinov, Mikail; Durgerian, Sally; Mourany, Lyla; Reece, Christine; Koenig, Katherine; Bullmore, Ed; Long, Jeffrey D; Paulsen, Jane S; Rao, Stephen M

    2015-08-01

    Cognitive, motor and psychiatric changes in prodromal Huntington's disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington's disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntington's disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved as disease

  10. Effect of Stress Management Training Based on PRECEDE Model on Prehospital Emergency Staff Occupational Tension in Mazandaran University of Medical Sciences in 2016

    Directory of Open Access Journals (Sweden)

    Gholamreza Esmailzadeh Gatabi

    2017-10-01

    Conclusion: The findings showed that education based on PRECEDE model increases the predisposing factor (knowledge and attitude, reinforcing factor, and enhancer factor. These factors have the potential to affect the behavior more effectively. According to this, educational intervention based on PRECEDE model structures is effective on job stress and behavior. Researchers have suggested training on this pattern.

  11. 17 CFR 230.153b - Definition of “preceded by a prospectus”, as used in section 5(b)(2), in connection with certain...

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Definition of âpreceded by a... RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.153b Definition of “preceded by a prospectus... are traded, for the purpose of redelivery to options customers upon their request, Provided That: (a...

  12. Upregulation of cognitive control networks in older adults’ speech comprehension

    Directory of Open Access Journals (Sweden)

    Julia eErb

    2013-12-01

    Full Text Available Speech comprehension abilities decline with age and with age-related hearing loss, but it is unclear how this decline expresses in terms of central neural mechanisms. The current study examined neural speech processing in a group of older adults (aged 56–77, n=16, with varying degrees of sensorineural hearing loss, and compared them to a cohort of young adults (aged 22–31, n=30, self-reported normal hearing. In an fMRI experiment, listeners heard and repeated back degraded sentences (4-band vocoding, which preserves the temporal envelope of the acoustic signal, while substantially degrading spectral information. Behaviourally, older adults adapted to degraded speech at the same rate as young listeners, although their overall comprehension of degraded speech was lower. Neurally, both older and young adults relied on the left anterior insula for degraded more than clear speech perception. However, anterior insula engagement in older adults was dependent on hearing acuity. Young adults additionally employed the anterior cingulate cortex (ACC. Interestingly, this age group × degradation interaction was driven by a reduced dynamic range in older adults, who displayed elevated levels of ACC activity in both conditions, consistent with a persistent upregulation in cognitive control irrespective of task difficulty. For correct speech comprehension, older adults recruited the middle frontal gyrus in addition to a core speech comprehension network on which young adults relied, suggestive of a compensatory mechanism. Taken together, the results indicate that older adults increasingly recruit cognitive control networks, even under optimal listening conditions, at the expense of these systems’ dynamic range.

  13. TRPA1 receptor is upregulated in human oral lichen planus.

    Science.gov (United States)

    Kun, J; Perkecz, A; Knie, L; Sétáló, G; Tornóczki, T; Pintér, E; Bán, Á

    2017-03-01

    Oral lichen planus (OLP) is a chronic inflammatory disease of unknown etiology with antigen-specific and non-specific mechanisms. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel activated by noxious stimuli such as oxidative stress products evoking pain and release of proinflammatory mediators from sensory nerve endings culminating in neurogenic inflammation. Extraneuronal TRPA1s, for example, on immune cells possess yet unknown functions. We studied the buccal mRNA expression (qPCR) and protein localization (immunohistochemistry) of TRPA1 receptors and key OLP mediator transcripts in oral mucosa samples of healthy volunteers (n = 9), OLP patients (n = 43), and OLP-like hyperkeratotic patients (n = 12). We measured 27.7- and 25.5-fold TRPA1 mRNA increase in OLP and OLP-like hyperkeratotic patients compared to healthy controls. TRPA1 transcripts elevated 2.4-fold in hypertensive OLP but not in hyperkeratotic patients compared to counterparts, reduced by 1.6-fold by angiotensin-convertase inhibitor intake. TRPA1 messenger RNA was more coexpressed with transcripts of tumor necrosis factor α than with interferon γ. Keratinocytes, macrophages but not T cells expressed TRPA1. We provided evidence for the extraneuronal presence and upregulation of the proinflammatory TRPA1 receptor in buccal samples of patients with OLP. This may implicate the ion channel in the pathomechanism of OLP. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Upregulation of cIAP2 in regenerating colonocytes in ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, J.B.; Vainer, Ben; Andresen, L.

    2007-01-01

    It has been reported that colonocytes in ulcerative colitis (UC) upregulate anti-apoptotic cytoprotective pathways. An expression-profiling study of apoptosis-related genes suggested that the cellular inhibitor of apoptosis protein-2 (cIAP2) could be upregulated in epithelial cells in UC. The role...

  15. Lack of upregulation of epidermal fatty acid binding protein in dithranol induced irritation.

    NARCIS (Netherlands)

    Kucharekova, M.; Vissers, W.H.P.M.; Schalkwijk, J.; Kerkhof, P.C.M. van de; Valk, P.G.M. van der

    2003-01-01

    The exact role of epidermal fatty acid binding protein (E-FABP) in skin is unknown. A restoration of the barrier function may be associated with an upregulation of E-FABP. Moreover, E-FABP is upregulated in a variety of cells in response to oxidative stress. A recent observation that dithranol

  16. Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Povlsen, Gro Klitgaard; Johansson, Sara Ellinor; Larsen, Carl Christian

    2013-01-01

    Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been...

  17. Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries

    DEFF Research Database (Denmark)

    Ahnstedt, Hilda; Cao, Lei; Krause, Diana N

    2013-01-01

    Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which...... is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation....

  18. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

    Science.gov (United States)

    Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

    2017-07-01

    Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological

  19. Stress fracture healing: fatigue loading of the rat ulna induces upregulation in expression of osteogenic and angiogenic genes that mimic the intramembranous portion of fracture repair.

    Science.gov (United States)

    Wohl, Gregory R; Towler, Dwight A; Silva, Matthew J

    2009-02-01

    Woven bone is formed in response to fatigue-induced stress fractures and is associated with increased local angiogenesis. The molecular mechanisms that regulate this woven bone formation are unknown. Our objective was to measure the temporal and spatial expression of osteo- and angiogenic genes in woven bone formation in response to increasing levels of fatigue-induced damage. We used the rat forelimb compression model to produce four discrete levels of fatigue damage in the right ulna of 115 male Fischer rats. Rats were killed at 0 (1 h), 1, 3 and 7 days after loading. Using qRT-PCR, we quantified gene expression associated with osteogenesis (BMP2, Msx2, Runx2, Osx, BSP, Osc), cell proliferation (Hist4), and angiogenesis (VEGF, PECAM-1) from the central half of the ulna. The spatial distribution of BMP2, BSP and PCNA was assessed by immunohistochemistry or in situ hybridization in transverse histological sections 1, 4, and 7 mm distal to the ulnar mid-diaphysis. One hour after loading, BMP2 was significantly upregulated in neurovascular structures in the medial ulnar periosteum. Expression of angiogenic markers (VEGF, PECAM-1) increased significantly between Day 0 and 1 and, as with BMP2 expression, remained upregulated through Day 7. While Osx and BSP were upregulated on Day 1, the other osteogenic genes (Msx2, Runx2, Osx, BSP and Osc) were induced on Day 3 in association with the initiation of periosteal woven bone formation and continued through Day 7. The magnitude of osteogenic gene expression, particularly matrix genes (BSP, Osc) was significantly proportional the level of fatigue damage. The woven bone response to fatigue injury is remarkably similar to the "intramembranous" portion of fracture repair - rapid formation of periosteal woven bone characterized by early BMP2 expression, cell proliferation, and upregulation of osteogenic genes. We speculate that woven bone repair of fatigue damage may be an abbreviated fracture response without the requirement

  20. Solar wind proton density increase that preceded Central Italy earthquakes occurred between 26 and 30 October 2016

    Science.gov (United States)

    Cataldi, Gabriele; Cataldi, Daniele; Straser, Valentino

    2017-04-01

    Between 26 and 30 October 2016 in Central Italy were recorded two strong earthquakes: M6.1 occurred on October 26, 2016 at 19:18:08 UTC and M6.6 occurred on October 30, 2016 at 06:40:18 UTC. The authors of this study noted that the two earthquakes were preceded by an increase in the proton density of the interplanetary medium: a phenomenon observed since 2012 and has always preceded the seismic events of high intensity (M6+) occurring on a global scale. To obtain these results the authors have analyzed the conditions of Spaceweather "near Earth" and the characteristics of the Earth's geomagnetic field in the days and in the hours that preceded the two earthquakes. The data relating to the two earthquakes were provided by the United States Geological Survey (USGS). The data on ion density used to realize the study are represented by: solar wind ion density variation detected by ACE (Advanced Composition Explorer) Satellite, in orbit near the L1 Lagrange point, at 1.5 million of km from Earth, in direction of the Sun. The instrument used to perform the measurement of the solar wind ion density is the Electron, Proton, and Alpha Monitor (EPAM) instrument, equipped on the ACE Satellite. To conduct the study, the authors have taken in consideration the variation of the solar wind protons density of three different energy fractions: differential proton flux 1060-1900 keV (p/cm^2-sec-ster-MeV); differential proton flux 761-1220 keV (p/cm^2-sec-ster-MeV); differential proton flux 310-580 keV (p/cm^2-sec-ster-MeV). In addition, the authors were analyzed the Earth's geomagnetic field variations through the geomagnetic data released by Tromsø Geomagnetic Observatory (TGO), Norway; Scoresbysund Geomagnetic Observatory (SCO), Greenland, Denmark; Dikson Geomagnetic Observatory (DIK), Russia and Pushkov Institute of terrestrial magnetism, ionosphere and radio wave propagation (IZMIRAN), Troitsk, Moscow Region. The results of the study, in agreement with what already ascertained

  1. EL PRECEDENTE EN LA DIMENSIÓN DE LA SEGURIDAD JURÍDICA THE PRECEDENT IN THE LEGAL CERTAINTY DIMENSION

    Directory of Open Access Journals (Sweden)

    Luiz Guilherme Marinon

    2012-01-01

    Full Text Available El estudio aquí presentado se destina a introducir a la comunidad jurídica latinoamericana la importancia del precedente vinculante como forma de tutela del valor constitucional seguridad jurídica. En ese sentido, es a través del precedente que obtiene importancia este valor constitucional pues, al constituirse en derecho fundamental para los ciudadanos, requiere de un medio de protección por estar consagrado en la Constitución, siendo este, el precedente vinculante. Asimismo, son presentados fundamentos para la construcción no sólo de una tutela de la seguridad jurídica, sino, de la confianza del ciudadano respecto a las decisiones del órgano jurisdiccional. Finalmente, el estudio intenta teorizar el apartamiento que existe entre la cosa juzgada y la calidad de estabilidad de las decisiones judiciales, siendo la primera la garantía que tiene el ciudadano de que su caso fue decidido y lo decidido no será variado, mientras que a través de la estabilidad propia del precedente, se contempla el derecho a obtener una decisión respetando la igualdad respecto de casos similares anteriormente decididos.The study given in this essay aims to introduce to the Latin-American legal community and academia the importance of the judicial precedent as a way to protect the constitutional value of legal certainty. In this respect, it is through the judicial precedent that the constitutional value of legal certainty could obtain the judicial protection because once it is constituted as a fundamental and constitutional right to the whole citizenship, this right claims an adequate protection, and this could be achieved by means of the judicial precedent. Also, not only foundations and basis to the protection of judicial certainty are presented here, but also reasons to theorize that by means of the judicial precedent, it could also be achieved the protection of the trust of the citizenship among the judicial decisions of diverse courts. Finally, this

  2. A dynamical model of car-following with the consideration of the multiple information of preceding cars

    International Nuclear Information System (INIS)

    Peng, G.H.; Sun, D.H.

    2010-01-01

    An improved multiple car-following (MCF) model is proposed, based on the full velocity difference (FVD) model, but taking into consideration multiple information inputs from preceding vehicles. The linear stability condition of the model is obtained by using the linear stability theory. Through nonlinear analysis, the modified Korteweg-de Vries (mKdV) equation is derived to describe the traffic behavior near the critical point. Numerical simulation shows that the proposed model is theoretically an improvement over others, while retaining many strong points in the previous ones by adjusting the information of the multiple leading vehicles.

  3. An investigation of the manifest dream content associated with migraine headaches: a study of the dreams that precede nocturnal migraines.

    Science.gov (United States)

    Heather-Greener, G Q; Comstock, D; Joyce, R

    1996-01-01

    Clinical observations of a relationship between unpleasant dreams and migraine headaches have been reported previously. Due to the anecdotal quality of these case reports, this study empirically investigated the significance of this relationship. Dream content categories were selected corresponding to emotional factors associated with stress that trigger migraine headaches. A total of 37 migraineurs recorded 10 dreams each, 5 that preceded migraines and 5 that did not. Univariate F tests revealed that 4 of the 5 variables contributed significantly to the overall effect, specifically anger, misfortune, apprehension, and aggressive interactions. Recommendations include discussing the predictive value of dreams with regard to nocturnal migraine attacks, and therapeutic implications are suggested.

  4. Influence of meteorological parameters during the preceding fall and winter on the questing activity of nymphal Ixodes ricinus ticks

    DEFF Research Database (Denmark)

    Vollack, Ken; Sodoudi, Sahar; Névir, Peter

    2017-01-01

    Wood ticks, Ixodes ricinus L., serve as vectors for various pathogens and are ubiquitous throughout Central Europe. Survival and development of I. ricinus depend on biotic and abiotic factors. We examined whether relative humidity (RH), air (T a ) and soil temperatures (T s ), or snow depth during...... the average number of nymphs questing during spring. Our observations suggest that RH, T s , and snow cover during the preceding months affect the questing activity of nymphal I. ricinus during their first peak of activity. Snow cover serves as an insulator between the atmosphere and soil, which not only...

  5. The effect of intervention using the PRECEDE-PROCEED model based on quality of life in diabetic patients.

    Science.gov (United States)

    Azar, Farbod Ebadifard; Solhi, Mahnaz; Nejhaddadgar, Nazila; Amani, Firoz

    2017-08-01

    Poor quality of life is common among diabetic patients, and educational intervention is one of the most effective strategies to improve the quality of life for chronic patients. To determine the effect of an educational intervention based on PRECEDE-PROCEED in quality of life of diabetic patients, in 2016. In this quasi-experimental study, 86 patients referred to diabetic centers of Ardabil participated. We used the components PRECEDE-PROCEED model for planning, implementation and evaluation of the program. Data collection tools were Diabetes Quality of Life questionnaire (DQOL) and a researcher-made questionnaire. Eight training sessions were conducted for the intervention group for self-efficiency, self- management, attitude, knowledge, and enabling reinforcing factors. Quality of life was followed one and three months after intervention. Data were analyzed through SPSS 16 software using descriptive and analytical tests. The mean age of patients was 55.88 (±12.1) years. The result showed that before intervention, no significant difference was observed among the mean scores of quality of life, self-management, knowledge, attitude, enabling and reinforcing factors, and self-efficiency in two groups. But one and three months after intervention a significant difference was observed (pmodel improved the diabetic patient's quality of life.

  6. Comparative analysis of insect succession data from Victoria (Australia) using summary statistics versus preceding mean ambient temperature models.

    Science.gov (United States)

    Archer, Mel

    2014-03-01

    Minimum postmortem interval (mPMI) can be estimated with preceding mean ambient temperature models that predict carrion taxon pre-appearance interval. But accuracy has not been compared with using summary statistics (mean ± SD of taxon arrival/departure day, range, 95% CI). This study collected succession data from ten experimental and five control (infrequently sampled) pig carcasses over two summers (n = 2 experimental, n = 1 control per placement date). Linear and exponential preceding mean ambient temperature models for appearance and departure times were constructed for 17 taxa/developmental stages. There was minimal difference in linear or exponential model success, although arrival models were more often significant: 65% of linear arrival (r2 = 0.09–0.79) and exponential arrival models (r2 = 0.05–81.0) were significant, and 35% of linear departure (r2 = 0.0–0.71) and exponential departure models (r2 = 0.0–0.72) were significant. Performance of models and summary statistics for estimating mPMI was compared in two forensic cases. Only summary statistics produced accurate mPMI estimates.

  7. When practice precedes theory - A mixed methods evaluation of students' learning experiences in an undergraduate study program in nursing.

    Science.gov (United States)

    Falk, Kristin; Falk, Hanna; Jakobsson Ung, Eva

    2016-01-01

    A key area for consideration is determining how optimal conditions for learning can be created. Higher education in nursing aims to prepare students to develop their capabilities to become independent professionals. The aim of this study was to evaluate the effects of sequencing clinical practice prior to theoretical studies on student's experiences of self-directed learning readiness and students' approach to learning in the second year of a three-year undergraduate study program in nursing. 123 nursing students was included in the study and divided in two groups. In group A (n = 60) clinical practice preceded theoretical studies. In group (n = 63) theoretical studies preceded clinical practice. Learning readiness was measured using the Directed Learning Readiness Scale for Nursing Education (SDLRSNE), and learning process was measured using the revised two-factor version of the Study Process Questionnaire (R-SPQ-2F). Students were also asked to write down their personal reflections throughout the course. By using a mixed method design, the qualitative component focused on the students' personal experiences in relation to the sequencing of theoretical studies and clinical practice. The quantitative component provided information about learning readiness before and after the intervention. Our findings confirm that students are sensitive and adaptable to their learning contexts, and that the sequencing of courses is subordinate to a pedagogical style enhancing students' deep learning approaches, which needs to be incorporated in the development of undergraduate nursing programs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Applying an Educational-participatory Program based on the PRECEDE Model for Promoting Self-esteem and Mental Health of Students in Iran

    Directory of Open Access Journals (Sweden)

    Mahdi Moshki

    2012-01-01

    Conclusion: Health promotion planning by using life skills training based on the PRECEDE model can result in participation and empowerment, in order to promote the self-esteem and mental health of the students.

  9. Sources Of Law And Circulation Of Legal Designs: Judicial Precedents In Common Law Systems And The New Code Of Civil Procedure

    OpenAIRE

    Soares, Fabiana de Menezes; Maciel, Caroline Stéphanie Francis dos Santos

    2016-01-01

    The new Code of Civil Procedure stipulated the enforcement of judicial precedents in brazilian law, as way to unify and stabilise the Courts decisions. Therefore, this paper retuns to the qualifying background of this institute as a source of law, in order to better comprehend its framework. In a row, the essay recover precedent’s theoretical basis and its functioning within common law tradition, which can contribute greatly to the entrechment of a doctrine of precedent law in Brazil.

  10. Sources Of Law And Circulation Of Legal Designs: Judicial Precedents In Common Law Systems And The New Code Of Civil Procedure

    Directory of Open Access Journals (Sweden)

    Fabiana de Menezes Soares

    2016-12-01

    Full Text Available The new Code of Civil Procedure stipulated the enforcement of judicial precedents in brazilian law, as way to unify and stabilise the Courts decisions. Therefore, this paper retuns to the qualifying background of this institute as a source of law, in order to better comprehend its framework. In a row, the essay recover precedent’s theoretical basis and its functioning within common law tradition, which can contribute greatly to the entrechment of a doctrine of precedent law in Brazil.

  11. Increased antigen presentation but impaired T cells priming after upregulation of interferon-beta induced by lipopolysaccharides is mediated by upregulation of B7H1 and GITRL.

    Directory of Open Access Journals (Sweden)

    Fang Wang

    Full Text Available Dendritic cells are able to present Ag-derived peptides on MHC class I and II molecules and induce T cells priming. Lipopolysaccharides (LPS, an activator of Toll-like 4 receptor (TLR4 signaling, has been demonstrated to facilitate Ag-presentation, up-regulate surface molecules expression but impair T cells priming. In this study, we investigated the effect of LPS on nicotine-enhanced DCs-dependent T cells priming and the mechanisms of LPS orchestrating the immunosuppressive program. We could demonstrate that the treatment with LPS resulted in increased surface molecules expression, enhanced Ag-presentation, up-regulated release of TGF-beta, TNF-alpha, IL-6, and IFN-beta. Concomititantly, the upregulation of IFN-beta in DCs induces the up-regulation of coinhibitory molecules B7H1 and GITRL, which cause an impaired activation of naïve Ag-specific T cells and the induction of T cell tolerance by enhancing B7H1-PD-1 interactions and promoting GITRL-GITL facilitated Treg generation, respectively. These data provide a mechanistic basis for the immunomodulatory action of IFN-beta which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune response and persistent infection.

  12. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation.

    Science.gov (United States)

    Li, Qingjie; Winston, John H; Sarna, Sushil K

    2016-02-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. Copyright © 2016 the American Physiological Society.

  13. A case of AML with preceding hypoplastic stage after oophoro-hysterectomy and 60Co-irradiation

    International Nuclear Information System (INIS)

    Yoshida, Takashi; Nakamura, Shinobu; Hattori, Kenichi; Tanimoto, Kazuo.

    1975-01-01

    A case of AML (preceded by a hypoplastic stage) which developed after oophoro-hysterectomy and 60 Co-irradiation is presented, and related literature concerning irradiation-induced leukemia and the early diagnosis of leukemia and/or preleukemia are discussed. The patient, a 47 year old female had had surgery and irradiation with a subsequent normachromic anemia necessitating transfusions 11 years prior to her presenting herself at our hospital because of anemia. Her pancytopenic peripheral blood picture combined with a relatively hypererythroid marron led to a diagnosis of atypical hypoplastic anemia. Two years after this she suddenly developed a high fever, general fatigue and a severe anemia. Hematological studies revealed acute myeloblastic leukemia. A combination therapy consisting of DM, 6MP, prednisolon and blood transfusions was given with no effect and 3 months after the onset, the patient died of asphyxia resulting from gross hemoptysis. Autopsy revealed pulmonary hemorrhage secondary to the leukemia. (J. Evans)

  14. Application of high resolution x-ray spectrometry preceded by neutron activation for elemental analysis of soil samples

    International Nuclear Information System (INIS)

    Hernandez Rivero, A.; Capote Rodriguez, G.; Herrera Peraza, E.

    1996-01-01

    Utilization of High Resolution X-Ray Spectrometry preceded by activation of the samples by irradiation with neutron fluxes (NAA R X) is a relatively modern trend in application of nuclear techniques. This method may complement advantageously the usual Neutron Activation Analysis by means of Gamma Spectrometry (NAA-G) In this work results obtained by the application of NAA-RX for non-destructive analysis of Cuban soil samples are discussed. The samples were irradiated with reactor neutron fluxes and the induced characteristic X-rays were measured by using Si(li)-detector. Concentrations of Fe, Zn and Eu as determined by NAA-RX are compared with both NAA-G and XRF data. For the elaboration of X-ray and Gamma Spectra the computer programs AXIL and ACTAN were used respectively

  15. Left in limbo – Experiences and needs among postmenopausal women newly diagnosed with osteoporosis without preceding osteoporotic fractures

    DEFF Research Database (Denmark)

    Jakobsen, Pernille Ravn; Hermann, Anne Pernille; Søndergaard, Jens

    2018-01-01

    Introduction Despite the fact that the first osteoporotic fracture is preventable, osteoporosis is still a major health challenge. The disease is highly prevalent among postmenopausal women. However little is known about how to meet and support women, when they are diagnosed with osteoporosis...... without preceding fractures. Therefore this study aims at gaining a deeper understanding of how women experience being diagnosed. Furthermore to describe and identify their needs, which should be met in future healthcare services. Methods We conducted a phenomenological qualitative study. We included 17...... women aged 52–65 and collected data through semi-structured interviews. We analysed data following Giorgi's methodology. Findings Needs among the women were classified into three main themes: (1) needs of targeted and tailored information about osteoporosis, (2) needs of being prepared for GP visit...

  16. The Precedent 443 of the Superior Labor Court and Judicial Activism: The Defense of a Non Selective Constitutional Hermeneutics

    Directory of Open Access Journals (Sweden)

    Humberto Lima de Lucena Filho

    2015-12-01

    Full Text Available This paper is dedicated to the analysis of the Precedent 443 of the Superior Labor Court, which deals with the discriminatory dismissal presumption of those labor with social stigma diseases from the perspective of judicial activism in the brazilian labor law and its objective influence on law and labor procedure law from the from the perspective of a not univocal constitutional hermeneutics. It aims, also, to conceptualize the stability institute in order to configure the dangers and misconceptions arising from it. Therefore, it concludes that the analogy that embodied the repeated judicial position was excessive. The research points out the logical-deductive method operated by the aid of the literature review, case law and positioning applicable law.

  17. Sleepwalking episodes are preceded by arousal-related activation in the cingulate motor area: EEG current density imaging.

    Science.gov (United States)

    Januszko, Piotr; Niemcewicz, Szymon; Gajda, Tomasz; Wołyńczyk-Gmaj, Dorota; Piotrowska, Anna Justyna; Gmaj, Bartłomiej; Piotrowski, Tadeusz; Szelenberger, Waldemar

    2016-01-01

    To investigate local arousal fluctuations in adults who received ICSD-2 diagnosis of somnambulism. EEG neuroimaging (eLORETA) was utilized to compare current density distribution for 4s epochs immediately preceding sleepwalking episode (from -4.0 s to 0 s) to the distribution during earlier 4s epochs (from -8.0 s to -4.0 s) in 20 EEG segments from 15 patients. Comparisons between eLORETA images revealed significant (t>4.52; psleepwalking, with greater current density within beta 3 frequency range (24-30 Hz) in Brodmann areas 33 and 24. Sleepwalking motor events are associated with arousal-related activation of cingulate motor area. These results support the notion of blurred boundaries between wakefulness and NREM sleep in sleepwalking. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  18. Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state.

    Science.gov (United States)

    Kanai, Ryuta; Ogawa, Haruo; Vilsen, Bente; Cornelius, Flemming; Toyoshima, Chikashi

    2013-10-10

    Na(+),K(+)-ATPase pumps three Na(+) ions out of cells in exchange for two K(+) taken up from the extracellular medium per ATP molecule hydrolysed, thereby establishing Na(+) and K(+) gradients across the membrane in all animal cells. These ion gradients are used in many fundamental processes, notably excitation of nerve cells. Here we describe 2.8 Å-resolution crystal structures of this ATPase from pig kidney with bound Na(+), ADP and aluminium fluoride, a stable phosphate analogue, with and without oligomycin that promotes Na(+) occlusion. These crystal structures represent a transition state preceding the phosphorylated intermediate (E1P) in which three Na(+) ions are occluded. Details of the Na(+)-binding sites show how this ATPase functions as a Na(+)-specific pump, rejecting K(+) and Ca(2+), even though its affinity for Na(+) is low (millimolar dissociation constant). A mechanism for sequential, cooperative Na(+) binding can now be formulated in atomic detail.

  19. Predicting effective factors on eating behaviors in the prevention of cardiovascular disease based on the PRECEDE model.

    Science.gov (United States)

    Radmerikhi, Samera; Tabatabaei, Seyed Vahid Ahmady; Jahani, Yunes; Mohseni, Mohabbat

    2017-12-01

    Changes in eating behavior can reduce the risk of developing cardiovascular disease. The aim of this study was to predict the effective factors of eating behaviors in the prevention of cardiovascular disease using the PRECEDE model. This cross-sectional study was performed on 400 subjects aged from 20 to 60 years old in Kerman, Iran in 2016. The participants were selected using a multistage random sampling method. A self-administered questionnaire including questions regarding demographic characteristics, eating behavior, and PRECEDE model constructs were completed by the participants. Data were analyzed using SPSS 22 and STATA 12. For data analysis, Spearman correlation coefficient, univariate and multiple median regression were applied. The predictive power of the model constructs was determined by analysis of artificial neural networks. Among participants, the score of knowledge was high (84.15±10.7), and the scores of perceived self-efficacy (59.1±16.57), reinforcing factors (60.66±14.01), enabling factors (56.5±12.91), and eating behavior (62.1±14.7) were intermediate, and the score of attitude was low (47.84±7.67). Attitude, self-perceived efficacy, enabling factors, and knowledge predicted 32%, 30%, 26%, and 0.93% of participants' eating behavior respectively. The relationship between all variables and eating behavior was positive and significant (pfactors the least correlation with eating behavior. According to the results of this study, self-efficacy, attitude, and enabling factors were the main predicting factors for eating behaviors; therefore, to prevent cardiovascular disease and enhance healthy eating behavior, it is recommended to change attitude, and enhance self-efficacy and enabling factors in the community.

  20. Influence of meteorological parameters during the preceding fall and winter on the questing activity of nymphal Ixodes ricinus ticks

    Science.gov (United States)

    Vollack, Ken; Sodoudi, Sahar; Névir, Peter; Müller, Klaus; Richter, Dania

    2017-10-01

    Wood ticks, Ixodes ricinus L., serve as vectors for various pathogens and are ubiquitous throughout Central Europe. Survival and development of I. ricinus depend on biotic and abiotic factors. We examined whether relative humidity (RH), air ( T a ) and soil temperatures ( T s ), or snow depth during November through February affect the questing activity of ticks during their subsequent season of activity. We related the number of host-seeking nymphs to meteorological parameters measured in close proximity at minutely intervals over the period of 6 years (2010-2015) in an urban park in Berlin. We defined thresholds at which associations appeared strongest. Although the annual variations in RH, T a , and snow depth were typical of the mid-latitudes, the questing activity of nymphs during their first peak of activity (March through July) varied among the 6 years more than threefold. The accumulated hours of RH below 77% in 2 m height during November through February affected the questing activity of nymphs during the following activity peak. In contrast to T a , accumulated hours of T s below -1 °C in 0.02 m depth or below -4 °C in 0.05 m depth during the preceding period significantly influenced the average number of nymphs questing during spring. Our observations suggest that RH, T s , and snow cover during the preceding months affect the questing activity of nymphal I. ricinus during their first peak of activity. Snow cover serves as an insulator between the atmosphere and soil, which not only stabilizes T s but also appears to protect ticks from exposure to frost and frequent temperature shifts.

  1. Food allergy preceded by contact urticaria due to the same food: involvement of epicutaneous sensitization in food allergy.

    Science.gov (United States)

    Inomata, Naoko; Nagashima, Mayumi; Hakuta, Amiko; Aihara, Michiko

    2015-01-01

    There have recently been reports suggesting that sensitization to food allergens may occur outside the intestinal tract, especially through the skin. To clarify the role of epicutaneous sensitization in food allergy, we investigated the clinical characteristics of adult patients with food allergies preceded by contact urticaria due to the same foods. We investigated clinical characteristics of 15 patients (20-51 years of age; 5 men and 10 women), who had food allergies preceded by contact urticaria. Fourteen patients were contact urticaria due to the causative foods during occupationally cooking, whereas 1 patient during face pack. In the occupational group, causative foods included rice, wheat, fruits, vegetables, fish, shrimp and cuttlefish; in the fresh cucumber paste case the cause was cucumber. In the 15 patients, the causative foods were fresh, not processed, and were tolerated by most (9/15, 60%) after heating. Regarding to symptoms after ingestion of the causative foods, the most frequently induced symptoms was oral symptoms (14/15, 93.3%), followed by urticaria (4/15, 26.7%), abdominal symptoms (3/15, 20%). The duration between the start of jobs or face pack, and the onset of contact urticaria was from 1 month to 19 years (mean, 8.7 years). The duration between the onset of contact urticaria and the onset of food allergy was from a few weeks to 6 years (mean, 11 months). One sushi cook experienced severe anaphylactic shock after ingestion of fish. In the occupational group, 13 of 15 patients (86.7%) had atopic dermatitis or hand eczema, indicating that the impaired skin barrier might be a risk for food allergies induced by epicutaneous sensitization. Epicutaneous sensitization of foods could induce food allergy under occupational cooking and skin-care treatment with foods in adults. Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  2. Examining the impact of migrant status on ethnic differences in mental health service use preceding a first diagnosis of schizophrenia.

    Science.gov (United States)

    Anderson, Kelly K; McKenzie, Kwame J; Kurdyak, Paul

    2017-08-01

    Some ethnic groups have more negative contacts with health services for first-episode psychosis, likely arising from a complex interaction between ethnicity, socio-economic factors, and immigration status. Using population-based health administrative data, we sought to examine the effects of ethnic group and migrant status on patterns of health service use preceding a first diagnosis of schizophrenia or schizoaffective disorder among people aged 14-35 over a 10-year period. We compared access to care and intensity of service use for first-generation ethnic minority groups to the general population of Ontario. To control for migrant status, we restricted the sample to first-generation migrants and compared service use indicators for ethnic minority groups to the European migrant group. Our cohort included 18,080 people with a first diagnosis of schizophrenia or schizoaffective disorder, of whom 14.4% (n = 2607) were the first-generation migrants. Our findings suggest that the magnitude of ethnic differences in health service use is reduced and no longer statistically significant when the sample is restricted to first-generation migrants. Of exception, nearly, all migrant groups have lower intensity of primary care use, and Caribbean migrants are consistently less likely to use psychiatric services. We observed fewer ethnic differences in health service use preceding the first diagnosis of psychosis when patterns are compared among first-generation migrants, rather than to the general population, suggesting that the choice of reference group influences ethnic patterning of health service use. We need a comprehensive understanding of the mechanisms behind observed differences for minority groups to adequately address disparities in access to care.

  3. FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

    Directory of Open Access Journals (Sweden)

    Emilios Gemenetzidis

    Full Text Available Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC.FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR, expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23, were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression.This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a

  4. Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages.

    Directory of Open Access Journals (Sweden)

    Fattah Sotoodehnejadnematalahi

    Full Text Available Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM, and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold by long term hypoxia (5 days than by 1 day of hypoxia (48 fold. We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K, LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression.

  5. Hydrometeorological conditions preceding wildfire, and the subsequent burning of a fen watershed in Fort McMurray, Alberta, Canada

    Science.gov (United States)

    Elmes, Matthew C.; Thompson, Dan K.; Sherwood, James H.; Price, Jonathan S.

    2018-01-01

    The destructive nature of the ˜ 590 000 ha Horse river wildfire in the Western Boreal Plain (WBP), northern Alberta, in May of 2016 motivated the investigation of the hydrometeorological conditions that preceded the fire. Historical climate and field hydrometeorological data from a moderate-rich fen watershed were used to (a) identify whether the spring 2016 conditions were outside the range of natural variability for WBP climate cycles, (b) explain the observed patterns in burn severity across the watershed, and (c) identify whether fall and winter moisture signals observed in peatlands and lowland forests in the region are indicative of wildfire. Field hydrometeorological data from the fen watershed confirmed the presence of cumulative moisture deficits prior to the fire. Hydrogeological investigations highlighted the susceptibility of fen and upland areas to water table and soil moisture decline over rain-free periods (including winter), due to the watershed's reliance on supply from localized flow systems originating in topographic highs. Subtle changes in topographic position led to large changes in groundwater connectivity, leading to greater organic soil consumption by fire in wetland margins and at high elevations. The 2016 spring moisture conditions measured prior to the ignition of the fen watershed were not illustrated well by the Drought Code (DC) when standard overwintering procedures were applied. However, close agreement was found when default assumptions were replaced with measured duff soil moisture recharge and incorporated into the overwintering DC procedure. We conclude that accumulated moisture deficits dating back to the summer of 2015 led to the dry conditions that preceded the fire. The infrequent coinciding of several hydrometeorological conditions, including low autumn soil moisture, a modest snowpack, lack of spring precipitation, and high spring air temperatures and winds, ultimately led to the Horse river wildfire spreading widely and

  6. On the Reflection in the Solar Radio Emission of Processes in the Chromosphere and the lower Corona preceded CMEs Registration

    Science.gov (United States)

    Durasova, M. S.; Tikhomirov, Yu. V.; Fridman, V. M.; Sheiner, O. A.

    The phenomena preceding the Coronal Mass Ejections (CMEs) and observed in the radio-frequency band represent a lot of sporadic components of the emission, that cover the wide frequency range. The study of these phenomena composes the new, prevailing for the last ten years direction. This is caused by the fact that solar radioastronomy possesses the developed network of observant tools, by the sensitive methods of observations. It makes possible in a number of cases to obtain information from the layers of solar atmosphere, inaccessible for the studies by other methods of observations. The purpose of this work is analysis of information about the CMEs preceding radio-events and their dynamics in the centimeter and decimeter radio emission in 1998. We use the data of the worldwide network of solar observatories in the radio-frequency band, the data about the CMEs phenomena and the characteristics are taken from Internet: http://sdaw.gsfc.nasa.gov./CME_list}. From great number of the CMEs we select only such, before which there were no more recorded events in the time interval of 8 hours, and before which sporadic radio emission was observed on 2-hours interval. The selection of this interval was caused by available study about the mean lifetime of precursors before CMEs and powerful flares, as a rule, accompanying CMEs, in the optical, X-ray and radio emissions. It constitutes, on the average, about 30 min. The total volume of data composed 68 analyzed events of CMEs in 1998. The analysis of the spectral- temporary characteristics of sporadic radio emission in the dependence on the CMEs parameters is carried out. The nature of processes at the stage of formation and initial propagation of CMEs, such as floating up of new magnetic fluxes, the development of instabilities, the characteristic scales of phenomena, that have an effect upon the observed radio emission is analyzed. The work is carried out with the support of Russian Fund of Basic Research (grant 03

  7. The Effect of Preceding Crops on the Chemical Fractions of Copper (Cu in the Rhizosphere and the Bulk Soil and its Relationship with Copper Uptake by Wheat

    Directory of Open Access Journals (Sweden)

    shahrzad kabirinejad

    2017-02-01

    Full Text Available Introduction: Preceding crops as a source of organic matter are an important source of micronutrient and can play an important role in the soil fertility and the micronutrients cycle of soil. In addition to the role of the organic matter in increasing the concentration of micronutrients in soil solution, attention also should be paid to the role of the kind and the quantity of the root’s exudates that are released in response to the incorporation of different plant residues in the rhizosphere. Present research was conducted with the objective of studying the effect of the kind of preceding crops: Trifolium (Trifolium pretense L, Sofflower (Carthamus tinectirus L, Sorghum (Sorghum bicolor L, Sunflower (Heliantus annus L and control (fallow on the chemical forms of copper in the wheat rhizosphere and the bulk soil and Cu uptake by wheat and also investigating the correlation between the fractions of Cu in soil and Cu uptake in wheat. Materials and Methods: The present research was conducted as split plot in a Randomized Complete Block design (RCBD with 3 replications and 5 treatments, in field conditions. In the beginning, the preceding crops were cultivated in the experimental plots and after ending growth, preceding crops were harvested. Then the wheat was cultivated in the experimental plots. Finally, after harvesting the wheat, soil samples were collected from the two parts of the root zone (the wheat rhizosphere and the bulk soil. The soil samples were air dried ground and passed through a 2-mm sieve and stored for chemical analysis. Soil pH (in the soil saturation extract and organic matter (Walkley–Black wet digestion were measured in standard methods (1. The Total Organic Carbon (TOC was measured by Analyzer (Primacs SLC TOC Analyzer (CS22, Netherlands. The available Cu in soil was extracted by DTPA and determined using atomic absorption spectroscopy (2. The fractionation of soil Cu was carried out using the MSEP method (3. Results and

  8. Cannabinoid 2 Receptor- and Beta Arrestin 2-Dependent Upregulation of Serotonin 2A Receptors

    OpenAIRE

    Franklin, J.M.; Vasiljevik, T.; Prisinzano, T.E.; Carrasco, G.A.

    2012-01-01

    Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT2A) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP 55,940) or selective CB2 receptor agonists (JWH 133 or GP 1a) upregulate 5-HT2A receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT2A recept...

  9. Morning cortisol secretion in school-age children is related to the sleep pattern of the preceding night.

    Science.gov (United States)

    Lemola, Sakari; Perkinson-Gloor, Nadine; Hagmann-von Arx, Priska; Brand, Serge; Holsboer-Trachsler, Edith; Grob, Alexander; Weber, Peter

    2015-02-01

    Sleep disturbance in childhood is common and a risk factor for poor mental health. Evidence indicates that disturbed sleep is associated with altered hypothalamic-pituitary-adrenal axis (HPAA) activity. Knowledge regarding the association between HPAA-activity and objective sleep measures particularly regarding sleep architecture in school-age children is missing. Sleep-electroencephalography was administered to 113 children aged 6-10 years (including 58 children born very preterm and 55 born at term) during one night at the children's homes and sleep duration, sleep continuity, and sleep architecture were assessed. To assess the cortisol awakening response at the following morning, cortisol secretion was measured at awakening, 10, 20, and 30min later. Regression analyses controlling child age, gender, prematurity status, and the awakening time revealed that morning cortisol secretion was negatively associated with sleep duration and slow wave sleep and positively associated with the relative amount of Stage 2 sleep during the preceding night. In addition, morning cortisol secretion linearly increased with age. In conclusion, associations of sleep disturbance with poor mental health may be confounded with altered HPAA-activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Tropical Pacific sea-surface temperatures and preceding sea level pressure anomalies in the subtropical North Pacific

    Science.gov (United States)

    Anderson, Bruce T.

    2003-12-01

    The correspondence of sea-surface temperature (SST) anomalies to changes in antecedent large-scale sea level pressure anomalies is investigated using reanalysis data. By statistically examining linearly coupled precursor sea level pressure fields and subsequent SST fields for different lag periods, it is possible to isolate a precursor mode of sea level pressure (SLP) variability in the central subtropical North Pacific that precedes variations in the January-March El Niño/Southern Oscillation (ENSO) by approximately 12-15 months. A sea level pressure index, which captures the important characteristics of this precursor mode of variability, is developed and evaluated. It is shown that both analyzed and observed versions of the index are significantly correlated with the January-March ENSO one year later. The SLP index is then used to examine the evolution of the surface circulation and temperature structures leading up to mature ENSO events. Initially, the January-March subtropical North Pacific SLP anomalies are associated with changes in the intensity of the subtropical trade wind regime over the North Pacific, as well as with SST anomalies over the eastern equatorial Pacific and subtropical central Pacific. In agreement with the correlation statistics associated with the SLP and lagged NINO3.4 indices, both the sea level pressure field and the SST field subsequently develop ENSO-like structures over the course of the following year. Significant discussion of these results and pertinent areas of future research are provided within the broader context of the ENSO system.

  11. Variations of b-values preceding large earthquakes in the shallow subduction zones of Cocos and Nazca plates

    Science.gov (United States)

    Kulhanek, Ota; Persson, Leif; Nuannin, Paiboon

    2018-03-01

    The potential of b-value variations as a medium-term (months, years) precursor was investigated by focusing on the eight largest earthquakes, Mw ≥ 7.0, occurring between January 2000 and April 2010 in the shallow subduction zones of Cocos and Nazca plates. The available ISC and NEIC lists of events are complete for threshold magnitudes 4.3 (4569 events) and 4.6 (2742 events), respectively. Spatial and temporal perturbations of b were investigated in six regions surrounding the eight largest shocks. A technique of moving spatial- and temporal-windows was applied. Deduced b-values reveal large variations between 0.6 and 2.2. All eight earthquakes took place within regions of low b and were all preceded by significant drops in b-values. Observed correspondence between low b and the occurrence of large earthquakes suggests that b(t) has a potential to be employed in medium-term earthquake predictions in subduction zones of Central and South America.

  12. The South African Constitutional Court's Use Of Foreign Precedent In Matters Of Religion: Without Fear Or Favour?

    Directory of Open Access Journals (Sweden)

    Christa Rautenbach

    2015-12-01

    Full Text Available Since its establishment in 1994, the South African Constitutional Court has been quite fearless in its citation of foreign precedents in its reasoning. Compared with that of similar adjudicative institutions elsewhere, the constitutional reasoning of the South African Constitutional Court is still in its infancy, but it has nevertheless earned itself high praise among observers worldwide. The Court has in particular been commended for some ground-breaking and courageous judgments which it handed down without casting either argumentative rigour or judicial self-restraint to the winds. Since its establishment in 1994 the Constitutional Court has cited foreign cases quite extensively. Although these cases deal with all matters of the law, especially human rights issues, the Constitutional Court's use of foreign cases in the area of religion is noteworthy. Against this background, this contribution remarks on the propensity of the Constitutional Court to look beyond its borders to deals with issues of religion within South Africa. The ultimate question is whether the notion of transjudicialism in the case of religion is detrimental to the reputation of the South African Constitutional Court or whether it is a characteristic of a court which is confident enough that its independence will remain intact in spite of its looking elsewhere for answers.

  13. TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors

    Directory of Open Access Journals (Sweden)

    Pierre-Benoit Ancey

    2017-07-01

    Full Text Available Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC and hydroxymethylation (5hmC are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A.

  14. Development of an mHealth Application for Women Newly Diagnosed with Osteoporosis without Preceding Fractures: A Participatory Design Approach.

    Science.gov (United States)

    Ravn Jakobsen, Pernille; Hermann, Anne Pernille; Søndergaard, Jens; Wiil, Uffe Kock; Clemensen, Jane

    2018-02-13

    mHealth is a useful tool to improve health outcome within chronic disease management. However, mHealth is not implemented in the field of postmenopausal osteoporosis even though it is a major worldwide health challenge. Therefore, this study aims to design and develop an mHealth app to support women in self-management of osteoporosis when they are diagnosed without preceding fractures. Participatory design is conducted in three phases. Based on identified needs in the first phase, a prototype is designed and developed in an iterative process in the second phase before the mHealth app is tested in the third phase. This paper focuses on the user activities in phase two and describes how a team of researchers, women, physicians, healthcare professionals, and app designers are involved in the participatory design process. The study shows that participatory design is a viable approach when developing an mHealth app for women with asymptomatic osteoporosis. Results obtained from the workshops and laboratory tests demonstrate the importance of feedback from users in the iterative process, as well as the participation of users and app designers in workshops and laboratory tests to enable mutual learning when developing new mHealth solutions. The regular member-checks and involvement of users helped to identify challenges associated with providing healthcare services through an app.

  15. Application of Behavioral Analysis Phase of PRECEDE Model on Women’s Psychological Well-being in the Menopausal Period

    Directory of Open Access Journals (Sweden)

    Mahdi Moshki

    2015-08-01

    Full Text Available Background and Aims Positive psychology introduce mental health as a positive psychological functioning and represent it as wellbeing psychology and having positive characteristics such as self-esteem, positive social relationships, and life satisfaction. The purpose of this study was to investigate the psychological wellbeing of postmenopausal women based on the behavioral analysis phase of PRECEDE model. Materials and Methods This study is a cross-sectional survey and carried out through random sampling in the case of 110 postmenopausal women at Ferdows city, Iran in 2014. The psychological wellbeing variable was studied by Ryff test, including 84 questions and six components containing autonomy, purposeful in life, dominance on environment, personal development, positive relationships with others, and self-acceptance. The collected data were analyzed by SPSS v.20 using descriptive statistics and analytic statistics through correlation and ANOVA. Results The mean age of participants and the average number of their children were 51.62 ± 4.26 and 3.42 ± 1.38, respectively. 61.80 percent of participants had primary education. Pearson correlation test indicated a positive and significant relationship between psychological wellbeing and predisposing factors (knowledge, attitude toward menopause, environmentalbehavioral factors, enabling factors and reinforcing factors (P < 0.01. Conclusion The results indicated that increasing awareness, creating positive attitude and promoting healthy behaviors are the effective steps to improve the psychological wellbeing in postmenopausal women. * Corresponding Author: Gonabad University of Medical Sciences, Faculty of Public Health. Email: Fpf357@gmail.com

  16. Spectral Sensitivity Change May Precede Habitat Shift in the Developing Retina of the Atlantic Tarpon (Megalops atlanticus).

    Science.gov (United States)

    Schweikert, Lorian E; Grace, Michael S

    Fish that undergo ontogenetic migrations between habitats often encounter new light environments that require changes in the spectral sensitivity of the retina. For many fish, sensitivity of the retina changes to match the environmental spectrum, but the timing of retinal change relative to habitat shift remains unknown. Does retinal change in fish precede habitat shift, or is it a response to encountered changes in environmental light? Spectral sensitivity changes were examined over the development of the Atlantic tarpon (Megalops atlanticus) retina relative to ontogenetic shifts in habitat light. Opsin gene isoform expression and inferred chromophore use of visual pigments were examined over the course of M. atlanticus development. Spectral sensitivity of the retina was then determined by electroretinography and compared to the spectroradiometric measurements of habitat light encountered by M. atlanticus from juveniles to adults. These data, along with previously known microspectrophotometric measurements of sensitivity in M. atlanticus, indicate retinal spectral sensitivity that matches the dominant wavelengths of environmental light for juvenile and adult fish. For the intervening subadult stage, however, spectral sensitivity does not match the dominant wavelength of light it occupies but better matches the dominant wavelengths of light in the habitat of its forthcoming migration. These results first indicate that the relationship between environmental light spectrum and spectral sensitivity of the retina changes during M. atlanticus development and then suggest that such changes may be programmed to support visual anticipation of new photic environments.

  17. Changes in myonuclear domain size do not precede muscle hypertrophy during prolonged resistance-type exercise training.

    Science.gov (United States)

    Snijders, T; Smeets, J S J; van Kranenburg, J; Kies, A K; van Loon, L J C; Verdijk, L B

    2016-02-01

    Muscle fibre hypertrophy is accompanied by an increase in myonuclear number, an increase in myonuclear domain size or both. It has been suggested that increases in myonuclear domain size precede myonuclear accretion and subsequent muscle fibre hypertrophy during prolonged exercise training. In this study, we assessed the changes in muscle fibre size, myonuclear and satellite cell content throughout 12 weeks of resistance-type exercise training in young men. Twenty-two young men (23 ± 1 year) were assigned to a progressive, 12-weeks resistance-type exercise training programme (3 sessions per week). Muscle biopsies from the vastus lateralis muscle were taken before and after 2, 4, 8 and 12 weeks of exercise training. Muscle fibre size, myonuclear content, myonuclear domain size and satellite cell content were assessed by immunohistochemistry. Type I and type II muscle fibre size increased gradually throughout the 12 weeks of training (type I: 18 ± 5%, type II: 41 ± 6%, P muscle fibres. No changes in type I and type II myonuclear domain size were observed at any time point throughout the intervention. Satellite cell content increased significantly over time in both type I and type II muscle fibres (P muscle fibre hypertrophy during prolonged resistance-type exercise training in vivo in humans. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  18. Pure small cell carcinoma of the prostate preceded by acute zonal occult outer retinopathy: A case report.

    Science.gov (United States)

    Ching, Daniel; Brown, Matthew; Forrest, Cindy; Hayne, Dickon

    2016-01-01

    Pure small cell prostate cancer (SCPC) cases are very rare. Acute zonal occult outer retinopathy (AZOOR) has been described as a non-neoplastic retinopathy. We report the first case of pure SCPC preceded by AZOOR in the literature. A 59year old gentleman presented with an obstructed infected urinary system. He had a diagnosis of AZOOR 6 months ago that was investigated with full body imaging without any suspicious findings. However, the most recent CT findings demonstrated extensive disease dissemination. The patient underwent rigid cystoscopy and resection that confirmed a diagnosis of pure SCPC. AZOOR is a clinical syndrome of photopsia and rapid zonal field loss. The exact aetiology remains unknown and its association with malignancy remains contentious. Paraneoplastic manifestations of unexplained visual loss in SCPC are rare with only 2 cases reported in the literature. There are no cases demonstrating an association between AZOOR and SCPC. Pure SCPC is an aggressive malignancy with most cases presenting with extensive disease dissemination on diagnosis. Early detection has a role in improving prognosis but is challenging. Further research is required to establish a standard treatment protocol. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  19. A53T Human α-Synuclein Overexpression in Transgenic Mice Induces Pervasive Mitochondria Macroautophagy Defects Preceding Dopamine Neuron Degeneration

    Science.gov (United States)

    Xie, Zhiguo; Turkson, Susie

    2015-01-01

    In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated a transgenic mouse line with human α-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of α-synuclein and their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration in an in vivo model based on known PD genetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have set the stage and direction of emphasis for future studies. PMID:25609609

  20. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-09-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

  1. Increased xanthine oxidase-related ROS production and TRPV1 synthesis preceding DOMS post-eccentric exercise in rats.

    Science.gov (United States)

    Retamoso, Leandro T; Silveira, Mauro E P; Lima, Frederico D; Busanello, Guilherme L; Bresciani, Guilherme; Ribeiro, Leandro R; Chagas, Pietro M; Nogueira, Cristina W; Braga, Ana Claudia M; Furian, Ana Flávia; Oliveira, Mauro S; Fighera, Michele R; Royes, Luiz Fernando F

    2016-05-01

    It is well-known that unaccustomed exercise, especially eccentric exercise, is associated to delayed onset muscle soreness (DOMS). Whether DOMS is associated with reactive oxygen species (ROS) and the transient receptor potential vanilloid 1 (TRPV1) is still an open question. Thus, the aim of this study was to investigate the association between TRPV1 and xanthine oxidase-related ROS production in muscle and DOMS after a bout of eccentric exercise. Male Wistar rats performed a downhill running exercise on a treadmill at a -16° tilt and a constant speed for 90min (5min/bout separated by 2min of rest). Mechanical allodynia and grip force tests were performed before and 1, 3, 6, 9, 12, 24, 48 and 72h after the downhill running. Biochemical assays probing oxidative stress, purine degradation, xanthine oxidase activity, Ca(2+) ATPase activity and TRPV1 protein content were performed in gastrocnemius muscle at 12, 24, and 48h after the downhill running. Our statistical analysis showed an increase in mechanical allodynia and a loss of strength after the downhill running. Similarly, an increase in carbonyl, xanthine oxidase activity, uric acid levels and TRPV1 immunoreactivity were found 12h post-exercise. On the other hand, Ca(2+) ATPase activity decreased in all analyzed times. Our results suggest that a possible relationship between xanthine oxidase-related ROS and TRPV1 may exist during the events preceding eccentric exercise-related DOMS. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. TMPRSS2-ERG Gene Fusion Causing ERG Overexpression Precedes Chromosome Copy Number Changes in Prostate Carcinomas, Paired HGPIN Lesions

    Directory of Open Access Journals (Sweden)

    Nuno Cerveira

    2006-10-01

    Full Text Available TMPRSS2-ETS gene fusions have been found recurrently in prostate carcinomas, but not in the presumed precursor lesion, high-grade prostatic intraepithelial neoplasia (HGPIN. However, HGPIN lesions may share chromosomal changes with prostate cancer. To determine the relative order of genetic events in prostate carcinogenesis, we have analyzed 34 prostate carcinomas, 19 paired HGPIN lesions, 14 benign prostate hyperplasias, 11 morphologically normal prostatic tissues for TMPRSS2-ERG, TMPRSS2-ETV1 rearrangements, genomic imbalances. TMPRSS2 exon 1 was fused in-frame with ERG exon 4 in 17 of 34 (50% prostate carcinomas, in 4 of 19 (21% HGPIN lesions, but in none of controls. The findings were further validated by sequencing analysis, by the real-time polymerase chain reaction quantification of TMPRSS2-ERG fusion transcript, the ERG exons 5/6:exons 1/2 expression ratio. Chromosome copy number changes were detected by comparative genomic hybridization in 42% of clinically confined carcinomas, in none of the 16 HGPIN lesions analyzed. We demonstrate for the first time that the TMPRSS2-ERG fusion gene can be detected in a proportion of HGPIN lesions, that this molecular rearrangement is an early event that may precede chromosome-level alterations in prostate carcinogenesis.

  3. The Legal Doctrine on 'Limitation of Liability' in the Precedent Analysis on Plastic Surgery Medical Malpractice Lawsuits.

    Science.gov (United States)

    Park, Bo Young; Pak, Ji-Hyun; Hong, Seung-Eun; Kang, So Ra

    2015-12-01

    This study intended to review the precedents on plastic surgery medical malpractice lawsuits in lower-court trials, classify the reasons of 'limitation of liability' by type, and suggest a standard in the acknowledgement of limitation of liability ratio. The 30 lower-court's rulings on the cases bearing the medical negligence of the defendants acknowledged the liability ratio of the defendants between 30% and 100%. Ten cases ruled that the defendants were wholly responsible for the negligence or malpractice, while 20 cases acknowledged the limitation of liability principle. In the determination of damage compensation amount, the court considered the cause of the victim side, which contributed in the occurrence of the damage. The court also believed that it is against the idea of fairness to have the assailant pay the whole compensation, even there is no victim-side cause such as previous illness or physical constitution of the patient, and applies the legal doctrine on limitation of liability, which is an independent damage compensation adjustment system. Most of the rulings also limited the ratio of responsibility to certain extent. When considering that the legal doctrine on limitation of liability which supports concrete validity for the fair sharing of damage, the tangible classification of causes of limitation of liability suggested in this study would be a useful tool in forecasting the ruling of a plastic surgery medical malpractice lawsuit.

  4. Preceding Vehicle Detection and Tracking Adaptive to Illumination Variation in Night Traffic Scenes Based on Relevance Analysis

    Science.gov (United States)

    Guo, Junbin; Wang, Jianqiang; Guo, Xiaosong; Yu, Chuanqiang; Sun, Xiaoyan

    2014-01-01

    Preceding vehicle detection and tracking at nighttime are challenging problems due to the disturbance of other extraneous illuminant sources coexisting with the vehicle lights. To improve the detection accuracy and robustness of vehicle detection, a novel method for vehicle detection and tracking at nighttime is proposed in this paper. The characteristics of taillights in the gray level are applied to determine the lower boundary of the threshold for taillights segmentation, and the optimal threshold for taillight segmentation is calculated using the OTSU algorithm between the lower boundary and the highest grayscale of the region of interest. The candidate taillight pairs are extracted based on the similarity between left and right taillights, and the non-vehicle taillight pairs are removed based on the relevance analysis of vehicle location between frames. To reduce the false negative rate of vehicle detection, a vehicle tracking method based on taillights estimation is applied. The taillight spot candidate is sought in the region predicted by Kalman filtering, and the disturbed taillight is estimated based on the symmetry and location of the other taillight of the same vehicle. Vehicle tracking is completed after estimating its location according to the two taillight spots. The results of experiments on a vehicle platform indicate that the proposed method could detect vehicles quickly, correctly and robustly in the actual traffic environments with illumination variation. PMID:25195855

  5. Upregulation of Mrps18a in breast cancer identified by selecting phage antibody libraries on breast tissue sections

    DEFF Research Database (Denmark)

    Sørensen, Karen Marie Juul; Meldgaard, Theresa; Melchjorsen, Connie Jenning

    2017-01-01

    . RESULTS: We identified the mitochondrial ribosomal protein s18a (Mrps18a) as a protein which is upregulated in breast cancer. However, Mrps18a was not homogeneously upregulated in all cancer cells, suggesting the existence of sub-populations within the tumor. The upregulation was not confined...... to cytokeratin 19 and cytokeratin 14 double positive cells. CONCLUSION: This study illustrates how phage display can be applied towards the discovery of proteins which exhibit changes in their expression patterns. We identified the mitochondrial protein Mrps18a as being upregulated in human breast cancer cells...

  6. Formation of the genital ridges is preceded by a domain of ectopic Sox9-expressing cells in Lepidochelys olivacea.

    Science.gov (United States)

    Díaz-Hernández, Verónica; Marmolejo-Valencia, Alejandro; Harfush, Martha; Merchant-Larios, Horacio

    2012-01-01

    Bipotential gonads represent the structural framework from which alternative molecular sex determination networks have evolved. Maintenance of Sox9 expression in Sertoli cells is required for the structural and functional integrity of male gonads in mammals and probably in most amniote vertebrates. However, spatial and temporal patterns of Sox9 expression have diversified along evolution. Species with temperature sex determination are an interesting predictive model since one of two alternative developmental outcomes, either ovary or testis occurs under controlled laboratory conditions. In the sea turtle Lepidochelys olivacea, Sox9 is expressed in the medullary cords of bipotential gonads when incubated at both female- or male-promoting temperature (FT or MT). Sox9 is then turned off in presumptive ovaries, while it remains turned on in testes. In the current study, Sox9 was used as a marker of the medullary cell lineage to investigate if the medullary cords originate from mesothelial cells at the genital ridges where Sox9 is upregulated, or, if they derive from a cell population specified at an earlier developmental stage, which maintains Sox9 expression. Using immunofluorescence and in situ hybridization, embryos were analyzed prior to, during and after gonadal sex determination. A T-shaped domain (T-Dom) formed by cytokeratin (CK), N-cadherin (Ncad) and SOX9-expressing cells was found at the upper part of the hindgut dorsal mesentery. The arms of the T-Dom were extended to both sides towards the ventromedial mesonephric ridge before the thickening of the genital ridges, indicating that they contained gonadal epithelial cell precursors. Thereafter, expression of Sox9 was maintained in medullary cords while it was downregulated at the surface epithelium of bipotential gonads in both FT and MT. This result contrasts with observations in mammals and birds, in which Sox9 upregulation starts at a later stage in the inner cells underlying the Sox9-negative surface

  7. APP upregulation contributes to retinal ganglion cell degeneration via JNK3.

    Science.gov (United States)

    Liu, Chao; Zhang, Cheng-Wu; Zhou, Yi; Wong, Wan Qing; Lee, Liying Corinne; Ong, Wei Yi; Yoon, Sung Ok; Hong, Wanjin; Fu, Xin-Yuan; Soong, Tuck Wah; Koo, Edward H; Stanton, Lawrence W; Lim, Kah-Leong; Xiao, Zhi-Cheng; Dawe, Gavin S

    2018-03-01

    Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1 + RGC loss. Pathway analysis of microarray data combined with chromatin immunoprecipitation and a luciferase reporter assay demonstrated that AICD interacts with the JNK3 gene locus and regulates JNK3 expression. Moreover, JNK3 was found to be upregulated after ONA and to contribute to Tuj1 + RGC death. APP knockout reduced the ONA-induced enhanced expression of JNK3 and phosphorylated JNK (pJNK). Gamma-secretase inhibitors prevented production of AICD, reduced JNK3 and pJNK expression similarly, and protected Tuj1 + RGCs from ONA-induced cell death. Together these data indicate that ONA induces APP expression and that gamma-secretase cleavage of APP releases AICD, which upregulates JNK3 leading to RGC death. This pathway may be a novel target for neuronal protection in optic neuropathies and other forms of neurotrauma.

  8. Utilization of Wind Turbines for Up-regulation of Power Grids

    DEFF Research Database (Denmark)

    Juelsgaard, Morten; Bendtsen, Jan Dimon; Wisniewski, Rafal

    2013-01-01

    This work considers the use of wind turbines for aiding up-regulation of an electrical grid, by employing temporary overproduction with respect to available power. We present a simple model describing a turbine, and show how the possible period of overproduction can be maximized by solving a series...

  9. Equine infectious anemia virus replication is upregulated during differentiation of blood monocytes from acutely infected horses.

    OpenAIRE

    Sellon, D C; Walker, K M; Russell, K E; Perry, S T; Covington, P; Fuller, F J

    1996-01-01

    Equine infectious anemia virus is a lentivirus that replicates in mature tissue macrophages of horses. Ponies were infected with equine infectious anemia virus. During febrile episodes, proviral DNA was detectable, but viral mRNA was not detectable. As cultured blood monocytes from these ponies differentiated into macrophages, viral expression was upregulated. In situ hybridization confirmed that viral transcription occurred in mature macrophages.

  10. Functional aspects of dexamethasone upregulated nicotinic acetylcholine receptors in C2C12 myotubes

    NARCIS (Netherlands)

    Maestrone, E; Lagostena, L; Henning, RH; DenHertog, A; Nobile, M

    1995-01-01

    Three days of treatment with the glucocorticoid dexamethasone (1 nM-mu M) induced a concentration-dependent up-regulation of muscle nicotinic acetylcholine receptor (nAChR) in C2C12 mouse myotubes (EC(50)=10+/-7.3 nM), as assessed by [H-3]alpha-BuTx binding. The maximum increase in binding amounted

  11. MDP up-regulates the gene expression of type I interferons in human aortic endothelial cells.

    Science.gov (United States)

    Lv, Qingshan; Yang, Mei; Liu, Xueting; Zhou, Lina; Xiao, Zhilin; Chen, Xiaobin; Chen, Meifang; Xie, Xiumei; Hu, Jinyue

    2012-03-23

    Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2). Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs) with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF) 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  12. MDP Up-Regulates the Gene Expression of Type I Interferons in Human Aortic Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Xiumei Xie

    2012-03-01

    Full Text Available Muramyldipeptide (MDP, the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2. Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  13. Up-regulation of Robo1 in dorsal root ganglia after sciatic nerve ...

    African Journals Online (AJOL)

    Yomi

    2012-01-05

    Jan 5, 2012 ... post-SNT. Neither normal, nor SNT DRG exhibited co-localization of Robo1 and 2, and this observation was independent of neuron diameter. These results suggest that Robo1 in DRG is upregulated following sciatic nerve transection in rats. Key words: Dorsal root ganglion, rat, roundabout 1, sciatic nerve ...

  14. Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

    DEFF Research Database (Denmark)

    Xu, Cang-Bao; Zheng, Jian-Pu; Zhang, Wei

    2014-01-01

    Vasoconstrictive endothelin type B (ET(B)) receptors promote vasospasm and ischemic cerebro- and cardiovascular diseases. The present study was designed to examine if low density lipoprotein (LDL) induces upregulation of vasoconstrictive ET(B) receptor expression and if extracellular signal-regul...

  15. Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury

    International Nuclear Information System (INIS)

    Jung, Michaela; Hotter, Georgina; Vinas, Jose Luis; Sola, Anna

    2009-01-01

    The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process

  16. Reactivation from latency displays HIV particle budding at plasma membrane, accompanying CD44 upregulation and recruitment

    Directory of Open Access Journals (Sweden)

    Sano Kouichi

    2009-07-01

    Full Text Available Abstract Background It has been accepted that HIV buds from the cell surface in T lymphocytes, whereas in macrophages it buds into intracellular endosomes. Recent studies, on the other hand, suggest that HIV preferentially buds from the cell surface even in monocytic cells. However, most studies are based on observations in acutely infected cells and little is known about HIV budding concomitant with reactivation from latency. Such studies would provide a better understanding of a reservoir for HIV. Results We observed HIV budding in latently infected T lymphocytic and monocytic cell lines following TNF-α stimulation and examined the upregulation of host factors that may be involved in particle production. Electron microscopy analysis revealed that reactivation of latently infected J1.1 cells (latently infected Jurkat cells with HIV-1 and U1 cells (latently infected U937 cells with HIV-1 displayed HIV particle budding predominantly at the plasma membrane, a morphology that is similar to particle budding in acutely infected Jurkat and U937 cells. When mRNA expression levels were quantified by qRT-PCR, we found that particle production from reactivated J1.1 and U1 cells was accompanied by CD44 upregulation. This upregulation was similarly observed when Jurkat and U937 cells were acutely infected with HIV-1 but not when just stimulated with TNF-α, suggesting that CD44 upregulation was linked with HIV production but not with cell stimulation. The molecules in endocytic pathways such as CD63 and HRS were also upregulated when U1 cells were reactivated and U937 cells were acutely infected with HIV-1. Confocal microscopy revealed that these upregulated host molecules were recruited to and accumulated at the sites where mature particles were formed at the plasma membrane. Conclusion Our study indicates that HIV particles are budded at the plasma membrane upon reactivation from latency, a morphology that is similar to particle budding in acute

  17. LPS ameliorates renal ischemia/reperfusion injury via Hsp27 up-regulation.

    Science.gov (United States)

    He, Kang; Xia, Lei; Zhang, Jianjun

    2018-03-01

    We have recently reported lipopolysaccharide (LPS) pretreatment attenuated renal ischemia/reperfusion injury (IRI), but the exact mechanism remains to be well elucidated. It was reported that heat shock protein (Hsp) 27 was up-regulated after administration of LPS, but whether a direct link existed between Hsp27 up-regulation and LPS-induced protection against renal IRI is still unknown. Mice were exposed to IRI or sham procedure, with pretreatment of LPS or not. Quercetin, an inhibitor of Hsp27 synthesis, was used, and an RNA interference with adenovirus vector using short hairpin RNA targeting Hsp27 was developed for inhibition of Hsp27 in mice. In addition, mice trans-infected with adenovirus vector encoding Hsp27 were used to testify the role of Hsp27 overexpression in LPS-induced renoprotection. Renal function, histological damage, inflammatory reaction, oxidative stress and apoptosis indices were measured. Western blot analysis was used to detect expression of Hsp27. We found LPS pretreatment stimulated renal up-regulation of Hsp27 and reduced renal IRI proven by less renal dysfunction, histological damage, inflammatory reaction, oxidative stress and apoptosis. It was observed that inhibition of Hsp27 synthesis by Quercetin abolished LPS-induced renoprotective effects. After renal knockdown of Hsp27, LPS-induced tolerance against renal IRI was largely removed. Mice with Hsp27 overexpression showed significantly improved renal function after IRI and LPS combined with Hsp27 overexpression had a synergistic effect on protection against renal IRI. Administration of LPS produces protective effects against renal IRI via Hsp27 up-regulation. Preconditional Hsp27 up-regulation might have a great potential for the treatment of renal IRI via ameliorating apoptosis.

  18. Voluntary upregulation of reflex cough is possible in healthy older adults and Parkinson's disease.

    Science.gov (United States)

    Brandimore, Alexandra E; Hegland, Karen W; Okun, Michael S; Davenport, Paul W; Troche, Michelle S

    2017-07-01

    Cough is an airway-protective mechanism that serves to detect and forcefully eject aspirate material. Existing research has identified the ability of healthy young adults to suppress or modify cough motor output based on external cueing. However, no study has evaluated the ability of people with Parkinson's disease (PD) and healthy older adults (HOAs) to upregulate cough motor output. The goal of this study was to evaluate the ability of people with PD and healthy age-matched controls (HOAs) to upregulate reflex and voluntary cough function volitionally with verbal instruction and visual biofeedback of airflow targets. Sixteen participants with PD and twenty-eight HOAs (56-83 yr old) were recruited for this study. Experimental procedures used spirometry to evaluate 1 ) baseline reflex cough (evoked with capsaicin) and voluntary sequential cough and 2 ) reflex and voluntary cough with upregulation biofeedback. Cough airflow was recorded and repeated-measures ANOVA was used to analyze differences in cough airflow parameters. Cough peak expiratory airflow rate and cough expired volume were significantly greater in the cueing condition for both induced reflex ( P cough ( P cough motor output volitionally. These results support the development of studies targeting improved cough effectiveness in patients with airway-protective deficits. NEW & NOTEWORTHY Aspiration pneumonia is a leading cause of death in Parkinson's disease (PD) and results from concurrent dysphagia and dystussia (cough dysfunction). This is the first study to demonstrate that people with PD and healthy age-matched controls can volitionally upregulate induced reflex and voluntary cough effectiveness when presented with novel cueing strategies. Thus targeting upregulation of cough effectiveness via biofeedback may be a viable way to enhance airway protection in people with PD. Copyright © 2017 the American Physiological Society.

  19. Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120

    Science.gov (United States)

    Ballester, Leomar Y.; Capó-Vélez, Coral M.; García-Beltrán, Wilfredo F.; Ramos, Félix M.; Vázquez-Rosa, Edwin; Ríos, Raymond; Mercado, José R.; Meléndez, Roberto I.; Lasalde-Dominicci, José A.

    2012-01-01

    Approximately 30–50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV+ individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120IIIB on the expression and function of the nicotinic receptor α7 (α7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of α7-nAChRs. Because α7-nAChRs have a high permeability to Ca2+, we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist α-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the α7-nAChR in gp120-transgenic mice brains. Specifically, α7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV+ patients. In summary, CXCR4 activation induces up-regulation of α7-nAChR, causing cell death, suggesting that α7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection. PMID:22084248

  20. Mitogen-Activated Protein Kinases Mediate Upregulation of Hypothalamic AT1 Receptors in Heart Failure Rats

    Science.gov (United States)

    Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua; Weiss, Robert M.; Felder, Robert B.

    2009-01-01

    In heart failure (HF), angiotensin type-1 receptor (AT1-R) expression is upregulated in brain regions regulating sympathetic drive, blood pressure and body fluid homeostasis. However, the mechanism by which brain AT1-R are upregulated in HF remains unknown. The present study examined the hypothesis that the angiotensin II (ANG II)-triggered mitogen-activated protein kinases (MAPK) p44/42, p38 and c-Jun N-terminal kinase (JNK) contribute to upregulation of the AT1-R in the hypothalamus of rats with HF. AT1-R protein, AT1-R mRNA and AT1-R immunoreactivity increased in the paraventricular nucleus of hypothalamus (PVN) and the subfornical organ (SFO) of rats with ischemia-induced HF, compared with sham-operated controls. Phosphorylated p44/42 MAPK, JNK, and p38 MAPK also increased in PVN and SFO. A 4-week intracerebroventricular (ICV) infusion of the AT1-R antagonist losartan decreased AT1-R protein and phosphorylation of p44/42 MAPK, JNK and p38 MAPK in the HF rats. A 4-week ICV infusion of the p44/42 MAPK inhibitor PD98059 or the JNK inhibitor SP600125 significantly decreased AT1-R protein and AT1-R immunoreactivity in the PVN and SFO, but the p38 MAPK inhibitor SB203580 did not. Treatment with ICV losartan, PD98059 and SP600125 had no effect on AT1-R expression by Western blot in sham-operated rats. In untreated HF rats 4 weeks after coronary ligation, a 3-hour ICV infusion of PD98059, SP600125 or losartan reduced AT1-R mRNA in PVN and SFO. These data indicate that MAPK plays an important role in the upregulation of AT1-R in the rat forebrain in heart failure, and suggest that ANG II upregulates its own receptor by this mechanism. PMID:18768402

  1. Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries.

    Directory of Open Access Journals (Sweden)

    Hilda Ahnstedt

    Full Text Available BACKGROUND AND PURPOSE: Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation. EXPERIMENTAL APPROACH: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B, angiotensin II type 1 (AT1 and endothelin-1 type A and B (ETA and ETB receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression. KEY RESULTS: Vascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture. CONCLUSIONS AND IMPLICATIONS: In spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries.

  2. Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats

    NARCIS (Netherlands)

    Hempenius, R.A.; Lina, B.A.R.; Haggitt, R.C.

    2000-01-01

    Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm,

  3. The effect of the training program on the quality of life in patients with asthma based on the Precede model in Ahvaz, Iran.

    Science.gov (United States)

    Nejad, Mina Motaghi; Nejad, Ghodratollah Shakeri; Tavakol, Heshmatollah; Cheraghi, Maria

    2017-06-01

    The aim of the study was to determine the effect of the training program based on the Precede model and its main components on improving the quality of life in patients with asthma. It was a randomized quasi-experimental study done on 120 patients with asthma who were referred to the Imam Khomeini hospital in Ahvaz who were selected using the convenience sampling method and were randomly divided into intervention and control groups. The data collection tool consisted of two questionnaires. The first questionnaire evaluated the quality of life in patients with asthma and the other one was developed by the researcher based on the structures of the Precede model. Training intervention was conducted during four sessions twice a week and each session was carried out for an hour based on the structures of the Precede model. In order to achieve the results, SPSS software, even t -test, and χ 2 were used. The results showed that after the training intervention in the experimental group, the mean scores of predisposing factors ( p quality of life in two groups after the intervention ( p quality of life of patients in the experimental group was improved after the training intervention. The design and implementation of the training program based on the Precede model can have a positive effect on the improvement of quality of life in patients with asthma.

  4. Time precedence in the relationship between organizational climate and organizational performance: a cross-lagged study at the business unit level

    NARCIS (Netherlands)

    Voorde, F.C. van de; Veldhoven, M.J.P.M. van; Paauwe, J.

    2010-01-01

    This article presents a two-wave cross-lagged study (average interval of two years) on time precedence in the relationship between organizational climate and organizational performance in 171 branches of a financial services organization in the Netherlands. It is argued that four HR-induced

  5. Spatial and Temporal Characteristics of the Microseismicity Preceding the 2016 M L 6.6 Meinong Earthquake in Southern Taiwan

    Science.gov (United States)

    Pu, Hsin-Chieh

    2018-02-01

    Before the M L 6.6 Meinong earthquake in 2016, intermediate-term quiescence (Q i), foreshocks, and short-term quiescence (Q s) were extracted from a comprehensive earthquake catalog. In practice, these behaviors are thought to be the seismic indicators of an earthquake precursor, and their spatiotemporal characteristics may be associated with location, magnitude, and occurrence time of the following main shock. Hence, detailed examinations were carried out to derive the spatiotemporal characteristics of these meaningful seismic behaviors. First, the spatial range of the Q i that occurred for 96 days was revealed in and around the Meinong earthquake. Second, a series of foreshocks was present for 1 day, clustered at the southeastern end of the Meinong earthquake. Third, Q s was present for 3 days and was pronounced after the foreshocks. Although these behaviors were recorded difficultly because the Q i was characterized by microseismicity at the lower cut-off magnitude, between M L 1.2 and 1.6, and most of the foreshocks were comprised of earthquakes with a magnitude lower than 1.8, they carried meaningful precursory indicators preceding the Meinong earthquake. These indicators provide the information of (1) the hypocenter, which was indicated by the area including the Q i, foreshocks, and Q s; (2) the magnitude, which could be associated to the spatial range of the Q i; (3) the asperity locations, which might be related to the areas of extraordinary low seismicity; and (4) a short-term warning leading of 3 days, which could have been announced based on the occurrence of the Q s. Particularly, Q i also appeared before strong inland earthquakes so that Q i might be an anticipative phenomenon before a strong earthquake in Taiwan.

  6. The role of information technology in translating educational interventions into practice: an analysis using the PRECEDE/PROCEED model.

    Science.gov (United States)

    Weir, Charlene; McLeskey, Nanci; Brunker, Cherie; Brooks, Denise; Supiano, Mark A

    2011-01-01

    The evidence base for information technology (IT) has been criticized, especially with the current emphasis on translational science. The purpose of this paper is to present an analysis of the role of IT in the implementation of a geriatric education and quality improvement (QI) intervention. A mixed-method three-group comparative design was used. The PRECEDE/PROCEED implementation model was used to qualitatively identify key factors in the implementation process. These results were further explored in a quantitative analysis. Thirty-three primary care clinics at three institutions (Intermountain Healthcare, VA Salt Lake City Health Care System, and University of Utah) participated. The program consisted of an onsite, didactic session, QI planning and 6 months of intense implementation support. Completion rate was 82% with an average improvement rate of 21%. Important predisposing factors for success included an established electronic record and a culture of quality. The reinforcing and enabling factors included free continuing medical education credits, feedback, IT access, and flexible support. The relationship between IT and QI emerged as a central factor. Quantitative analysis found significant differences between institutions for pre-post changes even after the number and category of implementation strategies had been controlled for. The analysis illustrates the complex dependence between IT interventions, institutional characteristics, and implementation practices. Access to IT tools and data by individual clinicians may be a key factor for the success of QI projects. Institutions vary widely in the degree of access to IT tools and support. This article suggests that more attention be paid to the QI and IT department relationship.

  7. Structural brain alterations associated with schizophrenia preceded by conduct disorder: a common and distinct subtype of schizophrenia?

    Science.gov (United States)

    Schiffer, Boris; Leygraf, Norbert; Müller, Bernhard W; Scherbaum, Norbert; Forsting, Michael; Wiltfang, Jens; Gizewski, Elke R; Hodgins, Sheilagh

    2013-09-01

    Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ-CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ-CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ-CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.

  8. The effect of preceding wintertime Arctic polar vortex on springtime NDVI patterns in boreal Eurasia, 1982-2015

    Science.gov (United States)

    Li, Jing; Fan, Ke; Xu, Jianjun; Powell, Alfred M.; Kogan, Felix

    2017-07-01

    The polar vortex is implicated in certain cold events in boreal Eurasia and has a further influence on land surface properties (e.g., vegetation and snow) during spring. The Normalized Difference Vegetation Index (NDVI) can be used as a proxy of land surface responses to climate changes to a certain degree. In this study, we demonstrate the significant correlation between preceding wintertime Arctic polar vortex intensity (WAPVI) and springtime NDVI (SNDVI) over a 34-year period (1982-2015) in boreal Eurasia (50°-75°N, 0°-150°E). Results show that a positive phase of WAPVI tends to increase the SNDVI in Europe and Lake Baikal, but causes a significant decrease in Siberia; the physical mechanisms involved in this relationship are then investigated. A positive phase of WAPVI leads to anomalies in surface air temperature and rainfall over Eurasia, which then induces a significant decrease in snow cover and snow depth in Europe and Lake Baikal and an increase of snow depth in Siberia. The colder ground temperature in Siberia during spring is considered responsible for the stronger snow depth and weaker vegetation growth in this region. The weaker and thinner snow cover in Europe and Baikal produces a decrease in albedo and an increase in heat. Thin snow melts fast in the following spring and land releases more heat to the atmosphere; consequently, warm and moist land surface facilitates vegetation growth in Europe and the Baikal regions during positive WAPVI years. In addition, WAPVI can induce sea surface temperature (SST) anomalies in the North Atlantic, which displays a tripole pattern similar to that of the empirical mode pattern in winter. Furthermore, the SST anomalous pattern persisting from winter to spring can trigger a stationary wave-train propagating from west to east in boreal Eurasia, with "negative-positive-negative-positive" geopotential height anomalies, which further exerts an impact on vegetation growth through modulation of the heat balance.

  9. Integration of sensory information precedes the sensation of vection: a combined behavioral and event-related brain potential (ERP) study.

    Science.gov (United States)

    Keshavarz, Behrang; Berti, Stefan

    2014-02-01

    Illusory self-motion (known as vection) describes the sensation of ego-motion in the absence of physical movement. Vection typically occurs in stationary observers being exposed to visual information that suggest self-motion (e.g. simulators, virtual reality). In the present study, we tested whether sensory integration of visual information triggers vection: participants (N=13) perceived patterns of moving altered black-and-white vertical stripes on a screen that was divided into a central and a surrounding peripheral visual field. In both fields the pattern was either moving or stationary, resulting in four combinations of central and peripheral motions: (1) central and peripheral stripes moved into the same direction, (2) central and peripheral stripes moved in opposite directions, or (3) either the central or (4) the peripheral stripes were stable while the other stripes were in motion. This stimulation induced vection: Results showed significantly higher vection ratings when the stationary center of the pattern was surrounded by a moving periphery. Event-related potentials mirrored this finding: The occipital N2 was largest with stationary central and moving peripheral stripes. Our findings suggest that sensory integration of peripheral and central visual information triggers the perception of vection. Furthermore, we found evidence that neural processes precede the subjective perception of vection strength prior to the actual onset of vection. We will discuss our findings with respect to the role of stimulus eccentricity, stimulus' depth, and neural correlates involved during the genesis of vection. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Informed Consent as a Litigation Strategy in the Field of Aesthetic Surgery: An Analysis Based on Court Precedents.

    Science.gov (United States)

    Park, Bo Young; Kwon, Jungwoo; Kang, So Ra; Hong, Seung Eun

    2016-09-01

    In an increasing number of lawsuits doctors lose, despite providing preoperative patient education, because of failure to prove informed consent. We analyzed judicial precedents associated with insufficient informed consent to identify judicial factors and trends related to aesthetic surgery medical litigation. We collected data from civil trials between 1995 and 2015 that were related to aesthetic surgery and resulted in findings of insufficient informed consent. Based on these data, we analyzed the lawsuits, including the distribution of surgeries, dissatisfactions, litigation expenses, and relationship to informed consent. Cases were found involving the following types of surgery: facial rejuvenation (38 cases), facial contouring surgery (27 cases), mammoplasty (16 cases), blepharoplasty (29 cases), rhinoplasty (21 cases), body-contouring surgery (15 cases), and breast reconstruction (2 cases). Common reasons for postoperative dissatisfaction were deformities (22%), scars (17%), asymmetry (14%), and infections (6%). Most of the malpractice lawsuits occurred in Seoul (population 10 million people; 54% of total plastic surgeons) and in primary-level local clinics (113 cases, 82.5%). In cases in which only invalid informed consent was recognized, the average amount of consolation money was KRW 9,107,143 (USD 8438). In cases in which both violation of non-malfeasance and invalid informed consent were recognized, the average amount of consolation money was KRW 12,741,857 (USD 11,806), corresponding to 38.6% of the amount of the judgment. Surgeons should pay special attention to obtaining informed consent, because it is a double-edged sword; it has clinical purposes for doctors and patients but may also be a litigation strategy for lawyers.

  11. Informed Consent as a Litigation Strategy in the Field of Aesthetic Surgery: An Analysis Based on Court Precedents

    Directory of Open Access Journals (Sweden)

    Bo Young Park

    2016-09-01

    Full Text Available BackgroundIn an increasing number of lawsuits doctors lose, despite providing preoperative patient education, because of failure to prove informed consent. We analyzed judicial precedents associated with insufficient informed consent to identify judicial factors and trends related to aesthetic surgery medical litigation.MethodsWe collected data from civil trials between 1995 and 2015 that were related to aesthetic surgery and resulted in findings of insufficient informed consent. Based on these data, we analyzed the lawsuits, including the distribution of surgeries, dissatisfactions, litigation expenses, and relationship to informed consent.ResultsCases were found involving the following types of surgery: facial rejuvenation (38 cases, facial contouring surgery (27 cases, mammoplasty (16 cases, blepharoplasty (29 cases, rhinoplasty (21 cases, body-contouring surgery (15 cases, and breast reconstruction (2 cases. Common reasons for postoperative dissatisfaction were deformities (22%, scars (17%, asymmetry (14%, and infections (6%. Most of the malpractice lawsuits occurred in Seoul (population 10 million people; 54% of total plastic surgeons and in primary-level local clinics (113 cases, 82.5%. In cases in which only invalid informed consent was recognized, the average amount of consolation money was KRW 9,107,143 (USD 8438. In cases in which both violation of non-malfeasance and invalid informed consent were recognized, the average amount of consolation money was KRW 12,741,857 (USD 11,806, corresponding to 38.6% of the amount of the judgment.ConclusionsSurgeons should pay special attention to obtaining informed consent, because it is a double-edged sword; it has clinical purposes for doctors and patients but may also be a litigation strategy for lawyers.

  12. Static osteogenesis does not precede dynamic osteogenesis in periosteal ossification of Pleurodeles (Caudata, Amphibia) and Pogona (Squamata, Lepidosauria).

    Science.gov (United States)

    Cubo, Jorge; Hui, Mylaine; Clarac, François; Quilhac, Alexandra

    2017-05-01

    Two successive mechanisms have been described in perichondral ossification: (1) in static osteogenesis, mesenchymal cells differentiate into stationary osteoblasts oriented randomly, which differentiate into osteocytes in the same site; (2) in dynamic osteogenesis, mesenchymal cells differentiate into osteoblasts that are all oriented in the same direction and move back as they secrete collagen fibers. This study is aimed at testing the hypothesis that the ontogenetic sequence static then dynamic osteogenesis observed in the chicken and in the rabbit is homologous and was acquired by the last common ancestor of amniotes or at a more inclusive node. For this we analyze the developmental patterns of Pleurodeles (Caudata, Amphibia) and those of the lizard Pogona (Squamata, Lepidosauria). We processed Pleurodeles larvae and Pogona embryos, prepared thin and ultrathin sections of appendicular bones, and analyzed them using light and transmission electron microscopy. We show that static osteogenesis does not precede dynamic osteogenesis in periosteal ossification of Pleurodeles and Pogona. Therefore, the null hypothesis is rejected and according to the parsimony method the ontogenetic sequence observed in the chicken and in the rabbit are convergent. In Pleurodeles and Pogona dynamic osteogenesis occur without a previous rigid mineralized framework, whereas in the chicken and in the rabbit dynamic osteogenesis seems to take place over a mineralized support whether bone (in perichondral ossification) or calcified cartilage (in endochondral ossification). Interestingly, in typical dynamic osteogenesis, osteoblasts show an axis (basal nucleus-distal endoplasmic reticulum) perpendicular to the front of secreted unmineralized bone matrix, whereas in Pleurodeles and Pogona this axis is parallel to the bone matrix. © 2017 Wiley Periodicals, Inc.

  13. Adolescent idiopathic scoliosis screening for school, community, and clinical health promotion practice utilizing the PRECEDE-PROCEED model

    Directory of Open Access Journals (Sweden)

    Wyatt Lawrence A

    2005-11-01

    Full Text Available Abstract Background Screening for adolescent idiopathic scoliosis (AIS is a commonly performed procedure for school children during the high risk years. The PRECEDE-PROCEDE (PP model is a health promotion planning model that has not been utilized for the clinical diagnosis of AIS. The purpose of this research is to study AIS in the school age population using the PP model and its relevance for community, school, and clinical health promotion. Methods MEDLINE was utilized to locate AIS data. Studies were screened for relevance and applicability under the auspices of the PP model. Where data was unavailable, expert opinion was utilized based on consensus. Results The social assessment of quality of life is limited with few studies approaching the long-term effects of AIS. Epidemiologically, AIS is the most common form of scoliosis and leading orthopedic problem in children. Behavioral/environmental studies focus on discovering etiologic relationships yet this data is confounded because AIS is not a behavioral. Illness and parenting health behaviors can be appreciated. The educational diagnosis is confounded because AIS is an orthopedic disorder and not behavioral. The administration/policy diagnosis is hindered in that scoliosis screening programs are not considered cost-effective. Policies are determined in some schools because 26 states mandate school scoliosis screening. There exists potential error with the Adam's test. The most widely used measure in the PP model, the Health Belief Model, has not been utilized in any AIS research. Conclusion The PP model is a useful tool for a comprehensive study of a particular health concern. This research showed where gaps in AIS research exist suggesting that there may be problems to the implementation of school screening. Until research disparities are filled, implementation of AIS screening by school, community, and clinical health promotion will be compromised. Lack of data and perceived importance by

  14. Identification of Characteristic Motor Patterns Preceding Freezing of Gait in Parkinson’s Disease Using Wearable Sensors

    Directory of Open Access Journals (Sweden)

    Luca Palmerini

    2017-08-01

    Full Text Available Freezing of gait (FOG is a disabling symptom that is common among patients with advanced Parkinson’s disease (PD. External cues such as rhythmic auditory stimulation can help PD patients experiencing freezing to resume walking. Wearable systems for automatic freezing detection have been recently developed. However, these systems detect a FOG episode after it has happened. Instead, in this study, a new approach for the prediction of FOG (before it actually happens is presented. Prediction of FOG might enable preventive cueing, reducing the likelihood that FOG will occur. Moreover, understanding the causes and circumstances of FOG is still an open research problem. Hence, a quantitative characterization of movement patterns just before FOG (the pre-FOG phase is of great importance. In this study, wearable inertial sensors were used to identify and quantify the characteristics of gait during the pre-FOG phase and compare them with the characteristics of gait that do not precede FOG. The hypothesis of this study is based on the threshold-based model of FOG, which suggests that before FOG occurs, there is a degradation of the gait pattern. Eleven PD subjects were analyzed. Six features extracted from movement signals recorded by inertial sensors showed significant differences between gait and pre-FOG. A classification algorithm was developed in order to test if it is feasible to predict FOG (i.e., detect it before it happens. The aim of the classification procedure was to identify the pre-FOG phase. Results confirm that there is a degradation of gait occurring before freezing. Results also provide preliminary evidence on the feasibility of creating an automatic algorithm to predict FOG. Although some limitations are present, this study shows promising findings for characterizing and identifying pre-FOG patterns, another step toward a better understanding, prediction, and prevention of this disabling symptom.

  15. Invasion Precedes Tumor Mass Formation in a Malignant Brain Tumor Model of Genetically Modified Neural Stem Cells

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    Oltea Sampetrean

    2011-09-01

    Full Text Available Invasiveness, cellular atypia, and proliferation are hallmarks of malignant gliomas. To effectively target each of these characteristics, it is important to understand their sequence during tumorigenesis. However, because most gliomas are diagnosed at an advanced stage, the chronology of gliomagenesis milestones is not well understood. The aim of the present study was to determine the onset of these characteristics during tumor development. Brain tumor-initiating cells (BTICs were established by overexpressing H-RasV12 in normal neural stem/progenitor cells isolated from the subventricular zone of adult mice harboring a homozygous deletion of the Ink4a/Arf locus. High-grade malignant brain tumors were then created by orthotopic implantation of 105 BTICs into the forebrain of 6-week-old wild-type mice. Micewere killed every week for 5 weeks, and tumors were assessed for cellular atypia, proliferation, hemorrhage, necrosis, and invasion. All mice developed highly invasive, hypervascular glioblastoma-like tumors. A 100% penetrance rate and a 4-week median survival were achieved. Tumor cell migration along fiber tracts started within days after implantation and was followed by perivascular infiltration of tumor cells with marked recruitment of reactive host cells. Next, cellular atypia became prominent. Finally, mass proliferation and necrosis were observed in the last stage of the disease. Video monitoring of BTICs in live brain slices confirmed the early onset of migration, as well as the main cell migration patterns. Our results showed that perivascular and intraparenchymal tumor cell migration precede tumor mass formation in the adult brain, suggesting the need for an early and sustained anti-invasion therapy.

  16. Myoclonic epilepsy in infancy with preceding or concurrent afebrile generalized tonic-clonic seizures in Chinese children.

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    Yang, Zhixian; Li, Hui; Xue, Jiao; Qian, Ping; Liu, Xiaoyan; Zhang, Yuehua

    2017-11-01

    To investigate the general characteristics and the category of myoclonic epilepsy in infancy (MEI) with or without afebrile generalized tonic-clonic seizures (GTCS). Thirty-three children were retrospectively recruited from approximately 42,814 video-electroencephalogram (VEEG) recordings monitored in our department over last nearly 10years. Myoclonic seizures (MS) must be identified by VEEG in all patients. The clinical, EEG features and outcome were analyzed among these patients. The 33 patients (25 boys and 8 girls) were divided into three groups: 11 patients with typical MEI; 16 patients with MEI experienced afebrile GTCS before MS onset; and 6 patients with MEI presented afebrile GTCS occurring concurrently with MS. No significant differences were found among the three groups, including gender distribution, family history, personal history of febrile seizures, the age at seizure onset and control, the duration of MS, the interval between age at onset and seizure control, the age at EEG normalization, the interval between seizure onset age and EEG normalization age and normal psychomotor development at the end of follow-up. More patients in group two and group three were controlled by two or three kinds of antiepileptic drugs compared with those in group one. In this study, three groups of patients had similar clinical, EEG features and outcome. Afebrile GTCS was associated with a stronger cortical hyperexcitability. It was worth considering whether MEI with preceding or concurrent afebrile GTCS should be recognized as subgroups or different epileptic syndromes independent of MEI. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  17. Isoform-Specific Na,K-ATPase Alterations Precede Disuse-Induced Atrophy of Rat Soleus Muscle

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    Violetta V. Kravtsova

    2015-01-01

    Full Text Available This study examines the isoform-specific effects of short-term hindlimb suspension (HS on the Na,K-ATPase in rat soleus muscle. Rats were exposed to 24–72 h of HS and we analyzed the consequences on soleus muscle mass and contractile parameters; excitability and the resting membrane potential (RMP of muscle fibers; the electrogenic activity, protein, and mRNA content of the α1 and α2 Na,K-ATPase; the functional activity and plasma membrane localization of the α2 Na,K-ATPase. Our results indicate that 24–72 h of HS specifically decreases the electrogenic activity of the Na,K-ATPase α2 isozyme and the RMP of soleus muscle fibers. This decrease occurs prior to muscle atrophy or any change in contractile parameters. The α2 mRNA and protein content increased after 24 h of HS and returned to initial levels at 72 h; however, even the increased content was not able to restore α2 enzyme activity in the disused soleus muscle. There was no change in the membrane localization of α2 Na,K-ATPase. The α1 Na,K-ATPase electrogenic activity, protein and mRNA content did not change. Our findings suggest that skeletal muscle use is absolutely required for α2 Na,K-ATPase transport activity and provide the first evidence that Na,K-ATPase alterations precede HS-induced muscle atrophy.

  18. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.

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    Norden, Diana M; Trojanowski, Paige J; Villanueva, Emmanuel; Navarro, Elisa; Godbout, Jonathan P

    2016-02-01

    Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge. © 2015 Wiley Periodicals, Inc.

  19. Discovering the impact of preceding units' characteristics on the wait time of cardiac surgery unit from statistic data.

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    Jiming Liu

    Full Text Available INTRODUCTION: Prior research shows that clinical demand and supplier capacity significantly affect the throughput and the wait time within an isolated unit. However, it is doubtful whether characteristics (i.e., demand, capacity, throughput, and wait time of one unit would affect the wait time of subsequent units on the patient flow process. Focusing on cardiac care, this paper aims to examine the impact of characteristics of the catheterization unit (CU on the wait time of cardiac surgery unit (SU. METHODS: This study integrates published data from several sources on characteristics of the CU and SU units in 11 hospitals in Ontario, Canada between 2005 and 2008. It proposes a two-layer wait time model (with each layer representing one unit to examine the impact of CU's characteristics on the wait time of SU and test the hypotheses using the Partial Least Squares-based Structural Equation Modeling analysis tool. RESULTS: Results show that: (i wait time of CU has a direct positive impact on wait time of SU (β = 0.330, p < 0.01; (ii capacity of CU has a direct positive impact on demand of SU (β = 0.644, p < 0.01; (iii within each unit, there exist significant relationships among different characteristics (except for the effect of throughput on wait time in SU. CONCLUSION: Characteristics of CU have direct and indirect impacts on wait time of SU. Specifically, demand and wait time of preceding unit are good predictors for wait time of subsequent units. This suggests that considering such cross-unit effects is necessary when alleviating wait time in a health care system. Further, different patient risk profiles may affect wait time in different ways (e.g., positive or negative effects within SU. This implies that the wait time management should carefully consider the relationship between priority triage and risk stratification, especially for cardiac surgery.

  20. CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller

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    Burwitz Benjamin J

    2012-11-01

    Full Text Available Abstract Background Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. Results Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. Conclusions Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

  1. Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules.

    Science.gov (United States)

    Glasner, Ariella; Oiknine-Djian, Esther; Weisblum, Yiska; Diab, Mohammad; Panet, Amos; Wolf, Dana G; Mandelboim, Ofer

    2017-11-15

    NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus

  2. Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor.

    Science.gov (United States)

    Mori, Seiichiro; Takeuchi, Takamasa; Ishii, Yoshiyuki; Yugawa, Takashi; Kiyono, Tohru; Nishina, Hiroshi; Kukimoto, Iwao

    2017-03-15

    The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis. IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1

  3. Induction of IL-17A precedes development of airway hyperresponsiveness during diet induced obesity and correlates with complement factor D

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    Joel A. Mathews, Phd

    2014-09-01

    Full Text Available Obesity is a risk factor for the development of asthma. Obese mice exhibit innate airway hyperresponsiveness (AHR, a characteristic feature of asthma, and IL-17A is required for development of AHR in obese mice. The purpose of this study was to examine the temporal association between the onset of AHR and changes in IL-17A during the development of obesity by high fat feeding in mice. At weaning, C57BL/6J mice were placed either on mouse chow or on a high fat diet (HFD and examined 9, 12, 15, 18, or 24 weeks later. Airway responsiveness to aerosolized methacholine (assessed via the forced oscillation technique was greater in mice fed HFD versus chow for 24 weeks, but not at earlier time points. Bronchoalveolar lavage and serum IL-17A were not affected by either the type or duration of diet, but increased pulmonary IL17a mRNA abundance was observed in HFD versus chow fed mice after both 18 and 24 weeks. Flow cytometry also confirmed an increase in IL-17A+ gd T cells and IL-17A+ CD4+ T (Th17 cells in lungs of HFD versus chow fed mice. Pulmonary expression of Cfd (complement factor D, adipsin, a gene whose expression can be reduced by IL-17A, decreased after both 18 and 24 weeks in HFD versus chow fed mice. Furthermore, pulmonary Cfd mRNA abundance correlated with elevations in pulmonary Il17a mRNA expression and with AHR. Serum levels of TNFa, MIP-1a and MIP-1b, classical markers of systemic inflammation of obesity, were significantly greater in HFD than chow fed mice after 24 weeks, but not earlier. In conclusion, our data indicate that pulmonary rather than systemic IL-17A is important for obesity-related AHR and suggest that changes in pulmonary Cfd expression contribute to these effects of IL-17A. Further, the observation that increases in Il17a preceded the development of AHR by several weeks suggests that IL-17A interacts with other factors to promote AHR. The observation that the onset of the systemic inflammation of obesity coincided

  4. Intestinal Metagenomes and Metabolomes in Healthy Young Males: Inactivity and Hypoxia Generated Negative Physiological Symptoms Precede Microbial Dysbiosis

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    Robert Šket

    2018-03-01

    Full Text Available We explored the metagenomic, metabolomic and trace metal makeup of intestinal microbiota and environment in healthy male participants during the run-in (5 day and the following three 21-day interventions: normoxic bedrest (NBR, hypoxic bedrest (HBR and hypoxic ambulation (HAmb which were carried out within a controlled laboratory environment (circadian rhythm, fluid and dietary intakes, microbial bioburden, oxygen level, exercise. The fraction of inspired O2 (FiO2 and partial pressure of inspired O2 (PiO2 were 0.209 and 133.1 ± 0.3 mmHg for the NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (~4,000 m simulated altitude for HBR and HAmb interventions, respectively. Shotgun metagenomes were analyzed at various taxonomic and functional levels, 1H- and 13C -metabolomes were processed using standard quantitative and human expert approaches, whereas metals were assessed using X-ray fluorescence spectrometry. Inactivity and hypoxia resulted in a significant increase in the genus Bacteroides in HBR, in genes coding for proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence, defense and mucin degradation, such as beta-galactosidase (EC3.2.1.23, α-L-fucosidase (EC3.2.1.51, Sialidase (EC3.2.1.18, and α-N-acetylglucosaminidase (EC3.2.1.50. In contrast, the microbial metabolomes, intestinal element and metal profiles, the diversity of bacterial, archaeal and fungal microbial communities were not significantly affected. The observed progressive decrease in defecation frequency and concomitant increase in the electrical conductivity (EC preceded or took place in absence of significant changes at the taxonomic, functional gene, metabolome and intestinal metal profile levels. The fact that the genus Bacteroides and proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence and mucin degradation were enriched at the end of HBR suggest that both constipation and EC decreased intestinal metal availability

  5. The use of complementary and alternative medicine products in preceding two days among Finnish parents - a population survey

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    Hämeen-Anttila Katri P

    2011-11-01

    Full Text Available Abstract Background The use of complementary and alternative medicines (CAM has been extensively studied globally among adult and paediatric populations. Parents, as a group, had not been studied to assess their knowledge and attitude to CAM and general medicine use. This study is necessary since parents' attitude to medicine use is known to influence their child's attitude to medicine use later in life. We therefore aim to assess the extent and types of CAM use among Finnish parents, and to determine the factors that promote the CAM use. Also, we aim to determine parents' attitude to general medicine use. Methods Children less than 12 years old, as of spring 2007, were identified from the database of the Finnish Population Register Centre and were selected by random sampling. The parents of these children were identified and a questionnaire was sent to them. Only the parent who regularly takes care of the child's medicine was requested to fill the questionnaire. Cross-tabulations and Chi-square test were used to determine the associations between categorical variables. CAMs were defined as natural products that are not registered as medicines, such as homeopathic preparations, dietary food supplements, and traditional medicinal products. Results The response rate of the survey was 67% (n = 4032. The use of CAM was 31% in the preceding two days. The most commonly used CAM products were vitamins and minerals, followed by fish oils and fatty acids. Prescription and OTC medicines were used concomitantly with CAM by one-third of the parents. CAM was frequently used by parents over 30 years (33%, female parents (32%, highly educated parents (35%, and parents with high monthly net income (3000-3999 euros, 34%. The users of CAM had more negative attitudes towards medicines than non-users of CAM. Conclusions Our findings are in accordance with those of previous studies that women over 30 years of age with a high education and income typically use CAMs

  6. Early cytoskeletal protein modifications precede overt structural degeneration in the DBA/2J mouse model of glaucoma

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    Gina Nicole Wilson

    2016-11-01

    Full Text Available Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma. Using anterograde tract tracing of the retinal projection, we assessed major cytoskeletal and transported elements as a function of transport integrity in different stages of pathological progression. Using capillary-based electrophoresis, single- and multiplex immunosorbent assays, and immunofluorescence, we quantified hyperphosphorylated neurofilament-heavy chain, phosphorylated tau (ptau, calpain-mediated spectrin breakdown product (145/150kDa, β –tubulin, and amyloid-β42 proteins based on age and transport outcome to the superior colliculus (SC, the main retinal target in mice. Phosphorylated neurofilament-heavy chain (pNF-H was elevated within the optic nerve (ON and SC of 8-10 month-old DBA/2J mice, but was not evident in the retina until 12-15 months, suggesting that cytoskeletal modifications first appear in the distal retinal projection. As expected, higher pNF-H levels in the SC and retina were correlated with axonal transport deficits. Elevations in hyperphosphorylated tau (ptau occurred in ON and SC between 3-8 month of age while retinal ptau accumulations occurred at 12-15 months in DBA/2J mice. In vitro co-immunoprecipitation experiments suggested increased affinity of ptau for the retrograde motor complex protein, dynactin. We observed a transport-related decrease of β-tubulin in ON of 10-12 month-old DBA/2J mice, suggesting destabilized microtubule array. Elevations in calpain-mediated spectrin breakdown product were seen in ON and SC at the earliest age examined, well before axonal transport loss is evident. Finally, transport

  7. Acute hypoxia induces upregulation of microRNA-210 expression in glioblastoma spheroids

    DEFF Research Database (Denmark)

    Rosenberg, Tine Agerbo; Thomassen, Mads; Jensen, Stine Skov

    2015-01-01

    AIM: Tumor hypoxia and presence of tumor stem cells are related to therapeutic resistance and tumorigenicity in glioblastomas. The aim of the present study was therefore to identify microRNAs deregulated in acute hypoxia and to identify possible associated changes in stem cell markers. MATERIALS...... & METHODS: Glioblastoma spheroid cultures were grown in either 2 or 21% oxygen. Subsequently, miRNA profiling was performed and expression of ten stem cell markers was examined. RESULTS: MiRNA-210 was significantly upregulated in hypoxia in patient-derived spheroids. The stem cell markers displayed...... a complex regulatory pattern. CONCLUSION: MiRNA-210 appears to be upregulated in hypoxia in immature glioblastoma cells. This miRNA may represent a therapeutic target although it is not clear from the results whether this miRNA may be related to specific cancer stem cell functions....

  8. Auxins Upregulate Expression of the Indole-3-Pyruvate Decarboxylase Gene in Azospirillum brasilense

    Science.gov (United States)

    Vande Broek, Ann; Lambrecht, Mark; Eggermont, Kristel; Vanderleyden, Jos

    1999-01-01

    Transcription of the Azospirillum brasilense ipdC gene, encoding an indole-3-pyruvate decarboxylase involved in the biosynthesis of indole-3-acetic acid (IAA), is induced by IAA as determined by ipdC-gusA expression studies and Northern analysis. Besides IAA, exogenously added synthetic auxins such as 1-naphthaleneacetic acid, 2,4-dichlorophenoxypropionic acid, and p-chlorophenoxyacetic acid were also found to upregulate ipdC expression. No upregulation was observed with tryptophan, acetic acid, or propionic acid or with the IAA conjugates IAA ethyl ester and IAA-l-phenylalanine, indicating structural specificity is required for ipdC induction. This is the first report describing the induction of a bacterial gene by auxin. PMID:9973364

  9. Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia

    International Nuclear Information System (INIS)

    Palumbo, B.; Palumbo, R.; Efthimiou, Y.; Stamatopoulos, J.; Sinzinger, H.; Oguogho, A.; Budinsky, A.; Sinzinger, H.

    2003-01-01

    The hypoglycemic effect of prickly pear is well known by native local Indian population since a long time. Beside the beneficial effects on lipid metabolism, oxidation injury and platelet function has been claimed in experimental animals. We recently found an upregulation of apo-B/E receptor. We therefore examined 10 patients with isolated heterozygous familial hypercholesterolemia (FH) being enrolled in a dietary run-in phase of 6 weeks after dietary counselling and a further 6 weeks of prickly pear addition. Uptake of autologous 123 I-radiolabeled LDL was determined at entry as well as after 6 weeks of daily prickly pear ingestion. We found a significant (p 176.4 mg/dl; p 123 I-LDL binding by prickly pear in FH-patients in vivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation. (author)

  10. Effect of age on upregulation of the cardiac adrenergic beta receptors

    International Nuclear Information System (INIS)

    Tumer, N.; Houck, W.T.; Roberts, J.

    1990-01-01

    Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors

  11. Upregulation of eIF5B controls cell-cycle arrest and specific developmental stages

    OpenAIRE

    Lee, Sooncheol; Truesdell, Samuel S.; Bukhari, Syed I. A.; Lee, Ju Huck; LeTonqueze, Olivier; Vasudevan, Shobha

    2014-01-01

    This study uncovers a critical role for a general translation factor in specific developmental stages, including immature oocytes and ES cells, and during growth-factor deprivation of mammalian cells, which induces the transition to cell-cycle arrest. These conditions alter and decrease general translation yet maintain ongoing translation. We reveal upregulation of the eukaryotic translation factor 5B (eIF5B), which becomes essential for general translation, specifically in these conditions. ...

  12. Equine infectious anemia virus replication is upregulated during differentiation of blood monocytes from acutely infected horses.

    Science.gov (United States)

    Sellon, D C; Walker, K M; Russell, K E; Perry, S T; Covington, P; Fuller, F J

    1996-01-01

    Equine infectious anemia virus is a lentivirus that replicates in mature tissue macrophages of horses. Ponies were infected with equine infectious anemia virus. During febrile episodes, proviral DNA was detectable, but viral mRNA was not detectable. As cultured blood monocytes from these ponies differentiated into macrophages, viral expression was upregulated. In situ hybridization confirmed that viral transcription occurred in mature macrophages. PMID:8523576

  13. Catalase activity prevents exercise-induced up-regulation of vasoprotective proteins in venous tissue.

    Science.gov (United States)

    Dao, Vu Thao-Vi; Floeren, Melanie; Kumpf, Stephanie; Both, Charlotte; Peter, Bärbel; Balz, Vera; Suvorava, Tatsiana; Kojda, Georg

    2011-11-01

    Physical activity induces favourable changes of arterial gene expression and protein activity, although little is known about its effect in venous tissue. Although our understanding of the initiating molecular signals is still incomplete, increased expression of endothelial nitric oxide synthase (eNOS) is considered a key event. This study sought to investigate the effects of two different training protocols on the expression of eNOS and extracellular superoxide dismutase (ecSOD) in venous and lung tissue and to evaluate the underlying molecular mechanisms. C57Bl/6 mice underwent voluntary exercise or forced physical activity. Changes of vascular mRNA and protein levels and activity of eNOS, ecSOD and catalase were determined in aorta, heart, lung and vena cava. Both training protocols similarly increased relative heart weight and resulted in up-regulation of aortic and myocardial eNOS. In striking contrast, eNOS expression in vena cava and lung remained unchanged. Likewise, exercise up-regulated ecSOD in the aorta and in left ventricular tissue but remained unchanged in lung tissue. Catalase expression in lung tissue and vena cava of exercised mice exceeded that in aorta by 6.9- and 10-fold, respectively, suggesting a lack of stimulatory effects of hydrogen peroxide. In accordance, treatment of mice with the catalase inhibitor aminotriazole for 6 weeks resulted in significant up-regulation of eNOS and ecSOD in vena cava. These data suggest that physiological venous catalase activity prevents exercise-induced up-regulation of eNOS and ecSOD. Furthermore, therapeutic inhibition of vascular catalase might improve pulmonary rehabilitation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  14. Fenofibrate suppressed proliferation and migration of human neuroblastoma cells via oxidative stress dependent of TXNIP upregulation

    Energy Technology Data Exchange (ETDEWEB)

    Su, Cunjin; Shi, Aiming; Cao, Guowen [Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Tao, Tao [Department of Urology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009 (China); Chen, Ruidong [Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Hu, Zhanhong; Shen, Zhu; Tao, Hong; Cao, Bin [Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Hu, Duanmin, E-mail: hudmsdfey@sina.com [Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Bao, Junjie, E-mail: baojjsdfey@sina.com [Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 (China)

    2015-05-15

    There are no appropriate drugs for metastatic neuroblastoma (NB), which is the most common extra-cranial solid tumor for childhood. Thioredoxin binding protein (TXNIP), the endogenous inhibitor of ROS elimination, has been identified as a tumor suppressor in various solid tumors. It reported that fenofibrate exerts anti-tumor effects in several human cancer cell lines. However, its detail mechanisms remain unclear. The present study assessed the effects of fenofibrate on NB cells and investigated TXNIP role in its anti-tumor mechanisms. We used MTT assay to detect cells proliferation, starch wound test to investigate cells migration, H{sub 2}DCF-DA to detect intracellular ROS, siRNA to interfere TXNIP and peroxisome proliferator-androgen receptor-alpha (PPAR-α) expression, western blot to determine protein levels, flow cytometry to analyze apoptosis. Fenofibrate suppressed proliferation and migration of NB cells, remarkably increased intracellular ROS, upregulated TXNIP expression, promoted cell apoptosis. Furthermore, inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-α had no influences. Our results indicated the anti-tumor role of fenofibrate on NB cells by exacerbating oxidative stress and inducing apoptosis was dependent on the upregulation of TXNIP. - Highlights: • We found that fenofibrate suppressed proliferation and migration of NB cells. • We found that fenofibrate remarkably increased intracellular ROS, upregulated TXNIP expression, and promoted cell apoptosis. • Inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-α had no influences. • Our results indicated the anti-tumor role of fenofibrate on NB cells was dependent on the upregulation of TXNIP.

  15. Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Shahrabi-Farahani, Shokoufeh; Gallottini, Marina; Martins, Fabiana; Li, Erik; Mudge, Dayna R; Nakayama, Hironao; Hida, Kyoko; Panigrahy, Dipak; D'Amore, Patricia A; Bielenberg, Diane R

    2016-04-01

    Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous cell carcinoma highly express the neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up-regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy

    OpenAIRE

    Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M.

    2009-01-01

    Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible ...

  17. Fenofibrate suppressed proliferation and migration of human neuroblastoma cells via oxidative stress dependent of TXNIP upregulation

    International Nuclear Information System (INIS)

    Su, Cunjin; Shi, Aiming; Cao, Guowen; Tao, Tao; Chen, Ruidong; Hu, Zhanhong; Shen, Zhu; Tao, Hong; Cao, Bin; Hu, Duanmin; Bao, Junjie

    2015-01-01

    There are no appropriate drugs for metastatic neuroblastoma (NB), which is the most common extra-cranial solid tumor for childhood. Thioredoxin binding protein (TXNIP), the endogenous inhibitor of ROS elimination, has been identified as a tumor suppressor in various solid tumors. It reported that fenofibrate exerts anti-tumor effects in several human cancer cell lines. However, its detail mechanisms remain unclear. The present study assessed the effects of fenofibrate on NB cells and investigated TXNIP role in its anti-tumor mechanisms. We used MTT assay to detect cells proliferation, starch wound test to investigate cells migration, H 2 DCF-DA to detect intracellular ROS, siRNA to interfere TXNIP and peroxisome proliferator-androgen receptor-alpha (PPAR-α) expression, western blot to determine protein levels, flow cytometry to analyze apoptosis. Fenofibrate suppressed proliferation and migration of NB cells, remarkably increased intracellular ROS, upregulated TXNIP expression, promoted cell apoptosis. Furthermore, inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-α had no influences. Our results indicated the anti-tumor role of fenofibrate on NB cells by exacerbating oxidative stress and inducing apoptosis was dependent on the upregulation of TXNIP. - Highlights: • We found that fenofibrate suppressed proliferation and migration of NB cells. • We found that fenofibrate remarkably increased intracellular ROS, upregulated TXNIP expression, and promoted cell apoptosis. • Inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-α had no influences. • Our results indicated the anti-tumor role of fenofibrate on NB cells was dependent on the upregulation of TXNIP

  18. Targeting of slug sensitizes anaplastic thyroid carcinoma SW1736 cells to doxorubicin via PUMA upregulation

    OpenAIRE

    Dong, Anbing; Jiao, Xuelong; Chen, Dong; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    Objective: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers and often shows resistance to multimodal therapeutic approaches. It has been shown that the transcriptional repressor Slug inhibits the chemotherapeutic agent-induced apoptosis of cancer cells. We evaluated whether targeting of Slug could augment doxorubicin (DOX)-induced apoptosis of ATC cells. We also determined changes in PUMA (p53-upregulated modulator of apoptosis) expression levels to identify poss...

  19. Appendix 1:Upregulated genes in gene expression profile (P<0.05 ...

    Indian Academy of Sciences (India)

    lazi

    Appendix 1: Upregulated genes in gene expression profile«P2). Probe_s. Gene_Symbol pvalues foldchange. Probe_S. et_ID. Gene_Symbol pvalues foldchange. et_ID. 1370355. 1393751. Scd1. 1.35E-04. 25.77. Loc1009122508.06E-03. 2.55. -at at. 1398250. 1370870. Acot1. 2.43E-02. 12.18. Me1.

  20. Lactobacillus rhamnosus GG supernatant upregulates serotonin transporter expression in intestinal epithelial cells and mice intestinal tissues.

    Science.gov (United States)

    Wang, Y M; Ge, X Z; Wang, W Q; Wang, T; Cao, H L; Wang, B L; Wang, B M

    2015-09-01

    The role that probiotics play in relieving irritable bowel syndrome (IBS) has been demonstrated; however, the mechanism by which IBS is affected remains unclear. In this study, serotonin transporter (SERT) mRNA and serotonin transporter protein (SERT-P) levels in HT-29, Caco-2 cells, and mice intestinal tissues were examined after treatment with Lactobacillus rhamnosus GG supernatant (LGG-s). HT-29 and Caco-2 cells were treated with different concentrations of LGG-s for 12 and 24 h and C57BL/6 mice received supplements of different concentrations for 4 weeks. SERT mRNA and SERT-P levels were detected by real-time PCR and Western blotting. SERT mRNA and SERT-P levels in HT-29 and Caco-2 cells were higher than those in the control 24 h after treatment. Undiluted LGG-s upregulated SERT mRNA levels by 9.4-fold in the first week, which dropped in the second week. The double-diluted LGG-s upregulated SERT mRNA by 2.07-fold in the first week; levels dropped to 1.75-fold within the second week and under base expression levels by the third week, while they again climbed to 1.56-fold in the fourth week. The triple-diluted LGG-s could not upregulate SERT mRNA expression until the end of the fourth week. The SERT-P levels in the double-diluted LGG-s group were higher than that in the control but fluctuated with time. SERT-P levels in the triple-diluted LGG-s were higher than that in the control in the last 2 weeks and increased with time. LGG-s can upregulate SERT mRNA and SERT-P levels in intestinal epithelial cells and mice intestinal tissues. © 2015 John Wiley & Sons Ltd.

  1. Hydroxytyrosyl ethyl ether exhibits stronger intestinal anticarcinogenic potency and effects on transcript profiles compared to hydroxytyrosol.

    Science.gov (United States)

    Pereira-Caro, G; Mateos, R; Traka, M H; Bacon, J R; Bongaerts, R; Sarriá, B; Bravo, L; Kroon, P A

    2013-06-01

    The anticarcinogenic activity of hydroxytyrosyl ethyl ether (HTy-Et) compared to its precursor hydroxytyrosol (HTy) has been studied in human Caco-2 colon adenocarcinoma cells. 451 and 977 genes were differentially expressed in Caco-2 cells exposed to HTy or HTy-Et for 24h, respectively, compared with untreated cells (Parrested the cell cycle by up-regulating p21 and CCNG2 and down-regulating CCNB1 protein expression. HTy and HTy-Et also altered the transcription of specific genes involved in apoptosis, as suggested by the up-regulation of BNIP3, BNIP3L, PDCD4 and ATF3 and the activation of caspase-3. Moreover, these polyphenols up-regulated xenobiotic metabolizing enzymes UGT1A10 and CYP1A1, enhancing carcinogen detoxification. In conclusion, these results highlight that HTy and its derivative HTy-Et modulate molecular mechanisms involved in colon cancer, with HTy-Et being more effective than HTy. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Smilacis Glabrae Rhizoma reduces oxidative stress caused by hyperuricemia via upregulation of catalase.

    Science.gov (United States)

    Hong, Quan; Yu, Shandong; Mei, Yan; Lv, Yang; Chen, Dapeng; Wang, Yuanda; Geng, Wenjia; Wu, Di; Cai, Guangyan; Chen, Xiangmei

    2014-01-01

    Reports have suggested that the traditional Chinese medicine Smilacis Glabrae Rhizoma attenuates hyperuricemia, but its mechanism is unclear. Our previous study demonstrated that uric acid could induce the generation of reactive oxygen species(ROS), which subsequently cause endothelial dysfunction. Therefore, we focused on the oxidative stress process. In this study, we would use LC-MS and bioinformatic analysis to investigate the underlying mechanism. We utilized LC-MS to reveal the differential protein expression in the kidneys of rats in the hyperuricemia group and the Smilacis Glabrae Rhizoma treatment group and then subjected the differentially expressed proteins to bioinformatic analysis. We also determined the serum ROS level of the two groups. According the above results, we built our hypothesis and performed in vitro experiments to validate this hypothesis. We found that catalase was upregulated in the group treated with Smilacis Glabrae Rhizoma, and the level of reactive oxygen species was higher in the hyperuricemia group. Thus, we speculated that Smilacis Glabrae Rhizoma could alleviate oxidative stress by upregulating catalase. In vitro experiments, we found that high concentrations of uric acid reduced catalase expression in endothelial cells, which was alleviated by Smilacis Glabrae Rhizoma and resulted in a reduction of reactive oxygen species. Knockdown of catalase led to an increase in reactive oxygen species. We demonstrated that Smilacis Glabrae Rhizoma could alleviate the oxidative stress caused by hyperuricemia by upregulating catalase expression. This finding could represent a new application for Smilacis Glabrae Rhizoma in the treatment of hyperuricemia. © 2014 S. Karger AG, Basel.

  3. HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

    Science.gov (United States)

    Huang, Qingsong; Niu, Zhiguo; Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

    2017-08-01

    Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

  4. Upregulating Positive Affectivity in the Transdiagnostic Treatment of Emotional Disorders: A Randomized Pilot Study.

    Science.gov (United States)

    González-Robles, Alberto; García-Palacios, Azucena; Baños, Rosa; Quero, Soledad; Botella, Cristina

    2017-10-01

    Transdiagnostic cognitive-behavioral therapy for emotional disorders (ED) has proven to be effective. However, current transdiagnostic treatment protocols address only the regulation of negative affectivity, and they do not include treatment components to more directly target the regulation of positive affectivity. In this study, we propose to evaluate the preliminary efficacy and acceptability of a transdiagnostic treatment protocol for ED that includes, as an innovative feature, a specific treatment component to directly upregulate positive affectivity based on positive psychology interventions. A total of 24 participants were randomized to either a transdiagnostic treatment protocol ( n = 12) or a transdiagnostic treatment protocol with an additional component designed to regulate positive affectivity ( n = 12). Participants completed measures of anxiety, depression, positive and negative affectivity, and quality of life, as well as treatment acceptability at pre- and posttreatment and at the 3-month follow-up. Both interventions led to improvements in all measures at posttreatment, and these outcomes were maintained at the 3-month follow-up, with large effect sizes for all measures. The effect sizes for positive affect were larger in the condition that included the component to upregulate positive affectivity. Attrition rate was low, and both treatment protocols were well accepted by participants. The results obtained in this study indicate the feasibility of testing the treatment protocol in a larger, randomized, controlled trial, and they suggest the potential of including treatment components for directly upregulating positive affectivity in future research on transdiagnostic treatment protocols for ED.

  5. N-Cadherin Upregulation Promotes the Neurogenic Differentiation of Menstrual Blood-Derived Endometrial Stem Cells.

    Science.gov (United States)

    Liu, Yanli; Yang, Fen; Liang, Shengying; Liu, Qing; Fu, Sulei; Wang, Zhenyu; Yang, Ciqing; Lin, Juntang

    2018-01-01

    Peripheral nerve injuries are typically caused by either trauma or medical disorders, and recently, stem cell-based therapies have provided a promising treatment approach. Menstrual blood-derived endometrial stem cells (MenSCs) are considered an ideal therapeutic option for peripheral nerve repair due to a noninvasive collection procedure and their high proliferation rate and immunological tolerance. Here, we successfully isolated MenSCs and examined their biological characteristics including their morphology, multipotency, and immunophenotype. Subsequent in vitro studies demonstrated that MenSCs express high levels of neurotrophic factors, such as NT3, NT4, BDNF, and NGF, and are capable of transdifferentiating into glial-like cells under conventional induction conditions. Moreover, upregulation of N-cadherin (N-cad) mRNA and protein expression was observed after neurogenic differentiation. In vivo studies clearly showed that N-cad knockdown via in utero electroporation perturbed the migration and maturation of mouse neural precursor cells (NPCs). Finally, a further transfection assay also confirmed that N-cad upregulation in MenSCs results in the expression of S100. Collectively, our results confirmed the paracrine effect of MenSCs on neuroprotection as well as their potential for transdifferentiation into glial-like cells and demonstrated that N-cad upregulation promotes the neurogenic differentiation of MenSCs, thereby providing support for transgenic MenSC-based therapy for peripheral nerve injury.

  6. Atomistic mechanism of microRNA translation upregulation via molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Wei Ye

    Full Text Available MicroRNAs are endogenous 23-25 nt RNAs that play important gene-regulatory roles in animals and plants. Recently, miR369-3 was found to upregulate translation of TNFα mRNA in quiescent (G0 mammalian cell lines. Knock down and immunofluorescence experiments suggest that microRNA-protein complexes (with FXR1 and AGO2 are necessary for the translation upregulation. However the molecular mechanism of microRNA translation activation is poorly understood. In this study we constructed the microRNA-mRNA-AGO2-FXR1 quadruple complex by bioinformatics and molecular modeling, followed with all atom molecular dynamics simulations in explicit solvent to investigate the interaction mechanisms for the complex. A combined analysis of experimental and computational data suggests that AGO2-FXR1 complex relocalize microRNA:mRNA duplex to polysomes in G0. The two strands of dsRNA are then separated upon binding of AGO2 and FXR1. Finally, polysomes may improve the translation efficiency of mRNA. The mutation research confirms the stability of microRNA-mRNA-FXR1 and illustrates importance of key residue of Ile304. This possible mechanism can shed more light on the microRNA-dependent upregulation of translation.

  7. Apoptosis inhibitor 5 (API-5; AAC-11; FIF) is upregulated in human carcinomas in vivo.

    Science.gov (United States)

    Koci, Lenka; Chlebova, Katarina; Hyzdalova, Martina; Hofmanova, Jirina; Jira, Miroslav; Kysela, Petr; Kozubik, Alois; Kala, Zdenek; Krejci, Pavel

    2012-04-01

    Apoptosis inhibitor 5 (API-5) is a 55 kDa nuclear protein with potent anti-apoptotic signaling in tumor cells in vitro. In this study, we analyzed the expression of the API-5 protein in vivo in a broad spectrum of human carcinomas, including those of the colon, lung, liver, kidney, pancreas, stomach and esophagus using tumor tissues obtained during tumor resection. The results showed significant upregulation of API-5 expression in biopsies of lung (23%, n=13) and colorectal tumors (33%, n=27) in comparison with biopsies from the adjacent normal tissue. Colon cancer biopsies were used to study the cell populations with an upregulated level of expression of API-5 more closely. Using a magnetic bead-based selection for the epithelial cell marker EpCAM, we purified epithelial cells from the tumor and control tissues and analyzed these cells for API-5 expression by western immunoblotting. We observed that EpCAM-positive tumor cells expressed API-5 in all three colorectal cancer cases tested, in contrast to the control EpCAM-positive and EpCAM-negative cells isolated from the control or tumor tissues. These data suggest that the expression of the API-5 protein is upregulated in tumor epithelial cells and may serve as a prognostic marker in colorectal cancer.

  8. LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Yun-Bo Feng

    2016-01-01

    Full Text Available Objective: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1 in human osteosarcoma cells. Methods: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. Results: Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1, since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. Conclusion: Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.

  9. DCLK1 is up-regulated and associated with metastasis and prognosis in colorectal cancer.

    Science.gov (United States)

    Gao, Tianbo; Wang, Min; Xu, Lingling; Wen, Tao; Liu, Jian; An, Guangyu

    2016-10-01

    Metastasis is a primary cause of colorectal cancer (CRC)-related death, and cancer stem cells (CSCs) are thought to be majorly responsible for initiating metastatic behaviors. Doublecortin-like kinase 1 (DCLK1) was recently discovered to be a marker for gastrointestinal CSCs. Here, we aimed to explore whether DCLK1 is associated with CRC metastasis through clinical and in vitro investigations. The expression levels of DCLK1 mRNA and protein in human CRC tissues were analyzed through quantitative RT-PCR and immunohistochemistry staining, respectively. Human CRC cell line SW480 was selected to explore the effect of DCLK1 overexpression on cell migration and invasion. Besides, the associations between DCLK1 and epithelial-mesenchymal transition (EMT) were determined. Compared to normal colorectal tissues, DCLK1 expression was significantly up-regulated in human CRC tissues and correlated well with high lymphatic metastasis and poor prognosis in patients. DCLK1 expression was inversely associated with overall survival in CRC patients. Overexpression of DCLK1 in SW480 cells markedly promoted cell migration and invasion. Furthermore, we validated that DCLK1 could facilitate EMT in cancer cells by up-regulation of the mesenchymal markers Vimentin and ZEB1 and down-regulation of the epithelial marker E-cadherin in SW480 cells. DCLK1 up-regulation may play a contributory role in CRC metastasis and poor prognosis via activation of EMT. DCLK1 may serve as an independent predictor for CRC prognosis.

  10. Upregulation of hyaluronan-mediated motility receptor in hepatocellular carcinoma predicts poor survival

    Science.gov (United States)

    HE, XIAOHU; LIAO, WEIJIA; LI, YULAN; WANG, YONGQIN; CHEN, QIAN; JIN, JUNFEI; HE, SONGQING

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common types of cancer across the world. Hyaluronic acid (HA) has been reported to serve an important role in tumor extension, progression, migration and invasion. In addition, the receptor for HA-mediated motility (RHAMM) has been demonstrated to be overexpressed in different types of cancer. However, whether the upregulation of RHAMM contributes to hepatocarcinogenesis of HCC remains unclear. The present study examined the RHAMM expression in 187 HCC patients by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). RHAMM expression was significantly upregulated in liver cancer tissues compared with that observed in adjacent normal liver tissues. The IHC analysis demonstrated that RHAMM was overexpressed in 18 (72.0%) of the 25 HCC tissues. Furthermore, overexpression of RHAMM was associated with tumor-node-metastasis (TNM), the presence of vascular invasion and recurrence. Notably, the present study indicated that the overexpression of RHAMM was closely associated with the shorter disease-free and overall survival, so it may be a potential independent predictor for disease-free and overall survival of HCC patients. In conclusion, the upregulation of RHAMM is associated with HCC progression and prognosis; and it may be a potential independent predictor of disease-free and overall survival of HCC following surgical resection. PMID:26788183

  11. Prevotella intermedia upregulates MMP-1 and MMP-8 expression in human periodontal ligament cells.

    Science.gov (United States)

    Guan, Su-Min; Shu, Lei; Fu, Shan-Min; Liu, Bin; Xu, Xiu-Li; Wu, Jun-Zheng

    2009-10-01

    Prevotella intermedia, a major periodontal pathogen, plays important roles in the initiation and development of periodontitis by stimulating the release of proinflammatory cytokines, proteinases and matrix metalloproteinases (MMPs). Our previous study demonstrated that P. intermedia induced MMP-9 expression in human periodontal ligament (hPDL) cells. In this study, we examined the effects of P. intermedia on other MMPs' expression. Semi-quantitative reverse transcriptase (RT)-PCR analysis revealed that P. intermedia ATCC 25611 supernatant increased MMP-1 and MMP-8 mRNA expression in a concentration- and time-dependent manner. Enzyme-linked immunosorbent assay and Western blot results confirmed the RT-PCR results at the protein level. Cyclooxygenase inhibitor indomethacin significantly attenuated the upregulatory effects of P. intermedia on MMP-1 and MMP-8 expression. Extracellular signal-related kinase inhibitor PD98059 and c-Jun N-terminal kinase inhibitor SP600125 considerably decreased the upregulated level of MMP-1, whereas p38 inhibitor SB203580 markedly inhibited MMP-8 expression, suggesting that prostaglandin E(2) and mitogen-activated protein kinase signaling pathways are involved in P. intermedia-induced MMP-1 and MMP-8 upregulation. Our results indicate that P. intermedia might contribute to periodontal connective tissue and bone matrix destruction through upregulating MMP production.

  12. Gene and functional up-regulation of the BCRP/ABCG2 transporter in hepatocellular carcinoma.

    Science.gov (United States)

    Sukowati, Caecilia Hc; Rosso, Natalia; Pascut, Devis; Anfuso, Beatrice; Torre, Giuliano; Francalanci, Paola; Crocè, Lory S; Tiribelli, Claudio

    2012-11-15

    The Breast Cancer Resistance Protein (BCRP/ABCG2) is one member of ABC transporters proteins super family responsible of drug resistance. Since data on ABCG2 expression in liver malignances are scanty, here we report the expression of ABCG2 in adult human hepatocellular carcinoma (HCC) in both in vivo and in vitro models with different degree of malignancy. In cell lines derived from human hepatocellular carcinoma, ABCG2 gene expression was assessed by reverse transcription quantitative real time PCR and function by Hoechst 33342 efflux assay; protein content was assessed by SDS-PAGE Western blot. ABCG2 expression was found to be highest in the most undifferentiated cell lines, and this was related with a higher functional activity. ABCG2 expression was sensitive to antineoplastic drugs since exposure to 5 μM doxorubicin for 24 hours resulted in significant up-regulations of ABCG2 in all cell lines, particularly in those lines with low basal ABCG2 expression (pexpression was also investigated in 51 adult liver tissues with HCC and related cirrhosis; normal liver tissue was used as control. ABCG2 gene expression was higher in HCC than both cirrhotic paired tissue and normal tissue. This up-regulation was greater (pexpression and differentiation stage both in human and HCC derived cell lines. The rapid up-regulation of ABCG2 to exposure to doxorubicin emphasizes the importance of this transporter in accounting for drug resistance in liver tumors.

  13. LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma.

    Science.gov (United States)

    Yun-Bo, Feng; Xiao-Po, Liu; Xiao-Li, Li; Guo-Long, Cao; Pei, Zhang; Fa-Ming, Tian

    2016-01-01

    To examine the expression and function of long non-coding RNA taurine up-regulated 1 ( TUG1 ) in human osteosarcoma cells. Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1 , since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.

  14. Sulf-2, a Proangiogenic Heparan Sulfate Endosulfatase, Is Upregulated in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Megumi Morimoto-Tomita

    2005-11-01

    Full Text Available Sulf-2 is an endosulfatase with activity against glucosamine-6-sulfate modifications within subregions of intact heparin. The enzyme has the potential to modify the sulfation status of extracellular heparan sulfate proteoglycan (HSPG glycosaminoglycan chains and thereby to regulate interactions with HSPG-binding proteins. In the present investigation, data mining from published studies was employed to establish Sulf-2 mRNA upregulation in human breast cancer. We further found that cultured breast carcinoma cells expressed Sulf-2 mRNA and released enzymatically active proteins into conditioned medium. In two mouse models of mammary carcinoma, Sulf-2 mRNA was upregulated in comparison to its expression in normal mammary gland. Although mRNA was present in normal tissues, Sulf-2 protein was undetectable; it was, however, detected in some premalignant lesions and in tumors. The protein was localized to the epithelial cells of the tumors. In support of the possible mechanistic relevance of Sulf- 2 upregulation in tumors, purified recombinant Sulf-2 promoted angiogenesis in the chick chorioallantoic membrane assay.

  15. β-Cryptoxanthin uptake in THP-1 macrophages upregulates the CYP27A1 signaling pathway.

    Science.gov (United States)

    Fu, Hongfei; Wu, Canjie; Riaz, Hasan; Zhang, Hualin; Han, Li; Bai, Liya; Yang, Feifei; Yang, Liguo

    2014-03-01

    Mitochondrial sterol 27-hydroxylase (CYP27A1), a mediator of cholesterol homeostasis, is reported to exhibit antiatherogenic properties. Many studies suggested that all-trans retinoic acid can be used to treat atherosclerosis through retinoic acid receptor (RAR)-mediated upregulation of CYP27A1 expression. In this study, we hypothesized that β-cryptoxanthin (β-cry), as a natural ligand of RAR, might act as antiatherogenic agent by upregulating CYP27A1. We found that β-cry treatment significantly upregulated genes involved in the uptake, transport, and metabolism of retinoids and the signaling pathway of CYP27A1 expression in THP-1 macrophages as detected by microarray analysis. Meanwhile, intracellular levels of β-cry were correlated to the concentration and exposure time of the treatment. The expression of genes, involved in signaling pathway of CYP27A1, was dramatically decreased due to repressed activity of RAR. Higher level of 27-hydroxycholesterol was detected in β-cry-treated macrophages by HPLC. Docking simulation showed that β-cry could interact with cellular retinoic acid binding protein 2. These findings were further confirmed through microarray results. Our results provide strong evidence that β-cry can be actively taken up by THP-1 macrophages and exhibits antiatherogenic effect on THP-1 macrophages by inducing CYP27A1 expression via RAR. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Upregulation of barrel GABAergic neurons is associated with cross-modal plasticity in olfactory deficit.

    Directory of Open Access Journals (Sweden)

    Hong Ni

    Full Text Available BACKGROUND: Loss of a sensory function is often followed by the hypersensitivity of other modalities in mammals, which secures them well-awareness to environmental changes. Cellular and molecular mechanisms underlying cross-modal sensory plasticity remain to be documented. METHODOLOGY/PRINCIPAL FINDINGS: Multidisciplinary approaches, such as electrophysiology, behavioral task and immunohistochemistry, were used to examine the involvement of specific types of neurons in cross-modal plasticity. We have established a mouse model that olfactory deficit leads to a whisking upregulation, and studied how GABAergic neurons are involved in this cross-modal plasticity. In the meantime of inducing whisker tactile hypersensitivity, the olfactory injury recruits more GABAergic neurons and their fine processes in the barrel cortex, as well as upregulates their capacity of encoding action potentials. The hyperpolarization driven by inhibitory inputs strengthens the encoding ability of their target cells. CONCLUSION/SIGNIFICANCE: The upregulation of GABAergic neurons and the functional enhancement of neuronal networks may play an important role in cross-modal sensory plasticity. This finding provides the clues for developing therapeutic approaches to help sensory recovery and substitution.

  17. Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

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    Ulises Urzúa

    2016-10-01

    Full Text Available Abstract Background Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE. Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. Results At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05 comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1, Birc5 (Survivin, Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. Conclusion Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes

  18. Mutations in BALB mitochondrial DNA induce CCL20 up-regulation promoting tumorigenic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Sligh, James [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Janda, Jaroslav [University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Jandova, Jana, E-mail: jjandova@email.arizona.edu [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States)

    2014-11-15

    Highlights: • Alterations in mitochondrial DNA are commonly found in various human cancers. • Mutations in BALB mitochondrial DNA induce up-regulation of chemokine CCL20. • Increased growth and motility of mtBALB cells is associated with CCL20 levels. • mtDNA changes in BALB induce in vivo tumor growth through CCL20 up-regulation. • Mutations in mitochondrial DNA play important roles in keratinocyte neoplasia. - Abstract: mtDNA mutations are common in human cancers and are thought to contribute to the process of neoplasia. We examined the role of mtDNA mutations in skin cancer by generating fibroblast cybrids harboring a mutation in the gene encoding the mitochondrial tRNA for arginine. This somatic mutation (9821insA) was previously reported in UV-induced hyperkeratotic skin tumors in hairless mice and confers specific tumorigenic phenotypes to mutant cybrids. Microarray analysis revealed and RT-PCR along with Western blot analysis confirmed the up-regulation of CCL20 and its receptor CCR6 in mtBALB haplotype containing the mt-Tr 9821insA allele compared to wild type mtB6 haplotype. Based on reported role of CCL20 in cancer progression we examined whether the hyper-proliferation and enhanced motility of mtBALB haplotype would be associated with CCL20 levels. Treatment of both genotypes with recombinant CCL20 (rmCCL20) resulted in enhanced growth and motility of mtB6 cybrids. Furthermore, the acquired somatic alteration increased the in vivo tumor growth of mtBALB cybrids through the up-regulation of CCL20 since neutralizing antibody significantly decreased in vivo tumor growth of these cells; and tumors from anti-CCL20 treated mice injected with mtBALB cybrids showed significantly decreased CCL20 levels. When rmCCL20 or mtBALB cybrids were used as chemotactic stimuli, mtB6 cybrids showed increased motility while anti-CCL20 antibody decreased the migration and in vivo tumor growth of mtBALB cybrids. Moreover, the inhibitors of MAPK signaling and NF

  19. Airborne fine particulate matter induces an upregulation of endothelin receptors on rat bronchi

    International Nuclear Information System (INIS)

    Wang, Rong; Xiao, Xue; Cao, Lei; Shen, Zhen-xing; Lei, Ying; Cao, Yong-xiao

    2016-01-01

    Airborne fine particulate matter (PM2.5) is a risk factor for respiratory diseases. However, little is known about the effects of PM2.5 on bronchi. The present study investigated the effect of airborne PM2.5 on rat bronchi and the underlying mechanisms. Isolated rat bronchial segments were cultured for 24 h. Endothelin (ET) receptor-mediated contractile responses were recorded using a wire myograph. The mRNA and protein expression levels of ET receptors were studied using quantitative real-time PCR, Western blotting, and immunohistochemistry. The results demonstrated that ET A and ET B receptor agonists induced remarkable contractile responses on fresh and cultured bronchial segments. PM2.5 (1.0 or 3.0 μg/ml) significantly enhanced ET A and ET B receptor-mediated contractile responses in bronchi with a markedly increased maximal contraction compared to the DMSO or fresh groups. PM2.5 increased the mRNA and protein expression levels of ET A and ET B receptors. U0126 (a MEK1/2 inhibitor) and SB203580 (a p38 inhibitor) significantly suppressed PM2.5-induced increases in ET B receptor-mediated contractile responses, mRNA and protein levels. SP600125 (a JNK inhibitor) and SB203580 significantly abrogated the PM2.5-induced enhancement of ET A receptor-mediated contraction and receptor expression. In conclusion, PM2.5 upregulates ET receptors in bronchi. ET B receptor upregulation is associated with MEK1/2 and p38 pathways, and the upregulation of ET A receptor is involved in JNK and p38 pathways. - Highlights: • Airborne PM2.5 induces bronchial hyperreactivity mediated with endothelin ET B and ET A receptors in rats. • PM2.5 increases mRNA and protein expressions of endothelin ET B and ET A receptors in bronchi. • The upregulation of ET B receptor is associated with MEK1/2 and p38 pathways. • The upregulation of ET A receptor is involved in JNK and p38 pathways. • The research provides novel understanding for PM2.5-associated respiratory diseases.

  20. The effect of the training program on the quality of life in patients with asthma based on the Precede model in Ahvaz, Iran

    Directory of Open Access Journals (Sweden)

    Mina Motaghi Nejad

    2017-05-01

    Full Text Available Aim: The aim of the study was to determine the effect of the training program based on the Precede model and its main components on improving the quality of life in patients with asthma. Material and methods: It was a randomized quasi-experimental study done on 120 patients with asthma who were referred to the Imam Khomeini hospital in Ahvaz who were selected using the convenience sampling method and were randomly divided into intervention and control groups. The data collection tool consisted of two questionnaires. The first questionnaire evaluated the quality of life in patients with asthma and the other one was developed by the researcher based on the structures of the Precede model. Training intervention was conducted during four sessions twice a week and each session was carried out for an hour based on the structures of the Precede model. In order to achieve the results, SPSS software, even t-test, and 2 were used. Results: The results showed that after the training intervention in the experimental group, the mean scores of predisposing factors (p < 0.001, enabling factors, reinforcing factors and behavioral factors were significantly increased (p < 0.001 as compared to the control group. A significant difference was observed in the mean scores of quality of life in two groups after the intervention (p < 0.001, and the quality of life of patients in the experimental group was improved after the training intervention. Conclusions : The design and implementation of the training program based on the Precede model can have a positive effect on the improvement of quality of life in patients with asthma.

  1. Diastolic And Systolic Right Ventricular Dysfunction Precedes Left Ventricular Dysfunction In Patients Paced From Right Ventricular Apex

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    Dwivedi SK

    2006-07-01

    .05 without any significant change in the resting cardiac output. Conclusion: The present study shows that dysfunction of right ventricle is the first abnormality that occurs in VVI paced patients, which manifests by 1 week followed by LV dysfunction which starts appearing by 1 month and the diastolic dysfunctions precede the systolic dysfunction in both ventricles.

  2. Mycorrhizal colonization and grain Cd concentration of field-grown durum wheat in response to tillage, preceding crop and phosphorus fertilization.

    Science.gov (United States)

    Gao, Xiaopeng; Akhter, Fardausi; Tenuta, Mario; Flaten, Donald N; Gawalko, Eugene J; Grant, Cynthia A

    2010-04-15

    A 3-year field trial was conducted to investigate the effect of agricultural management practices including tillage, preceding crop and phosphate fertilization on root colonization by arbuscular mycorrhizal (AM) fungi and grain cadmium (Cd) concentration of durum wheat (Triticum turgidum L.). The relationship between grain Cd and soil and plant variables was explored to determine the primary factors affecting grain Cd concentration. Mycorrhizal colonization of the roots was reduced by conventional tillage or when the preceding crop was canola (Brassica napus L.), compared to minimum tillage or when the preceding crop was flax (Linum usitatissimum L.). In contrast, grain Cd was not consistently affected by any treatment. Grain Cd was generally below the maximum permissible concentration (MPC) of 100 microg Cd kg(-1) proposed by WHO. Grain Cd varied substantially from year to year, and could be predicted with 70% of variance accounted for by using the model: grain Cd concentration = - 321.9 + 44.5x ln(grain yield) + 0.26x soil DTPA-Cd + 182.5x soil electrical conductivity (EC)- 0.98x grain Zn concentration. These common agricultural management practices had no effect on grain Cd concentration in durum wheat though they impacted mycorrhizal colonization of roots. Grain yield and to a lesser extent soil conditions of EC and DTPA-Cd and grain Zn influenced grain Cd, whereas mycorrhizal colonization levels did not. (c) 2010 Crown in the right of Canada. Published by John Wiley & Sons, Ltd.

  3. Upregulation of intervertebral disc-cell matrix synthesis by pulsed electromagnetic field is mediated by bone morphogenetic proteins.

    Science.gov (United States)

    Okada, Motohiro; Kim, Jin Hwan; Hutton, William C; Yoon, Sangwook Tim

    2013-05-01

    An in vitro study on the effects of pulsed electromagnetic field (PEMF) on intervertebral disc-cell matrix synthesis. The objective of the study was to determine whether (1) PEMF can upregulate intervertebral disc-cell matrix synthesis and (2) any upregulation obtained is through transforming growth factor (TGF)-β or bone morphogenetic proteins (BMPs). PEMF has been reported to produce cell proliferation, enhance cell function, and upregulate matrix synthesis in cell types such as osteoblasts, chondroblasts, endothelial cells, and fibroblasts through the upregulation of several growth factors. PEMF has been used clinically in the treatment of delayed bone union. However, PEMF has never been tested on human intervertebral disc cells. The PEMF signal used was similar to that used in the clinical treatment of delayed fracture healing. Human disc cells were treated with PEMF for 8 hours per day for 3 days. Quantitative real-time polymerase chain reaction was performed to determine mRNA expression levels of aggrecan, collagen-2, TGF-β, BMP-2, and BMP-7. Sulfated glycosaminoglycan synthesis was analyzed using the dimethylmethylene blue (DMMB) method. Western blot analysis was performed to determine the protein levels of TGF-β, BMP-2, and BMP-7. To determine whether any action of PEMF was through BMP, recombinant human Noggin was used at a dose of 100 ng/mL to block BMP. PEMF could upregulate intervertebral disc-cell matrix synthesis. BMP-7 was markedly upregulated by PEMF and was upregulated much more than BMP-2. TGF-β was not upregulated by PEMF. The effect of PEMF on disc-cell matrix was entirely inhibited in the presence of Noggin. PEMF acts through BMPs to upregulate intervertebral disc-cell matrix synthesis.

  4. Heart ischemia-reperfusion induces local upregulation of vasoconstrictor endothelin receptor type B in rat coronary arteries downstream of occlusion

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Kruse, L.S.; Larsen, R

    2014-01-01

    . However, under pathophysiological conditions ETB receptors may also be expressed in vascular smooth muscle cells mediating vasoconstriction. We aimed to investigate whether vasoconstrictor ETB receptors are upregulated in coronary arteries after experimental myocardial ischemia in rats....

  5. Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-induced apoptosis through upregulation of Bim expression.

    Science.gov (United States)

    Seo, Seung Un; Woo, Seon Min; Min, Kyoung-Jin; Kwon, Taeg Kyu

    2018-04-15

    Inhibition of cathespsin S not only inhibits invasion and angiogenesis, but also induces apoptosis and autophagy in cancer cells. In present study, we revealed that pharmacological inhibitor [Z-FL-COCHO (ZFL)] of cathepsin S up-regulates pro-apoptotic protein Bim expression at the posttranslational levels. These effects were not associated with MAPKs and AMPK signal pathways. Interestingly, pretreatment with the chemical chaperones (TUDCA and PBA) and knockdown of protein phosphatase 2A (PP2A) markedly inhibited ZFL-induced Bim upregulation. ZFL enhances oxaliplatin-mediated apoptosis through ER stress-induced Bim upregulation in cancer cells. Collectively, our results suggest that inhibition of cathepsin S-induced Bim upregulation contribute to anti-cancer drug-induced apoptotic cell death in renal carcinoma Caki cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

    Science.gov (United States)

    Qie, Shuo; Chu, Clarissa; Li, Weihua; Wang, Chenguang; Sang, Nianli

    2015-01-01

    Active glutamine utilization is critical for tumor cell proliferation. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase (GLS). Activation of ErbB2 is one of the major causes of breast cancers, the second most common cause of death for women in many countries. However, it remains unclear whether ErbB2 signaling affects glutaminase expression in breast cancer cells. In this study, we show that MCF10A-NeuT cell line has higher GLS1 expression at both mRNA and protein levels than its parental line MCF10A, and knockdown of ErbB2 decreases GLS1 expression in MCF10A-NeuT cells. We further show that in these cells, ErbB2-mediated upregulation of GLS1 is not correlated to c-Myc expression. Moreover, activation of neither PI3K-Akt nor MAPK pathway is sufficient to upregulate GLS1 expression. Interestingly, inhibition of NF-κB blocks ErbB2-stimulated GLS1 expression, whereas stimulation of NF-κB is sufficient to enhance GLS1 levels in MCF10A cells, suggesting a PI3K-Akt-independent activation of NF-κB upregulates GLS1 in ErbB2-positive breast cancer cells. Finally, knockdown or inhibition of GLS1 significantly decreased the proliferation of breast cancer cells with high GLS1 levels. Taken together, our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-κB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression, and thus promoting glutamine utilization in cancer cells. These findings, if validated by in vivo model, may facilitate the identification of novel biochemical targets for cancer prevention and therapy. PMID:24122876

  7. Abrogation of radiation-inducible telomerase upregulation in HPV16 E6 transfectants of human lymphoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Neuhof, D.; Auberger, F.; Ruess, A.; Weber, K.J. [Radiobiology Research Lab., Dept. of Clinical Radiology, Univ. of Heidelberg (Germany); Wenz, F. [Section for Radiation Oncology, Univ. Clinic Mannheim (Germany)

    2004-01-01

    Background: telomerase activity in a human lymphoblastoid cell line with wild-type p53 status (TK6) was previously shown to be rapidly induced by ionizing radiation doses as low as 10 cgy. Since this low-dose response was absent in a closely related cell line overexpressing a mutant form of p53 (WTK1), the putative involvement of p53 was further investigated using stable human papillomavirus 16 (HPV16) E6 transfectants of these cell lines. The E6 product mediates rapid degradation of wild-type p53, but has also been found to upregulate telomerase. Material and methods: telomerase activity in HPV16 E6 transfectants of the human lymphoblastoid cell lines TK6 and WTK1 was measured by PCR/ELISA and was quantified using internal standards (titration by cell number) run within each separate assay. Mean telomere length was determined by southern hybridization of terminal restriction fragments with a biotin-labeled telomeric DNA probe. Results: the TK6E6 and the WTK1E6 cells exhibited higher baseline telomerase activities than the parental cells. This was also accompanied by increased telomere lengths. Radiation exposure (up to 10 gy) was unable to significantly further enhance telomerase activities, although the dynamic range of the assay would have allowed to record higher signals. Conclusion: the lacking radiation induction of telomerase activities in the E6 transfectants could reflect saturation, if E6 and radiation would share a common pathway of telomerase upregulation. Present evidence from the literature, however, suggests that E6 mediates telomerase reverse transcriptase (TERT) subunit transcriptional activation, whereas radiation signals to posttranscriptional/posttranslational control of telomerase activity. Therefore, the present data enforce the previous hypothesis of a p53 dependence of telomerase upregulation by low doses of radiation and its abrogation, likely due to p53 degradation, in E6-expressing cells. (orig.)

  8. Smilacis Glabrae Rhizoma Reduces Oxidative Stress Caused by Hyperuricemia via Upregulation of Catalase

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    Quan Hong

    2014-11-01

    Full Text Available Background/Aims: Reports have suggested that the traditional Chinese medicine Smilacis Glabrae Rhizoma attenuates hyperuricemia, but its mechanism is unclear. Our previous study demonstrated that uric acid could induce the generation of reactive oxygen species(ROS, which subsequently cause endothelial dysfunction. Therefore, we focused on the oxidative stress process. In this study, we would use LC-MS and bioinformatic analysis to investigate the underlying mechanism. Methods: We utilized LC-MS to reveal the differential protein expression in the kidneys of rats in the hyperuricemia group and the Smilacis Glabrae Rhizoma treatment group and then subjected the differentially expressed proteins to bioinformatic analysis. We also determined the serum ROS level of the two groups. According the above results, we built our hypothesis and performed in vitro experiments to validate this hypothesis. Results: We found that catalase was upregulated in the group treated with Smilacis Glabrae Rhizoma, and the level of reactive oxygen species was higher in the hyperuricemia group. Thus, we speculated that Smilacis Glabrae Rhizoma could alleviate oxidative stress by upregulating catalase. In vitro experiments, we found that high concentrations of uric acid reduced catalase expression in endothelial cells, which was alleviated by Smilacis Glabrae Rhizoma and resulted in a reduction of reactive oxygen species. Knockdown of catalase led to an increase in reactive oxygen species. Conclusion: We demonstrated that Smilacis Glabrae Rhizoma could alleviate the oxidative stress caused by hyperuricemia by upregulating catalase expression. This finding could represent a new application for Smilacis Glabrae Rhizoma in the treatment of hyperuricemia.

  9. Up-regulation of the chemokine CCL21 in the skin of subjects exposed to irritants

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    Kuznitzky Raquel

    2004-04-01

    Full Text Available Abstract Background Expression of murine CCL21 by dermal lymphatic endothelial cells (LEC has been demonstrated to be one of the most important steps in Langerhans cell emigration from skin. Previously, our group and others have found that this chemokine is up-regulated in different human inflammatory skin diseases mediated by diverse specific immune responses. This study was carried out to investigate the involvement of CCL21 in human skin after challenge with irritant agents responsible for inducing Irritant Contact Dermatitis (ICD. Results Eleven normal individuals were challenged with different chemical or physical irritants. Two patients with Allergic Contact Dermatitis (ACD were also challenged with the relevant antigen in order to have a positive control for CCL21 expression. Macroscopic as well as microscopic responses were evaluated. We observed typical ICD responses with mostly mononuclear cells in perivascular areas, but a predominance of polymorphonuclear cells away from the inflamed blood vessels and in the epidermis at 24 hours. Immunohistochemical studies showed up-regulation of CCL21 by lymphatic endothelial cells in all the biopsies taken from ICD and ACD lesions compared to normal skin. Kinetic study at 10, 48, 96 and 168 hours after contact with a classical irritant (sodium lauryl sulphate showed that the expression of CCL21 was increased in lymphatic vessels at 10 hours, peaked at 48 hours, and then gradually declined. There was a strong correlation between CCL21 expression and the macroscopic response (r = 0.69; p = 0.0008, but not between CCL21 and the number of infiltrating cells in the lesions. Conclusions These results provide new evidence for the role of CCL21 in inflammatory processes. Since the up-regulation of this chemokine was observed in ICD and ACD, it is tempting to speculate that this mechanism operates independently of the type of dermal insult, facilitating the emigration of CCR7+ cells.

  10. Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall

    Directory of Open Access Journals (Sweden)

    Zhaoyu Liu

    2014-01-01

    Full Text Available Epidemiological studies have shown that estrogens have protective effects in cardiovascular diseases, even though the results from human clinical trials remain controversial, while most of the animal experiments confirmed this effect, but the detailed mechanism remains unclear. In this study, we found that estradiol (E2 treatment significantly increases the expression of mitochondrial superoxide dismutase (SOD2 in mice and in vitro in human aorta endothelial cells. Further investigation shows that E2 up-regulates SOD2 through tethering of estrogen receptor (ER to Sp1 and the increased binding of Sp1 to GC-box on the SOD2 promoter, where ERα responses E2-mediated gene activation, and ERβ maintains basal gene expression level. The E2/ER-mediated SOD2 up-regulation results in minimized ROS generation, which highly favors healthy cardiovascular function. Gene therapy through lentivirus-carried endothelium-specific delivery to the vascular wall in high-fat diet (HFT mice shows that the SOD2 expression in endothelial cells normalizes E2 deficiency-induced ROS generation with ameliorated mitochondrial dysfunction and vascular damage, while SOD2 knockdown worsens the problem despite the presence of E2, indicating that E2-induced SOD2 expression plays an important vasculoprotective role. To our knowledge, this is the first report for the mechanism by which E2 improves cardiovascular function through up-regulation of SOD2 in endothelial cells. In turn, this suggests a novel gene therapy through lentivirus-carried gene delivery to vascular wall for E2 deficiency-induced cardiovascular damage in postmenopausal women.

  11. Up-regulation of CLDN1 in gastric cancer is correlated with reduced survival

    International Nuclear Information System (INIS)

    Eftang, Lars L; Esbensen, Ying; Tannæs, Tone M; Blom, Gustav P; Bukholm, Ida RK; Bukholm, Geir

    2013-01-01

    The genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. There are also remarkable geographical differences in the distribution of this disease. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection. Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 20 patients immediately following surgical resection of the tumor. Whole genome, cDNA microarray analysis was performed on the RNA isolated from the sample pairs to compare the gene expression profiles between the tumor against matched mucosa. The samples were microscopically examined to classify gastritis. The presence of H. pylori was examined using microscopy and immunohistochemistry. 130 genes showed differential regulation above a predefined cut-off level. Interleukin-8 (IL-8) and Claudin-1 (CLDN1) were the most consistently up-regulated genes in the tumors. Very high CLDN1 expression in the tumor was identified as an independent and significant predictor gene of reduced post-operative survival. There were distinctly different expression profiles between the tumor group and the control mucosa group, and the histological subsets of mixed type, diffuse type and intestinal type cancer demonstrated further sub-clustering. Up-regulated genes were mapped to cell-adhesion, collagen-related processes and angiogenesis, whereas normal intestinal functions such as digestion and excretion were associated with down-regulated genes. We relate the current findings to our previous study on the gene response of gastric epithelial cells to H. pylori infection. CLDN1 was highly up-regulated in gastric cancer, and CLDN1 expression was independently associated with a poor post-operative prognosis, and may have important prognostic

  12. Identification of a conserved set of upregulated genes in mouse skeletal muscle hypertrophy and regrowth

    Science.gov (United States)

    Chaillou, Thomas; Jackson, Janna R.; England, Jonathan H.; Kirby, Tyler J.; Richards-White, Jena; Esser, Karyn A.; Dupont-Versteegden, Esther E.

    2014-01-01

    The purpose of this study was to compare the gene expression profile of mouse skeletal muscle undergoing two forms of growth (hypertrophy and regrowth) with the goal of identifying a conserved set of differentially expressed genes. Expression profiling by microarray was performed on the plantaris muscle subjected to 1, 3, 5, 7, 10, and 14 days of hypertrophy or regrowth following 2 wk of hind-limb suspension. We identified 97 differentially expressed genes (≥2-fold increase or ≥50% decrease compared with control muscle) that were conserved during the two forms of muscle growth. The vast majority (∼90%) of the differentially expressed genes was upregulated and occurred at a single time point (64 out of 86 genes), which most often was on the first day of the time course. Microarray analysis from the conserved upregulated genes showed a set of genes related to contractile apparatus and stress response at day 1, including three genes involved in mechanotransduction and four genes encoding heat shock proteins. Our analysis further identified three cell cycle-related genes at day and several genes associated with extracellular matrix (ECM) at both days 3 and 10. In conclusion, we have identified a core set of genes commonly upregulated in two forms of muscle growth that could play a role in the maintenance of sarcomere stability, ECM remodeling, cell proliferation, fast-to-slow fiber type transition, and the regulation of skeletal muscle growth. These findings suggest conserved regulatory mechanisms involved in the adaptation of skeletal muscle to increased mechanical loading. PMID:25554798

  13. The Natural Antimicrobial Enzyme Lysozyme is Up-Regulated in Gastrointestinal Inflammatory Conditions

    Directory of Open Access Journals (Sweden)

    Carlos A. Rubio

    2014-01-01

    Full Text Available The cells that line the mucosa of the human gastrointestinal tract (GI, that is, oral cavity, oesophagus, stomach, small intestine, large intestine, and rectum are constantly challenged by adverse micro-environmental factors, such as different pH, enzymes, and bacterial flora. With exception of the oral cavity, these microenvironments also contain remnant cocktails of secreted enzymes and bacteria from upper organs along the tract. The density of the GI bacteria varies, from 103/mL near the gastric outlet, to 1010/mL at the ileocecal valve, to 1011 to 1012/mL in the colon. The total microbial population (ca. 1014 exceeds the total number of cells in the tract. It is, therefore, remarkable that despite the prima facie inauspicious mixture of harmful secretions and bacteria, the normal GI mucosa retains a healthy state of cell renewal. To counteract the hostile microenvironment, the GI epithelia react by speeding cell exfoliation (the GI mucosa has a turnover time of two to three days, by increasing peristalsis, by eliminating bacteria through secretion of plasma cell-immunoglobulins and by increasing production of natural antibacterial compounds, such as defensin-5 and lysozyme. Only recently, lysozyme was found up-regulated in Barrett’s oesophagitis, chronic gastritis, gluten-induced atrophic duodenitis (coeliac disease, collagenous colitis, lymphocytic colitis, and Crohn’s colitis. This up-regulation is a response directed to the special types of bacteria recently detected in these diseases. The aim of lysozyme up-regulation is to protect individual mucosal segments to chronic inflammation. The molecular mechanisms connected to the crosstalk between the intraluminal bacterial flora and the production of lysozyme released by the GI mucosae, are discussed. Bacterial resistance continues to exhaust our supply of commercial antibiotics. The potential use of lysozyme to treat infectious diseases is receiving much attention.

  14. Identification of a conserved set of upregulated genes in mouse skeletal muscle hypertrophy and regrowth.

    Science.gov (United States)

    Chaillou, Thomas; Jackson, Janna R; England, Jonathan H; Kirby, Tyler J; Richards-White, Jena; Esser, Karyn A; Dupont-Versteegden, Esther E; McCarthy, John J

    2015-01-01

    The purpose of this study was to compare the gene expression profile of mouse skeletal muscle undergoing two forms of growth (hypertrophy and regrowth) with the goal of identifying a conserved set of differentially expressed genes. Expression profiling by microarray was performed on the plantaris muscle subjected to 1, 3, 5, 7, 10, and 14 days of hypertrophy or regrowth following 2 wk of hind-limb suspension. We identified 97 differentially expressed genes (≥2-fold increase or ≥50% decrease compared with control muscle) that were conserved during the two forms of muscle growth. The vast majority (∼90%) of the differentially expressed genes was upregulated and occurred at a single time point (64 out of 86 genes), which most often was on the first day of the time course. Microarray analysis from the conserved upregulated genes showed a set of genes related to contractile apparatus and stress response at day 1, including three genes involved in mechanotransduction and four genes encoding heat shock proteins. Our analysis further identified three cell cycle-related genes at day and several genes associated with extracellular matrix (ECM) at both days 3 and 10. In conclusion, we have identified a core set of genes commonly upregulated in two forms of muscle growth that could play a role in the maintenance of sarcomere stability, ECM remodeling, cell proliferation, fast-to-slow fiber type transition, and the regulation of skeletal muscle growth. These findings suggest conserved regulatory mechanisms involved in the adaptation of skeletal muscle to increased mechanical loading. Copyright © 2015 the American Physiological Society.

  15. KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity

    International Nuclear Information System (INIS)

    Bajaj, Bharat G.; Verma, Subhash C.; Lan, Ke; Cotter, Murray A.; Woodman, Zenda L.; Robertson, Erle S.

    2006-01-01

    Pim kinases are proto-oncogenes that are upregulated in a number of B cell cancers, including Epstein-Barr Virus (EBV) associated Burkitt's lymphoma. They have also been shown to be upregulated in Kaposi sarcoma-associated herpes virus (KSHV) infected primary B cells. Most cells in KSHV-associated tumors are latently infected and express only a small subset of viral genes, with KSHV latency associated nuclear antigen (LANA) being constitutively expressed. LANA regulates the transcription of a large number of cellular and viral genes. Here, we show that LANA upregulates transcription from the Pim-1 promoter (pPim-1) and map this activation to a region in the promoter located within the sequence (-681 to +37). We show that LANA expressing cells can proliferate faster and are better protected from drug induced apoptosis. Since transition through cell cycle check points and anti-apoptosis are functions associated with Pim-1, it is likely that higher Pim-1 expression in cells expressing LANA is responsible, at least in part, for this effect. A Pim-1 phosphorylation site was also identified within the amino-terminal domain of LANA. Using in vitro kinase assays, we confirmed that LANA was indeed a Pim-1 substrate, and the failure of Pim-1 to phosphorylate LANA mutated at SS205/6RR identified this site as the specific serine residues phosphorylated by Pim-1. This report provides valuable insight into yet another cellular signaling pathway subverted by KSHV LANA and suggests a contribution to KSHV related oncogenesis

  16. Portland cement induces human periodontal ligament cells to differentiate by upregulating miR-146a

    Directory of Open Access Journals (Sweden)

    Min-Ching Wang

    2018-04-01

    Full Text Available Background/Purpose: Bioaggregates such as Portland cement (PC can be an economical alternative for mineral trioxide aggregate (MTA with additional benefit of less discoloration. MTA has been known to induce differentiations of several dental cells. MicroRNAs are important regulators of biological processes, including differentiation, physiologic homeostasis, and disease progression. This study is to explore how PC enhances the differentiation of periodontal ligament (PDL cells in microRNAs level. Methods: PDL cells were cultured in a regular PC- or MTA-conditioned medium or an osteoinduction medium (OIM. Alizarin red staining was used to evaluate the extent of mineralization. Transfection of microRNA mimics induced exogenous miR-31 and miR-146a expression. The expression of microRNAs and differentiation markers was assayed using reverse-transcriptase polymerase chain reaction. Results: PC enhanced the mineralization of PDL cells in a dose-dependent manner in the OIM. Exogenous miR-31 and miR-146a expression upregulated alkaline phosphatase (ALP, bone morphogenic protein (BMP, and dentin matrix protein 1 (DMP1 expression. However, miR-31 and miR-146a modulates cementum protein 1 (CEMP1 expression in different ways. PC also enhanced ALP and BMP but attenuated CEMP1 in the OIM. Although the OIM or PC treatment upregulated miR-21, miR-29b, and miR-146a, only miR-146a was able to be induced by PC in combination with OIM. Conclusion: This study demonstrated that PC enhances the differentiation of PDL cells, especially osteogenic through miR-146a upregulation. In order to control the ankylosis after regenerative endodontics with the usage of bioaggregates, further investigations to explore these differentiation mechanisms in the miRNA level may be needed. Keywords: Portland cement, Bioaggregate, miR-146a, Osteogenic differentiation, Periodontal ligament (PDL

  17. Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4

    LENUS (Irish Health Repository)

    Cronin, Patricia A

    2010-05-21

    Abstract Background Chemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α. Methods Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability. Results CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α in vitro. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness. Conclusions CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.

  18. DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers

    Directory of Open Access Journals (Sweden)

    Suba Z

    2015-05-01

    Full Text Available Zsuzsanna Suba Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary Abstract: Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant

  19. Prenatal administration of retinoic acid upregulates connective tissue growth factor in the nitrofen CDH model.

    Science.gov (United States)

    Ruttenstock, Elke Maria; Doi, Takashi; Dingemann, Jens; Puri, Prem

    2011-06-01

    Recent studies have suggested that retinoids may be involved in the molecular mechanisms of pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). Connective tissue growth factor (CTGF) plays a key role in foetal lung development and remodelling during later gestation. CTGF knockout mice exhibit PH with similar characteristics to the human and nitrofen-induced PH. Prenatal administration of retinoic acid (RA) has been shown to stimulate alveologenesis in nitrofen-induced PH. In vitro studies have revealed that RA can induce CTGF gene expression. We hypothesized that pulmonary gene expression of CTGF is downregulated during the later stages of lung development, and that prenatal administration of RA upregulates CTGF in the nitrofen CDH model. Pregnant rats were exposed to either olive oil or nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Foetuses were harvested on D21 and divided into control, CDH, control + RA and CDH + RA group. Pulmonary CTGF gene and protein expression levels were determined using RT-PCR and immunohistochemistry. On D21, CTGF relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, expression levels of CTGF were significantly upregulated in CDH + RA and control + RA compared to the CDH group. Immunohistochemical studies confirmed these results. Downregulation of pulmonary CTGF gene and protein expression during later stages of lung development may interfere with normal alveologenesis in the nitrofen CDH model. Upregulation of CTGF pulmonary gene expression after prenatal RA treatment may promote lung growth by promoting alveologenesis in the nitrofen-induced CDH model.

  20. Myostatin signaling is up-regulated in female patients with advanced heart failure.

    Science.gov (United States)

    Ishida, Junichi; Konishi, Masaaki; Saitoh, Masakazu; Anker, Markus; Anker, Stefan D; Springer, Jochen

    2017-07-01

    Myostatin, a negative regulator of skeletal muscle mass, is up-regulated in the myocardium of heart failure (HF) and increased myostatin is associated with weight loss in animal models with HF. Although there are disparities in pathophysiology and epidemiology between male and female patients with HF, it remains unclear whether there is gender difference in myostatin expression and whether it is associated with weight loss in HF patients. Heart tissue samples were collected from patients with advanced heart failure (n=31, female n=5) as well as healthy control donors (n=14, female n=6). Expression levels of myostatin and its related proteins in the heart were evaluated by western blotting analysis. Body mass index was significantly lower in female HF patients than in male counterparts (20.0±4.2 in female vs 25.2±3.8 in male, p=0.04). In female HF patients, both mature myostatin and pSmad2 were significantly up-regulated by 1.9 fold (p=0.05) and 2.5 fold (p<0.01) respectively compared to female donors, while expression of pSmad2 was increased by 2.8 times in male HF patients compared to male healthy subjects, but that of myostatin was not. There was no significant difference in protein expression related to myostatin signaling between male and female patients. In this study, myostatin and pSmad2 were significantly up-regulated in the failing heart of female patients, but not male patients, and female patients displayed lower body mass index. Enhanced myostatin signaling in female failing heart may causally contribute to pathogenesis of HF and cardiac cachexia. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Upregulation of pirin expression by chronic cigarette smoking is associated with bronchial epithelial cell apoptosis

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    Zabner Joseph

    2007-02-01

    Full Text Available Abstract Background Cigarette smoke disrupts the protective barrier established by the airway epithelium through direct damage to the epithelial cells, leading to cell death. Since the morphology of the airway epithelium of smokers does not typically demonstrate necrosis, the most likely mechanism for epithelial cell death in response to cigarette smoke is apoptosis. We hypothesized that cigarette smoke directly up-regulates expression of apoptotic genes, which could play a role in airway epithelial apoptosis. Methods Microarray analysis of airway epithelium obtained by bronchoscopy on matched cohorts of 13 phenotypically normal smokers and 9 non-smokers was used to identify specific genes modulated by smoking that were associated with apoptosis. Among the up-regulated apoptotic genes was pirin (3.1-fold, p In vitro studies using human bronchial cells exposed to cigarette smoke extract (CSE and an adenovirus vector encoding the pirin cDNA (AdPirin were performed to test the direct effect of cigarette smoke on pirin expression and the effect of pirin expression on apoptosis. Results Quantitative TaqMan RT-PCR confirmed a 2-fold increase in pirin expression in the airway epithelium of smokers compared to non-smokers (p Overexpression of pirin, using the vector AdPirin, in human bronchial epithelial cells was associated with an increase in the number of apoptotic cells assessed by both TUNEL assay (5-fold, p Conclusion These observations suggest that up-regulation of pirin may represent one mechanism by which cigarette smoke induces apoptosis in the airway epithelium, an observation that has implications for the pathogenesis of cigarette smoke-induced diseases.

  2. Reciprocal upregulation of Notch signaling molecules in hematopoietic progenitor and mesenchymal stromal cells

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    Kikuchi Y

    2011-01-01

    Full Text Available Although mesenchymal stem cells (MSCs play pivotal supportive roles in hematopoiesis, how they interact with hematopoietic stem cells (HSCs is not well understood. We investigated the interaction between HSCs and surrogate MSCs (C3H10T1/2 stromal cells, focusing on the molecular events induced by cell contact of these bipartite populations. C3H10T1/2 is a mesenchymal stromal cell line that can be induced to differentiate into preadipocytes (A54 and myoblasts (M1601. The stromal cell derivatives were cocultured with murine HSCs (Lineage-Sca1+, and gene expression profiles in stromal cells and HSCs were compared before and after the coculture. HSCs gave rise to cobblestone areas only on A54 cells, with ninefold more progenitors than on M1601 or undifferentiated C3H10T1/2 cells. Microarray-based screening and a quantitative reverse transcriptase directed-polymerase chain reaction showed that the levels of Notch ligands (Jagged1 and Delta-like 3 were increased in A54 cells upon interaction with HSCs. On the other hand, the expression of Notch1 and Hes1 was upregulated in the HSCs cocultured with A54 cells. A transwell assay revealed that the reciprocal upregulation was dependent on cell-to-cell contact. The result suggested that in the hematopoietic niche, HSCs help MSCs to produce Notch ligands, and in turn, MSCs help HSCs to express Notch receptor. Such a reciprocal upregulation would reinforce the downstream signaling to determine the fate of hematopoietic cell lineage. Clarification of the initiating events on cell contact should lead to the identification of specific molecular targets to facilitate HSC engraftment in transplantation therapy.

  3. Upregulation of microRNA-100 predicts poor prognosis in patients with pediatric acute myeloid leukemia

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    Kuai W

    2012-09-01

    Full Text Available Jin Bai,1 Aiping Guo,2 Ze Hong,3 Wenxia Kuai31Department of Pediatrics, Huai'an Hospital to Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an, China; 2Department of Pediatrics, Chuzhou Hospital, Huai'an, China; 3Department of Pediatrics, Huai'an First People's Hospital, Huai'an, ChinaObjective: MicroRNA-100 (miR-100, a small noncoding RNA molecule, acts as a tumor suppressor or an oncogene in different cancers. The aberrant expression of this microRNA has been demonstrated as a frequent event in adult patients with acute myeloid leukemia (AML, but little is known for pediatric AML. The aim of this study was to investigate the expression and clinical significance of miR-100 in pediatric AML.Methods: The expression levels of miR-100 in bone marrow mononuclear cells were detected by real-time quantitative polymerase chain reaction in a cohort of 106 patients with de novo pediatric AML. The prognostic values of miR-100 in pediatric AML were also analyzed.Results: Compared with normal controls, upregulation of miR-100 in the bone marrow of pediatric AML patients with statistically significant differences (P < 0.001 was found. The expression levels of miR-100 were found to be significantly higher in pediatric AML patients with extramedullary disease, with the French–American–British classification subtype M7, and with unfavorable day 7 response to induction chemotherapy (P = 0.008, 0.001 and 0.01, respectively. Moreover, both univariate and multivariate analyses revealed that miR-100 upregulation was associated with poorer relapse-free and overall survival in pediatric AML patients.Conclusion: This is the first report demonstrating the upregulation of miR-100 in pediatric AML, and its association with poor relapse-free and overall survival. These results suggest that miR-100 upregulation may be used as an unfavorable prognostic marker in pediatric AML.Keywords: pediatric acute myeloid leukemia, microRNA-100, real

  4. Airway epithelial platelet-activating factor receptor expression is markedly upregulated in chronic obstructive pulmonary disease

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    Shukla SD

    2014-08-01

    Full Text Available Shakti Dhar Shukla,1,* Sukhwinder Singh Sohal,1,* Malik Quasir Mahmood,1 David Reid,2 Hans Konrad Muller,1 Eugene Haydn Walters1 1NHMRC Centre for Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia; 2Queensland Institute of Medical Research, Iron Metabolism Laboratory, Brisbane, Queensland, Australia *Shakti Dhar Shukla and Sukhwinder Singh Sohal are joint first authors Background: We recently published that platelet-activating factor receptor (PAFr is upregulated on the epithelium of the proximal airways of current smokers and also in bronchial epithelial cells exposed to cigarette smoke extract. These treated cells also showed upregulation of Streptococcus pneumoniae adhesion. Bacterial wall phosphorylcholine specifically binds to PAFr expressed on airway epithelium, thus facilitating adherence and tissue invasion, which may be relevant to chronic obstructive pulmonary disease (COPD. Moreover, the use of inhaled corticosteroids (ICS in COPD patients is associated with an increased risk of invasive respiratory pneumococcal infections. Objective: In this study, we have investigated whether PAFr expression is especially upregulated in airway epithelium in COPD patients and whether this expression may be modulated by ICS therapy. Methods: We cross-sectionally evaluated PAFr expression in bronchial biopsies from 15 COPD patients who were current smokers (COPD-smokers and 12 COPD-ex-smokers, and we compared these to biopsies from 16 smokers with normal lung function. We assessed immunostaining with anti-PAFr monoclonal antibody. We also used material from a previous double-blinded randomized placebo-controlled 6-month ICS intervention study in COPD patients to explore the effect of ICS on PAFr expression. We employed computer-aided image analysis to quantify the percentage of epithelium stained for PAFr. Results: Markedly enhanced expression of PAFr was found

  5. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

    OpenAIRE

    Amersi, Farin; Buelow, Roland; Kato, Hirohisa; Ke, Bibo; Coito, Ana J.; Shen, Xiu-Da; Zhao, Delai; Zaky, Joseph; Melinek, Judy; Lassman, Charles R.; Kolls, Jay K.; Alam, J.; Ritter, Thomas; Volk, Hans-Dieter; Farmer, Douglas G.

    1999-01-01

    We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibito...

  6. LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma

    OpenAIRE

    Yun-Bo, Feng; Xiao-Po, Liu; Xiao-Li, Li; Guo-Long, Cao; Pei, Zhang; Fa-Ming, Tian

    2016-01-01

    Abstract Objective: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1) in human osteosarcoma cells. Methods: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection eff...

  7. Recipients with In Utero Induction of Tolerance Upregulated MHC Class I in the Engrafted Donor Skin

    OpenAIRE

    Chen, Jeng-Chang; Ou, Liang-Shiou; Yu, Hsiu-Yueh; Kuo, Ming-Ling; Chang, Pei-Yeh; Chang, Hsueh-Ling

    2014-01-01

    The alterations in MHC class I expression play a crucial step in immune evasion of cancer or virus-infected cells. This study aimed to examine whether tolerized grafts modified MHC class I expression. FVB/N mice were rendered tolerant of C57BL/6 alloantigens by in utero transplantation of C57BL/6 marrows. Postnatally, engrafted donor skins and leukocytes were examined for their MHC expression by quantitative real-time PCR and flow cytometry. Engrafted donor skins upregulated their MHC class I...

  8. Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer?s disease

    OpenAIRE

    Chen, Po-Ting; Chen, Zih-ten; Hou, Wen-Chi; Yu, Lung-Chih; Chen, Rita P.-Y.

    2016-01-01

    Neprilysin (NEP) is the most important A?-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer?s disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer?s disease. Here, we used a sensitive fluorescence-based A? digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity...

  9. Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARα activation and oxidative stress

    International Nuclear Information System (INIS)

    Zhang, X.; Li, L.; Prabhakaran, K.; Zhang, L.; Leavesley, H.B.; Borowitz, J.L.; Isom, G.E.

    2007-01-01

    Uncoupling protein 2 (UCP-2) is an inner mitochondrial membrane proton carrier that modulates mitochondrial membrane potential (ΔΨ m ) and uncouples oxidative phosphorylation. We have shown that up-regulation of UCP-2 by Wy14,643, a selective peroxisome proliferator-activated receptor-α (PPARα) agonist, enhances cyanide cytotoxicity. The pathway by which Wy14,643 up-regulates UCP-2 was determined in a dopaminergic cell line (N27 cells). Since dopaminergic mesencephalic cells are a primary brain target of cyanide, the N27 immortalized mesencephalic cell was used in this study. Wy14,643 produced a concentration- and time-dependent up-regulation of UCP-2 that was linked to enhanced cyanide-induced cell death. MK886 (PPARα antagonist) or PPARα knock-down by RNA interference (RNAi) inhibited PPARα activity as shown by the peroxisome proliferator response element-luciferase reporter assay, but only partially decreased up-regulation of UCP-2. The role of oxidative stress as an alternative pathway to UCP-2 up-regulation was determined. Wy14,643 induced a rapid surge of ROS generation and loading cells with glutathione ethyl ester (GSH-EE) or pre-treatment with vitamin E attenuated up-regulation of UCP-2. On the other hand, RNAi knockdown of PPARα did not alter ROS generation, suggesting a PPARα-independent component to the response. Co-treatment with PPARα-RNAi and GSH-EE blocked both the up-regulation of UCP-2 by Wy14,643 and the cyanide-induced cell death. It was concluded that a PPARα-mediated pathway and an oxidative stress pathway independent of PPARα mediate the up-regulation of UCP-2 and subsequent increased vulnerability to cyanide-induced cytotoxicity

  10. Insecticide-Mediated Up-Regulation of Cytochrome P450 Genes in the Red Flour Beetle (Tribolium castaneum

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    Xiao Liang

    2015-01-01

    Full Text Available Some cytochrome P450 (CYP genes are known for their rapid up-regulation in response to insecticide exposures in insects. To date, however, limited information is available with respect to the relationships among the insecticide type, insecticide concentration, exposure duration and the up-regulated CYP genes. In this study, we examined the transcriptional response of eight selected CYP genes, including CYP4G7, CYP4Q4, CYP4BR3, CYP12H1, CYP6BK11, CYP9D4, CYP9Z5 and CYP345A1, to each of four insecticides in the red flour beetle, Tribolium castaneum. Reverse transcription quantitative PCR (RT-qPCR revealed that CYP4G7 and CYP345A1 can be significantly up-regulated by cypermethrin (1.97- and 2.06-fold, respectively, permethrin (2.00- and 2.03-fold and lambda-cyhalothrin (1.73- and 1.81-fold, whereas CYP4BR3 and CYP345A1 can be significantly up-regulated by imidacloprid (1.99- and 1.83-fold when 20-day larvae were exposed to each of these insecticides at the concentration of LC20 for 24 h. Our studies also showed that similar levels of up-regulation can be achieved for CYP4G7, CYP4BR3 and CYP345A1 by cypermethrin, permethrin, lambda-cyhalothrin or imidacloprid with approximately one fourth of LC20 in 6 h. Our study demonstrated that up-regulation of these CYP genes was rapid and only required low concentrations of insecticides, and the up-regulation not only depended on the CYP genes but also the type of insecticides. Our results along with those from previous studies also indicated that there were no specific patterns for predicting the up-regulation of specific CYP gene families based on the insecticide classification.

  11. Hibiscus chlorotic ringspot virus coat protein upregulates sulfur metabolism genes for enhanced pathogen defense.

    Science.gov (United States)

    Gao, Ruimin; Ng, Florence Kai Lin; Liu, Peng; Wong, Sek-Man

    2012-12-01

    In both Hibiscus chlorotic ringspot virus (HCRSV)-infected and HCRSV coat protein (CP) agroinfiltrated plant leaves, we showed that sulfur metabolism pathway related genes-namely, sulfite oxidase (SO), sulfite reductase, and adenosine 5'-phosphosulfate kinase-were upregulated. It led us to examine a plausible relationship between sulfur-enhanced resistance (SED) and HCRSV infection. We broadened an established method to include different concentrations of sulfur (0S, 1S, 2S, and 3S) to correlate them to symptom development of HCRSV-infected plants. We treated plants with glutathione and its inhibitor to verify the SED effect. Disease resistance was induced through elevated glutathione contents during HCRSV infection. The upregulation of SO was related to suppression of symptom development induced by sulfur treatment. In this study, we established that HCRSV-CP interacts with SO which, in turn, triggers SED and leads to enhanced plant resistance. Thus, we have discovered a new function of SO in the SED pathway. This is the first report to demonstrate that the interaction of a viral protein and host protein trigger SED in plants. It will be interesting if such interaction applies generally to other host-pathogen interactions that will lead to enhanced pathogen defense.

  12. Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease.

    Science.gov (United States)

    Grammatikos, Georgios; Mühle, Christiane; Ferreiros, Nerea; Schroeter, Sirkka; Bogdanou, Dimitra; Schwalm, Stephanie; Hintereder, Gudrun; Kornhuber, Johannes; Zeuzem, Stefan; Sarrazin, Christoph; Pfeilschifter, Josef

    2014-07-01

    Sphingolipids constitute bioactive molecules with functional implications in homeostasis and pathogenesis of various diseases. However, the role of sphingolipids as possible disease biomarkers in chronic liver disease remains largely unexplored. In the present study we used mass spectrometry and spectrofluorometry methods in order to quantify various sphingolipid metabolites and also assess the activity of an important corresponding regulating enzyme in the serum of 72 healthy volunteers as compared to 69 patients with non-alcoholic fatty liver disease and 69 patients with chronic hepatitis C virus infection. Our results reveal a significant upregulation of acid sphingomyelinase in the serum of patients with chronic liver disease as compared to healthy individuals (phepatitis C infection acid sphingomyelinase activity correlated significantly with markers of hepatic injury (r=0.312, p=0.009) and showed a high discriminative power. Accumulation of various (dihydro-) ceramide species was identified in the serum of patients with non-alcoholic fatty liver disease (pliver disease (phepatic injury was identified. Chronic hepatitis C virus infection and non-alcoholic fatty liver disease induce a significant upregulation of serum acid sphingomyelinase which appears as a novel biomarker in chronic hepatopathies. Further studies are required to elucidate the potential of the sphingolipid signaling pathway as putative therapeutic target in chronic liver disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Interleukin-20 targets podocytes and is upregulated in experimental murine diabetic nephropathy.

    Science.gov (United States)

    Hsu, Yu-Hsiang; Li, Hsing-Hui; Sung, Junne-Ming; Chen, Wei-Yu; Hou, Ya-Chin; Weng, Yun-Han; Lai, Wei-Ting; Wu, Chih-Hsing; Chang, Ming-Shi

    2017-03-31

    Interleukin (IL)-20, a proinflammatory cytokine of the IL-10 family, is involved in acute and chronic renal failure. The aim of this study was to elucidate the role of IL-20 during diabetic nephropathy development. We found that IL-20 and its receptor IL-20R1 were upregulated in the kidneys of mice and rats with STZ-induced diabetes. In vitro, IL-20 induced MMP-9, MCP-1, TGF-β1 and VEGF expression in podocytes. IL-20 was upregulated by hydrogen peroxide, high-dose glucose and TGF-β1. In addition, IL-20 induced apoptosis in podocytes by activating caspase-8. In STZ-induced early diabetic nephropathy, IL-20R1-deficient mice had lower blood glucose and serum BUN levels and a smaller glomerular area than did wild-type controls. Anti-IL-20 monoclonal antibody (7E) treatment reduced blood glucose and the glomerular area and improved renal functions in mice in the early stage of STZ-induced diabetic nephropathy. ELISA showed that the serum IL-20 level was higher in patients with diabetes mellitus than in healthy controls. The findings of this study suggest that IL-20 induces cell apoptosis of podocytes and plays a role in the pathogenesis of early diabetic nephropathy.

  14. In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT

    International Nuclear Information System (INIS)

    Kassiou, Michael; Eberl, Stefan; Meikle, Steven R.; Birrell, Alex; Constable, Chris; Fulham, Michael J.; Wong, Dean F.; Musachio, John L.

    2001-01-01

    To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[ 123 I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[ 123 I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution (V d ) and binding potential (BP) derived from 3-compartment model fits. In the (-)-nicotine treated animal V d was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in V d or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment

  15. Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes.

    Directory of Open Access Journals (Sweden)

    Xiaoling Wang

    Full Text Available The objective was to examine the protective effect of metformin (Met on myocardial ischemia-reperfusion (IR injury and whether the mechanism was related to the AMPK/ antioxidant enzymes signaling pathway. Rat Langendorff test and H2O2-treated rat cardiomyocytes (H9c2 were used in this study. Met treatment significantly improved left ventricular (LV function, reduced infarct size and CK-MB release in comparison with IR group. Decreased TUNEL staining positive cells were also observed in IR+Met group ex vivo. Met treatment markedly inhibited IR inducing cell death and significantly decreased apoptosis with few generations of reactive oxygen species (ROS in H9c2 cells in comparison with IR group. Up-regulated expressions of phosphorylated LKB1/AMPK/ACC, as well as down-regulated expressions of apoptotic proteins (Bax and cleaved caspase 3 were found in IR+Met group when compared to the IR group. Importantly, Met significantly up-regulated the expression of antioxidant enzymes (MnSOD and catalase during IR procedure either ex vivo or in vitro. Compound C, a conventional inhibitor of AMPK, abolished the promoting effect of Met on antioxidant enzymes, and then attenuated the protective effect of Met on IR injury in vitro. In conclusion, Met exerted protective effect on myocardial IR injury, and this effect was AMPK/ antioxidant enzymes dependent.

  16. Ski diminishes TGF-β1-induced myofibroblast phenotype via up-regulating Meox2 expression.

    Science.gov (United States)

    Chen, Zhaowei; Li, Wenjing; Ning, Yan; Liu, Tong; Shao, Jingxiang; Wang, Yaojun

    2014-12-01

    The aim of the present work was to investigate the mechanism of transforming growth factor (TGF)-β1 and Sloan-Kettering Institute (Ski) in the pathogenesis of hypertrophic scars (HS). Wound healing is an inherent process, but the aberrant wound healing of skin injury may lead to HS. There has been growing evidence suggesting a role for TGF-β1 and Ski in the pathogenesis of fibrosis. The MTT assay was used to detect the cell proliferation induced by TGF-β1. The Ski gene was transduced into cells with an adenovirus, and then the function of Ski in cell proliferation and differentiation was observed. Ski mRNA levels were measured by RT-PCR. Western blotting was used to detect the protein expression of α-SMA, E-cadherin, Meox1, Meox2, Zeb1 and Zeb2. TGF-β1 can promote human skin fibroblast (HSF) cell proliferation in a time-dependent manner, but the promoting effect could be suppressed by Ski. TGF-β1 also induces the formation of the myofibroblast phenotype and the effect of TGF-β1 could be diminished by Ski. Also, Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by up-regulating the expression of Meox2. Ski diminishes the myofibroblast phenotype induced by TGF-β1 through the suppression of Zeb2 by up-regulating the expression of Meox2. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Hypothalamic L-Histidine Decarboxylase Is Up-Regulated During Chronic REM Sleep Deprivation of Rats.

    Directory of Open Access Journals (Sweden)

    Gloria E Hoffman

    Full Text Available A competition of neurobehavioral drives of sleep and wakefulness occurs during sleep deprivation. When enforced chronically, subjects must remain awake. This study examines histaminergic neurons of the tuberomammillary nucleus of the posterior hypothalamus in response to enforced wakefulness in rats. We tested the hypothesis that the rate-limiting enzyme for histamine biosynthesis, L-histidine decarboxylase (HDC, would be up-regulated during chronic rapid eye movement sleep deprivation (REM-SD because histamine plays a major role in maintaining wakefulness. Archived brain tissues of male Sprague Dawley rats from a previous study were used. Rats had been subjected to REM-SD by the flowerpot paradigm for 5, 10, or 15 days. For immunocytochemistry, rats were transcardially perfused with acrolein-paraformaldehyde for immunodetection of L-HDC; separate controls used carbodiimide-paraformaldehyde for immunodetection of histamine. Immunolocalization of histamine within the tuberomammillary nucleus was validated using carbodiimide. Because HDC antiserum has cross-reactivity with other decarboxylases at high antibody concentrations, titrations localized L-HDC to only tuberomammillary nucleus at a dilution of ≥ 1:300,000. REM-SD increased immunoreactive HDC by day 5 and it remained elevated in both dorsal and ventral aspects of the tuberomammillary complex. Our results suggest that up-regulation of L-HDC within the tuberomammillary complex during chronic REM-SD may be responsible for maintaining wakefulness.

  18. Exendin-4 Upregulates Adiponectin Level in Adipocytes via Sirt1/Foxo-1 Signaling Pathway.

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    Anping Wang

    Full Text Available Glucagon-like peptide-1 (GLP-1 receptor plays an essential role in regulating glucose metabolism. GLP-1 receptor agonists have been widely used for treating diabetes and other insulin resistance-related diseases. However, mechanisms underlying the anti-diabetic effects of GLP-1 receptor agonists remain largely unknown. In this study, we investigated the effects of GLP-1 agonist exendin-4 on the expression of adiponectin, an insulin sensitizing hormone. We found that exendin-4 increased the expression and secretion of adiponectin both in vitro and in vivo. Our data showed that exendin-4 upregulated adiponectin expression at both mRNA and protein levels in adipocytes and adipose tissues. The effects of exendin-4 on adiponectin expression were dependent on the GLP-1 receptor. We further demonstrated important roles of Sirt1 and transcriptional factor Foxo-1 in mediating the function of exendin-4 in regulating adiponectin expression. Suppression of Sirt1 or Foxo-1 expression significantly impaired exendin-4-induced adiponectin expression. Consistently, exendin-4 up-regulated Sirt1 and Foxo-1 expression in vivo. Our work is the first study demonstrating the role of Sirt1/Foxo-1 in regulating the regulatory function of a GLP-1 receptor agonist in adiponectin expression both in vitro and in vivo. The results provide important information for the mechanism underlying the function of GLP-1R on improving insulin resistance and related diseases.

  19. Upregulating Nonneuronal Cholinergic Activity Decreases TNF Release from Lipopolysaccharide-Stimulated RAW264.7 Cells

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    Yi Lv

    2014-01-01

    Full Text Available Nonneuronal cholinergic system plays a primary role in maintaining homeostasis. It has been proved that endogenous neuronal acetylcholine (ACh could play an anti-inflammatory role, and exogenous cholinergic agonists could weaken macrophages inflammatory response to lipopolysaccharide (LPS stimulation through activation of α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR. We assumed that nonneuronal cholinergic system existing in macrophages could modulate inflammation through autocrine ACh and expressed α7nAChR on the cells. Therefore, we explored whether LPS continuous stimulation could upregulate the nonneuronal cholinergic activity in macrophages and whether increasing autocrine ACh could decrease TNF release from the macrophages. The results showed that, in RAW264.7 cells incubated with LPS for 20 hours, the secretion of ACh was significantly decreased at 4 h and then gradually increased, accompanied with the enhancement of α7nAChR expression level. The release of TNF was greatly increased from RAW264.7 cells at 4 h and 8 h exposure to LPS; however, it was suppressed at 20 h. Upregulating choline acetyltransferase (ChAT expression through ChAT gene transfection could enhance ACh secretion and reduce TNF release from the infected RAW264. 7cells. The results indicated that LPS stimulation could modulate the activity of nonneuronal cholinergic system of RAW264.7 cells. Enhancing autocrine ACh production could attenuate TNF release from RAW264.7 cells.

  20. High glucose induces apoptosis via upregulation of Bim expression in proximal tubule epithelial cells.

    Science.gov (United States)

    Zhang, Xiao-Qian; Dong, Jian-Jun; Cai, Tian; Shen, Xue; Zhou, Xiao-Jun; Liao, Lin

    2017-04-11

    Diabetic nephropathy is the primary cause of end-stage renal disease. Apoptosis of tubule epithelial cells is a major feature of diabetic nephropathy. The mechanisms of high glucose (HG) induced apoptosis are not fully understood. Here we demonstrated that, HG induced apoptosis via upregulating the expression of proapoptotic Bcl-2 homology domain 3 (BH3)-only protein Bim protein, but not bring a significant change in the baseline level of autophagy in HK2 cells. The increase of Bim expression was caused by the ugregulation of transcription factors, FOXO1 and FOXO3a. Bim expression initiates BAX/BAK-mediated mitochondria-dependent apoptosis. Silence of Bim by siRNA in HK2 cells prevented HG-induced apoptosis and also sensitized HK2 cells to autophagy during HG treatment. The autophagy inhibitor 3-MA increased the injury in Bim knockdown HK2 cells by retriggering apoptosis. The above results suggest a Bim-independent apoptosis pathway in HK2 cells, which normally could be inhibited by autophagy. Overall, our results indicate that HG induces apoptosis via up-regulation of Bim expression in proximal tubule epithelial cells.

  1. Honey constituents up-regulate detoxification and immunity genes in the western honey bee Apis mellifera.

    Science.gov (United States)

    Mao, Wenfu; Schuler, Mary A; Berenbaum, May R

    2013-05-28

    As a managed pollinator, the honey bee Apis mellifera is critical to the American agricultural enterprise. Recent colony losses have thus raised concerns; possible explanations for bee decline include nutritional deficiencies and exposures to pesticides and pathogens. We determined that constituents found in honey, including p-coumaric acid, pinocembrin, and pinobanksin 5-methyl ether, specifically induce detoxification genes. These inducers are primarily found not in nectar but in pollen in the case of p-coumaric acid (a monomer of sporopollenin, the principal constituent of pollen cell walls) and propolis, a resinous material gathered and processed by bees to line wax cells. RNA-seq analysis (massively parallel RNA sequencing) revealed that p-coumaric acid specifically up-regulates all classes of detoxification genes as well as select antimicrobial peptide genes. This up-regulation has functional significance in that that adding p-coumaric acid to a diet of sucrose increases midgut metabolism of coumaphos, a widely used in-hive acaricide, by ∼60%. As a major component of pollen grains, p-coumaric acid is ubiquitous in the natural diet of honey bees and may function as a nutraceutical regulating immune and detoxification processes. The widespread apicultural use of honey substitutes, including high-fructose corn syrup, may thus compromise the ability of honey bees to cope with pesticides and pathogens and contribute to colony losses.

  2. MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.

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    Emeric Deruy

    Full Text Available Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2O(2 overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2O(2 level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2O(2. This H(2O(2-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria.

  3. Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation and the ubiquitin proteasome pathway.

    Science.gov (United States)

    Wright, C; Edelmann, M; diGleria, K; Kollnberger, S; Kramer, H; McGowan, S; McHugh, K; Taylor, S; Kessler, B; Bowness, P

    2009-10-01

    To determine if peripheral blood monocytes from patients with ankylosing spondylitis (AS) differed in protein expression compared to rheumatoid arthritis (RA) and healthy controls (HC). Monocyte protein expression was characterised by 2D gel electrophoresis and by label-free quantitative expression profiling, using nano-ultra performance liquid chromatography coupled to electrospray ionisation mass spectrometry (ESI-MS(E), where (E) refers to low/high collision energy switching). Data sets were analysed using the Waters expression profiling system and Ingenuity pathway analysis (IPA). Two-dimensional gel electrophoresis showed upregulation of proteasomal constituents in AS monocytes, including the beta subunit of proteasome activator (PA)28. Monocyte expression profiling and IPA showed that significant changes in protein expression within the ubiquitin proteasome pathway (UPP) were restricted to AS monocytes. Statistically significant differences in protein expression involving the leucocyte extravasation, vascular endothelial growth factor, integrin and Toll-like receptor signalling pathways were seen in AS and RA monocytes compared to healthy controls. No evidence of upregulation of proteins involved in the endoplasmic reticulum stress response pathway was found in either AS or RA monocytes. Finally, the PA28 complex was shown to increase the generation of human leucocyte antigen (HLA)-B27 antigenic epitopes by the proteasome in vitro. Our proteomic analyses support the hypothesis that monocytes play an important role in the pathogenesis of AS and RA, and further suggest a specific role in AS for the UPP. Quantitative proteomic expression profiling constitutes a powerful new tool for rheumatology research.

  4. Utrophin up-regulation by an artificial transcription factor in transgenic mice.

    Directory of Open Access Journals (Sweden)

    Elisabetta Mattei

    2007-08-01

    Full Text Available Duchenne Muscular Dystrophy (DMD is a severe muscle degenerative disease, due to absence of dystrophin. There is currently no effective treatment for DMD. Our aim is to up-regulate the expression level of the dystrophin related gene utrophin in DMD, complementing in this way the lack of dystrophin functions. To this end we designed and engineered several synthetic zinc finger based transcription factors. In particular, we have previously shown that the artificial three zinc finger protein named Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from the utrophin promoter "A". Here we report on the characterization of Vp16-Jazz-transgenic mice that specifically over-express the utrophin gene at the muscular level. A Chromatin Immunoprecipitation assay (ChIP demonstrated the effective access/binding of the Jazz protein to active chromatin in mouse muscle and Vp16-Jazz was shown to be able to up-regulate endogenous utrophin gene expression by immunohistochemistry, western blot analyses and real-time PCR. To our knowledge, this is the first example of a transgenic mouse expressing an artificial gene coding for a zinc finger based transcription factor. The achievement of Vp16-Jazz transgenic mice validates the strategy of transcriptional targeting of endogenous genes and could represent an exclusive animal model for use in drug discovery and therapeutics.

  5. Neural cell 3D microtissue formation is marked by cytokines' up-regulation.

    Directory of Open Access Journals (Sweden)

    Yinzhi Lai

    Full Text Available Cells cultured in three dimensional (3D scaffolds as opposed to traditional two-dimensional (2D substrates have been considered more physiologically relevant based on their superior ability to emulate the in vivo environment. Combined with stem cell technology, 3D cell cultures can provide a promising alternative for use in cell-based assays or biosensors in non-clinical drug discovery studies. To advance 3D culture technology, a case has been made for identifying and validating three-dimensionality biomarkers. With this goal in mind, we conducted a transcriptomic expression comparison among neural progenitor cells cultured on 2D substrates, 3D porous polystyrene scaffolds, and as 3D neurospheres (in vivo surrogate. Up-regulation of cytokines as a group in 3D and neurospheres was observed. A group of 13 cytokines were commonly up-regulated in cells cultured in polystyrene scaffolds and neurospheres, suggesting potential for any or a combination from this list to serve as three-dimensionality biomarkers. These results are supportive of further cytokine identification and validation studies with cells from non-neural tissue.

  6. A eukaryotic initiation factor 5C is upregulated during metamorphosis in the cotton bollworm, Helicoverpa armigera.

    Science.gov (United States)

    Dong, Du-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2009-03-08

    The orthologs of eukaryotic initiation factor 5C (eIF5C) are essential to the initiation of protein translation, and their regulation during development is not well known. A cDNA encoding a polypeptide of 419 amino acids containing an N-terminal leucine zipper motif and a C-terminal eIF5C domain was cloned from metamorphic larvae of Helicoverpa armigera. It was subsequently named Ha-eIF5C. Quantitative real-time PCR (QRT-PCR) revealed a high expression of the mRNA of Ha-eIF5C in the head-thorax, integument, midgut, and fat body during metamorphosis. Immunohistochemistry suggested that Ha-eIF5C was distributed into both the cytoplasm and the nucleus in the midgut, fat body and integument. Ha-eIF5C expression was upregulated by 20-hydroxyecdysone (20E). Furthermore, the transcription of Ha-eIF5C was down regulated after silencing of ecdysteroid receptor (EcR) or Ultraspiracle protein (USP) by RNAi. These results suggested that during metamorphosis of the cotton bollworm, Ha-eIF5C was upregulated by 20E through the EcR and USP transcription factors.

  7. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

    Science.gov (United States)

    Amersi, Farin; Buelow, Roland; Kato, Hirohisa; Ke, Bibo; Coito, Ana J.; Shen, Xiu-Da; Zhao, Delai; Zaky, Joseph; Melinek, Judy; Lassman, Charles R.; Kolls, Jay K.; Alam, J.; Ritter, Thomas; Volk, Hans-Dieter; Farmer, Douglas G.; Ghobrial, Rafik M.; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

    1999-01-01

    We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy–induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation. J. Clin. Invest. 104:1631–1639 (1999). PMID:10587527

  8. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina.

    Science.gov (United States)

    Young, T L; Matsuda, T; Cepko, C L

    2005-03-29

    With the advent of genome-wide analyses, it is becoming evident that a large number of noncoding RNAs (ncRNAs) are expressed in vertebrates. However, of the thousands of ncRNAs identified, the functions of relatively few have been established. In a screen for genes upregulated by taurine in developing retinal cells, we identified a gene that appears to be a ncRNA. Taurine Upregulated Gene 1 (TUG1) is a spliced, polyadenylated RNA that does not encode any open reading frame greater than 82 amino acids in its full-length, 6.7 kilobase (kb) RNA sequence. Analyses of Northern blots and in situ hybridization revealed that TUG1 is expressed in the developing retina and brain, as well as in adult tissues. In the newborn retina, knockdown of TUG1 with RNA interference (RNAi) resulted in malformed or nonexistent outer segments of transfected photoreceptors. Immunofluorescent staining and microarray analyses suggested that this loss of proper photoreceptor differentiation is a result of the disregulation of photoreceptor gene expression. A function for a newly identified ncRNA, TUG1, has been established. TUG1 is necessary for the proper formation of photoreceptors in the developing rodent retina.

  9. Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration.

    Science.gov (United States)

    Hu, Yingying; Sun, Xiangwei; Mao, Chenchen; Guo, Gangqiang; Ye, Sisi; Xu, Jianfeng; Zou, Ruanmin; Chen, Jun; Wang, Ledan; Duan, Ping; Xue, Xiangyang

    2017-02-01

    Long noncoding RNAs (lncRNAs), a novel class of transcripts that have critical roles in carcinogenesis and progression, have emerged as important gene expression modulators. Recent evidence indicates that lncRNA taurine-upregulated gene 1 (TUG1) functions as an oncogene in numerous types of human cancers. However, its function in the development of cervical cancer remains unknown. The aim of this research was to investigate the clinical significance and biological functions of TUG1 in cervical cancer. TUG1 was found to be significantly upregulated in cervical cancer tissues and four cervical cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Elevated TUG1 expression was correlated with larger tumor size, advanced international federation of gynecology and obstetrics (FIGO) stage, poor differentiation, and lymph node metastasis. Furthermore, knockdown of TUG1 suppressed cell proliferation with activation of apoptosis, in part by regulating the expression of Bcl-2 and caspase-3. Silencing of TUG1 inhibited cell migration and invasion via the progression of epithelial-mesenchymal transition (EMT). Taken together, our findings indicate that TUG1 acts as an oncogene in cervical cancer and may represent a novel therapeutic target. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  10. IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance.

    Science.gov (United States)

    Tsai, Pei-Yun; Zhang, Bingkun; He, Wei-Qi; Zha, Juan-Min; Odenwald, Matthew A; Singh, Gurminder; Tamura, Atsushi; Shen, Le; Sailer, Anne; Yeruva, Sunil; Kuo, Wei-Ting; Fu, Yang-Xin; Tsukita, Sachiko; Turner, Jerrold R

    2017-06-14

    Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na + channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. A eukaryotic initiation factor 5C is upregulated during metamorphosis in the cotton bollworm, Helicoverpa armigera

    Directory of Open Access Journals (Sweden)

    Zhao Xiao-Fan

    2009-03-01

    Full Text Available Abstract Background The orthologs of eukaryotic initiation factor 5C (eIF5C are essential to the initiation of protein translation, and their regulation during development is not well known. Results A cDNA encoding a polypeptide of 419 amino acids containing an N-terminal leucine zipper motif and a C-terminal eIF5C domain was cloned from metamorphic larvae of Helicoverpa armigera. It was subsequently named Ha-eIF5C. Quantitative real-time PCR (QRT-PCR revealed a high expression of the mRNA of Ha-eIF5C in the head-thorax, integument, midgut, and fat body during metamorphosis. Immunohistochemistry suggested that Ha-eIF5C was distributed into both the cytoplasm and the nucleus in the midgut, fat body and integument. Ha-eIF5C expression was upregulated by 20-hydroxyecdysone (20E. Furthermore, the transcription of Ha-eIF5C was down regulated after silencing of ecdysteroid receptor (EcR or Ultraspiracle protein (USP by RNAi. Conclusion These results suggested that during metamorphosis of the cotton bollworm, Ha-eIF5C was upregulated by 20E through the EcR and USP transcription factors.

  12. p53 inhibits the upregulation of sirtuin 1 expression induced by c-Myc.

    Science.gov (United States)

    Yuan, Fang; Liu, Lu; Lei, Yonghong; Tang, Peifu

    2017-10-01

    Sirtuin 1 (Sirt1), a conserved NAD + dependent deacetylase, is a mediator of life span by calorie restriction. However, Sirt1 may paradoxically increase the risk of cancer. Accordingly, the expression level of Sirt1 is selectively elevated in numerous types of cancer cell; however, the mechanisms underlying the differential regulation remain largely unknown. The present study demonstrated that oncoprotein c-Myc was a direct regulator of Sirt1, which accounts for the upregulation of Sirt1 expression only in the cells without functional p53. In p53 deficient cells, the overexpression of c-Myc increased Sirt1 mRNA and protein expression levels as well as its promoter activity, whereas the inhibitor of c-Myc, 10058-F4, induced decreased Sirt1 basal mRNA and protein expression levels. Deletion/mutation mapping analyses revealed that c-Myc bound to the conserved E-box[-189 to -183 base pair (bp)] of the Sirt1 promoter. In addition, p53 and c-Myc shared at least response element and the presence of p53 may block the binding of c-Myc to the Sirt1 promoter, thus inhibit the c-Myc mediated upregulation of Sirt1 promoter activity. The present study indicated that the expression level of Sirt1 was tightly regulated by oncoprotein c-Myc and tumor suppressor p53, which aids an improved understanding of its expression regulation and tumor promoter role in certain conditions.

  13. Upregulations of CRH and CRHR1 in the Epileptogenic Tissues of Patients with Intractable Infantile Spasms.

    Science.gov (United States)

    Yang, Xiao-Lin; Chen, Bing; Zhang, Xiao-Qing; Chen, Xin; Yang, Mei-Hua; Zhang, Wei; Chen, Huan-Ran; Zang, Zhen-Le; Li, Wei; Yang, Hui; Liu, Shi-Yong

    2017-01-01

    Infantile spasms (IS) are an age-specific epileptic syndrome with specific clinical symptom and electroencephalogram (EEG) features, lacking treatment options, and a poor prognosis. Excessive endogenous corticotropin-releasing hormone (CRH) in infant brain might result in IS. However, the data from human IS are limited. In our study, we investigated the expressions of CRH and its receptor type 1 (CRHR1) in surgical tissues from patients with IS and autopsy controls. Specimens surgically removed from 17 patients with IS, and six autopsy controls were included in the study. Real-time PCR, Western blotting, and immunostaining were used to detect the expressions of mRNA, protein expression, and distribution. The correlation between variates was analyzed by Spearman rank correlation. The expressions of CRH and CRHR1 were significantly upregulated in the epileptogenic tissues of IS patients compared with the control group. CRH was distributed mainly in neurons, while CRHR1 was distributed in neurons, astrocytes, and microglia. The expression levels of CRH and CRHR1 were positively correlated with the frequency of epileptic spasms. Moreover, the expression of protein kinase C (PKC), which was an important downstream factor of CRHR1, was significantly upregulated in the epileptogenic tissues of patients with IS and was positively correlated with the CRHR1 expression levels and the frequency of epileptic spasms. These results suggest that the CRH signal transduction pathway might participate in the epileptogenesis of IS, supporting the hypothesis that CRH is related to the pathogenesis of IS. © 2016 John Wiley & Sons Ltd.

  14. IFN-alpha-induced upregulation of CCR5 leads to expanded HIV tropism in vivo.

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    Cheryl A Stoddart

    2010-02-01

    Full Text Available Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu Thy/Liv mice with X4 and R5 HIV. X4 HIV was observed to infect CD3(-CD4(+CD8(-CXCR4(+CCR5(- intrathymic T-cell progenitors (ITTP and to abrogate thymopoiesis. R5 HIV, by contrast, first established a nonpathogenic infection of thymic macrophages and then, after many weeks, began to replicate in ITTP. We demonstrate here that the tropism of R5 HIV is expanded and pathogenicity enhanced by upregulation of CCR5 on these key T-cell progenitors. Such CCR5 induction was mediated by interferon-alpha (IFN-alpha in both thymic organ cultures and in SCID-hu mice, and antibody neutralization of IFN-alpha in R5 HIV-infected SCID-hu mice inhibited both CCR5 upregulation and infection of the T-cell progenitors. These observations suggest a mechanism by which IFN-alpha production may paradoxically expand the tropism of R5 HIV and, in so doing, accelerate disease progression.

  15. Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis.

    LENUS (Irish Health Repository)

    O'Connor, Terence M

    2012-02-03

    Substance P (SP) is a proinflammatory neuropeptide that is secreted by sensory nerves and inflammatory cells. Increased levels of SP are found in sarcoid bronchoalveolar lavage fluid. SP acts by binding to the neurokinin-1 receptor and increases secretion of tumor necrosis factor-alpha in many cell types. We sought to determine neurokinin-1 receptor expression in patients with sarcoidosis compared with normal controls. Neurokinin-1 receptor messenger RNA and protein expression were below the limits of detection by reverse transcriptase-polymerase chain reaction and immunohistochemistry in peripheral blood mononuclear cells of healthy volunteers (n = 9) or patients with stage 1 or 2 pulmonary sarcoidosis (n = 10), but were detected in 1\\/9 bronchoalveolar lavage cells of controls compared with 8\\/10 patients with sarcoidosis (p = 0.012) and 2\\/9 biopsies of controls compared with 9\\/10 patients with sarcoidosis (p = 0.013). Immunohistochemistry localized upregulated neurokinin-1 receptor expression to bronchial and alveolar epithelial cells, macrophages, lymphocytes, and sarcoid granulomas. The patient in whom neurokinin-1 receptor was not detected was taking corticosteroids. Incubation of the type II alveolar and bronchial epithelial cell lines A549 and SK-LU 1 with dexamethasone downregulated neurokinin-1 receptor expression. Upregulated neurokinin-1 receptor expression in patients with sarcoidosis may potentiate substance P-induced proinflammatory cytokine production in patients with sarcoidosis.

  16. ROS-dependent HMGA2 upregulation mediates Cd-induced proliferation in MRC-5 cells.

    Science.gov (United States)

    Xie, Huaying; Wang, Jiayue; Jiang, Liping; Geng, Chengyan; Li, Qiujuan; Mei, Dan; Zhao, Lian; Cao, Jun

    2016-08-01

    Cadmium (Cd) is a heavy metal widely found in a number of environmental matrices, and the exposure to Cd is increasing nowadays. In this study, the role of high mobility group A2 (HMGA2) in Cd-induced proliferation was investigated in MRC-5 cells. Exposure to Cd (2μM) for 48h significantly enhanced the growth of MRC-5 cells, increased reactive oxygen species (ROS) production, and induced both mRNA and protein expression of HMGA2. Evidence for Cd-induced reduction of the number of G0/G1 phase cells and an increase in the number of cells in S phase and G2/M phase was sought by flow cytometric analysis. Western blot analysis showed that cyclin D1, cyclin B1, and cyclin E were upregulated in Cd-treated cells. Further study revealed that N-acetyl cysteine (NAC) markedly prevented Cd-induced proliferation of MRC-5 cells, ROS generation, and the increasing protein level of HMGA2. Silencing of HMGA2 gene by siRNA blocked Cd-induced cyclin D1, cyclin B1, and cyclin E expression and reduction of the number of G0/G1 phase cells. Combining, our data showed that Cd-induced ROS formation provoked HMGA2 upregulation, caused cell cycle changes, and led to cell proliferation. This suggests that HMGA2 might be an important biomarker in Cd-induced cell proliferation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. A Transporter of Ibuprofen is Upregulated in MDCK I Cells under Hyperosmotic Culture Conditions

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Rasmussen, Rune N; Mo, Junying

    2016-01-01

    Ibuprofen is a widely used drug. It has been identified as an inhibitor of several transporters, but it is not clear if ibuprofen is a substrate of any transporter itself. In the present work, we have characterized a transporter of ibuprofen, which is upregulated by hyperosmotic culture conditions...... in Madin-Darby canine kidney I (MDCK I) renal cells. [(3)H]-Ibuprofen uptake rate was measured in MDCK I cell cultured under normal (300 mOsm) and hyperosmotic (500 mOsm) conditions. Hyperosmotic conditions were obtained by supplementing urea, NaCl, mannitol, or raffinose to culture medium. The effect...... of increased osmolarity was investigated for different incubation times. [(3)H]-Ibuprofen uptake in MDCK I cells was upregulated by hyperosmotic culture condition, and was saturable with a Km value of 0.37 ± 0.08 μM and a Vmax of 233.1 ± 17.2 pmol· cm(-2)· min(-1). Racemic [(3)H]-ibuprofen uptake could...

  18. Recipients with In Utero Induction of Tolerance Upregulated MHC Class I in the Engrafted Donor Skin

    Directory of Open Access Journals (Sweden)

    Jeng-Chang Chen

    2014-01-01

    Full Text Available The alterations in MHC class I expression play a crucial step in immune evasion of cancer or virus-infected cells. This study aimed to examine whether tolerized grafts modified MHC class I expression. FVB/N mice were rendered tolerant of C57BL/6 alloantigens by in utero transplantation of C57BL/6 marrows. Postnatally, engrafted donor skins and leukocytes were examined for their MHC expression by quantitative real-time PCR and flow cytometry. Engrafted donor skins upregulated their MHC class I related gene transcripts after short-term (1~2 weeks or long-term (>1 month engraftment. This biological phenomenon was simultaneously associated with upregulation of TAP1 gene transcripts, suggesting an important role of TAP1 in the regulation of MHC class I pathway. The surface MHC class I molecules of H-2Kb in engrafted donor leukocytes consistently showed overexpression. Conclusively, the induction of allograft tolerance involved biological modifications of donor transplants. The overexpression of MHC class I within engrafted transplants of tolerant mice might be used as the tolerance biomarkers for identifying a state of graft tolerance.

  19. Retrospective Rescreening of Negative Cervical Cytology Samples Preceding Histologically Proven CIN2-3 and Squamous Cell Carcinoma: An Educational Opportunity to Understand and Prevent Laboratory Errors.

    Science.gov (United States)

    Feoli, Francesco; Renard, Christine; Abouyahia, Meryme; De Wind, Roland; Larsimont, Denis; Arbyn, Marc

    2015-01-01

    We aimed to analyze the false-negative (FN) liquid-based cytology diagnoses from the 5 years preceding all the 2013 histologically proven cervical intraepithelial neoplasia (CIN)2-3 and squamous cell carcinoma (SCC) and to propose corrective actions. This was a retrospective, blinded rescreening ('5-year look-back') of liquid-based cytology samples with negative categorizations, which occurred before histologically proven CIN2-3 and SCC. The FN rate was 7.8% (21/256 samples preceding CIN2-3 and 0/13 samples preceding SCC). Slides confirmed as 'negative', 'interpretation error' and 'screening error', respectively, were 3.3% (9/269), 2.6% (7/269) and 1.9% (5/269). In 9/12 cases, error was associated with small atypical cells. In 7/12 cases, these diagnostic cells were less than 5/10 HPF. Inflammation and prominent reactive changes were present in 5/12 cases. Five patients had a positive clinical history. In 2 cases, there were multiple-cell-layer artifacts. Dense groups of small blue atypical cells were missed in 2 other cases. Dotting was imprecise in 6/7 samples. Considering the above results, we specifically reoriented our continuous education activities, focusing rapid rescreening on scanty, isolated, small, atypical cells and dense cell groups. Prior to final diagnosis, pathologists should systematically review the entire surface of the dotted slides, with special attention being devoted to slides with multiple cell layers and tridimensional groups. © 2015 S. Karger AG, Basel.

  20. Variation in the costs of dying and the role of different health services, socio-demographic characteristics, and preceding health care expenses.

    Science.gov (United States)

    Rolden, Herbert J A; van Bodegom, David; Westendorp, Rudi G J

    2014-11-01

    The health care costs of population ageing are for an important part attributable to higher mortality rates in combination with high costs of dying. This paper answers three questions that remain unanswered regarding the costs of dying: (1) contributions of different health services to the costs of dying; (2) variation in the costs of dying; and (3) the influence of preceding health care expenses on the costs of dying. We retrieved data on 61,495 Dutch subjects aged 65 and older from July 2007 through 2010 from a regional health care insurer. We included all deceased subjects of whom health care expenses were known for 26 months prior to death (n=2833). Costs of dying were defined as health care expenses made in the last six months before death. Lorenz curves, generalized linear models and a two-part model were used for our analyses. (1) The average costs of dying are €25,919. Medical care contributes to 57% of this total, and long-term care 43%. The costs of dying mainly relate to hospital care (40%). (2) In the costs of dying, 75% is attributable to the costliest half of the population. For medical care, this distribution figure is 86%, and for long-term care 92%. Age and preceding expenses are significant determinants of this variation in the costs of dying. (3) Overall, higher preceding health care expenses are associated with higher costs of dying, indicating that the costs of dying are higher for those with a longer patient history. To summarize, there is not a large variation in the costs of dying, but there are large differences in the nature of these costs. Before death, the oldest old utilize more long-term care while their younger counterparts visit hospitals more often. To curb the health care costs of population ageing, a further understanding of the costs of dying is crucial. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: Possible role in mechanical stress-induced hyperpigmentation

    Energy Technology Data Exchange (ETDEWEB)

    Kurita, Masakazu, E-mail: masakazukurita@gmail.com [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Okazaki, Mutsumi [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Fujino, Takashi [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Takushima, Akihiko; Harii, Kiyonori [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)

    2011-05-27

    Highlights: {yields} Influence of cyclic stretch on melanogenetic paracrine cytokines was investigated. {yields} Keratinocyte-derived endothelin-1 was upregulated with cyclic stretch. {yields} Degree of upregulation increases dose-dependently. {yields} This upregulation possibly plays a role in the pathogenesis of pigmented disorders. -- Abstract: The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1{alpha}, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.

  2. G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors*

    Science.gov (United States)

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2013-01-01

    We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. PMID:23592773

  3. Upregulation of a tonoplast-localized cytochrome P450 during petal senescence in Petunia inflata

    Directory of Open Access Journals (Sweden)

    Ishida Hiroyuki

    2006-04-01

    Full Text Available Abstract Background Gene expression in Petunia inflata petals undergoes major changes following compatible pollination. Severe flower wilting occurs reproducibly within 36 hours, providing an excellent model for investigation of petal senescence and programmed cell death. Expression of a number of genes and various enzyme activities involved in the degradation and remobilization of macromolecules have been found to be upregulated during the early stages of petal senescence. Results By performing differential display of cDNAs during Petunia inflata petal senescence, a highly upregulated gene encoding a cytochrome P450 was identified. Analysis of the complete cDNA sequence revealed that the predicted protein is a member of the CYP74C family (CYP74C9 and is highly similar to a tomato CYP74C allene oxide synthase (AOS that is known to be active on 9-hydroperoxides. Cloning of the petunia genomic DNA revealed an intronless gene with a promoter region that carries signals found in stress-responsive genes and potential binding sites for Myb transcription factors. Transcripts were present at detectable levels in root and stem, but were 40 times more abundant in flowers 36 hours after pollination. Ethylene and jasmonate treatment resulted in transitory increases in expression in detached flowers. A protein fusion of the CYP74C coding region to a C-terminal GFP was found to be located in the tonoplast. Conclusion Though oxylipins, particularly jasmonates, are known to be involved in stress responses, the role of other products of CYP74 enzymes is less well understood. The identification of a CYP74C family member as a highly upregulated gene during petal senescence suggests that additional products of fatty acid metabolism may play important roles during programmed cell death. In contrast to the chloroplast localization of AOS proteins in the CYP74A subfamily, GFP fusion data indicates that the petunia CYP74C9 enzyme is in the tonoplast. This result

  4. Upregulation of metastasis-associated gene 2 promotes cell proliferation and invasion in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Wu MH

    2016-03-01

    Full Text Available Minhua Wu,1,2,* Xiaoxia Ye,2,* Xubin Deng,3,* Yanxia Wu,4 Xiaofang Li,4 Lin Zhang11Department of Histology and Embryology, Southern Medical University, Guangzhou, 2Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, 3Affiliated Cancer Hospital of Guangzhou Medical University, Cancer Center of Guangzhou Medical University, Guangzhou, 4Pathological Diagnosis and Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China*These authors contributed equally to this workAims: Metastasis-associated gene 2 (MTA2 is reported to play an important role in tumor progression, but little is known about the role of MTA2 in nasopharyngeal carcinoma (NPC. The aim of the study was to explore the expression and function of MTA2 in NPC.Methods: Expression of MTA2 in NPC tissues and cell lines was detected by immunohistochemistry and Western blotting. Relationship between MTA2 expression and clinicopathological features was analyzed. Stable MTA2-overexpressing and MTA2-siliencing NPC cells were established by transfection with plasmids encoding MTA2 cDNA and lentivirus-mediated short hairpin RNA, respectively. Cell viability was determined by Cell Counting Kit-8 and colony formation assay. Cell migration ability was evaluated by wound healing and transwell invasion assay. The impact of MTA2 knockdown on growth and metastasis of CNE2 cells in vivo was determined by nude mouse xenograft models. Expression of several Akt pathway proteins was detected by Western blotting.Results: MTA2 was upregulated in NPC tissues and three NPC cell lines detected (CNE1, CNE2, and HNE1. MTA2 expression was related to clinical stage and lymph node metastasis of patients with NPC. MTA2 upregulation promoted proliferation and invasion of CNE1 cells, while MTA2 depletion had opposite effects on CNE2 cells. Moreover, MTA2 depletion suppressed growth and metastasis of CNE2 cells in vivo. MTA2 overexpression

  5. E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation

    International Nuclear Information System (INIS)

    Hao, Hongying; Dong, Yanbin; Bowling, Maria T; Gomez-Gutierrez, Jorge G; Zhou, H Sam; McMasters, Kelly M

    2007-01-01

    PUMA is a pro-apoptotic Bcl-2 family member that has been shown to be involved in apoptosis in many cell types. We sought to ascertain whether induction of PUMA plays a crucial role in E2F-1-induced apoptosis in melanoma cells. PUMA gene and protein expression levels were detected by real-time PCR and Western blot in SK-MEL-2 and HCT116 cell lines after Ad-E2F-1 infection. Activation of the PUMA promoter by E2F-1 overexpression was detected by dual luciferase reporter assay. E2F-1-induced Bax translocation was shown by immunocytochemistry. The induction of caspase-9 activity was measured by caspase-9 colorimetric assay kit. Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line. In support of this finding, we found six putative E2F-1 binding sites within the PUMA promoter. Subsequent dual luciferase reporter assay showed that E2F-1 expression could increase the PUMA gene promoter activity 9.3 fold in SK-MEL-2 cells. The role of PUMA in E2F-1-induced apoptosis was further investigated in a PUMA knockout cell line. Cell viability assay showed that the HCT116 PUMA-/- cell line was more resistant to Ad-E2F-1-mediated cell death than the HCT116 PUMA+/+ cell line. Moreover, a 2.2-fold induction of the PUMA promoter was also noted in the HCT116 PUMA+/+ colon cancer cell line after Ad-E2F-1 infection. Overexpression of a truncated E2F-1 protein that lacks the transactivation domain failed to up-regulate PUMA promoter, suggesting that PUMA may be a transcriptional target of E2F-1. E2F-1-induced cancer cell apoptosis was accompanied by Bax translocation from the cytosol to mitochondria and the induction of caspase-9 activity, suggesting that E2F-1-induced apoptosis is mediated by PUMA through the cytochrome C/Apaf-1-dependent pathway. Our studies strongly demonstrated that E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation. The signaling

  6. Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells.

    Directory of Open Access Journals (Sweden)

    Aki Kato

    Full Text Available Osteopontin (OPN is a multifunctional protein that plays important roles in cell growth, differentiation, migration and tissue fibrosis. In human idiopathic pulmonary fibrosis and murine bleomycin-induced lung fibrosis, OPN is upregulated in type II alveolar epithelial cells (AEC II. However, the mechanism of OPN induction in AEC II is not fully understood. In this study, we demonstrate the molecular mechanism of OPN induction in AEC II and elucidate the functions of OPN in AEC II and lung fibroblasts. Human lung adenocarcinoma cells (A549 and mouse alveolar epithelial cells (MLE12, used as type II alveolar epithelial cell lines for in vitro assays, and human pulmonary alveolar epithelial cells (HPAEpiC were treated with either bleomycin, doxorubicin or tunicamycin. The mechanism of OPN induction in these cells and its function as a pro-fibrotic cytokine on A549 and lung fibroblasts were analyzed. The DNA damaging reagents bleomycin and doxorubicin were found to induce OPN expression in A549, MLE12 and HPAEpiC. OPN expression was induced via activation of the extracellular signal-regulated protein kinase (ERK-dependent signaling pathway in A549 and MLE12. The endoplasmic reticulum (ER stress-inducing reagent tunicamycin induced OPN mRNA expression in A549, MLE12 and HPAEpiC, and OPN mRNA expression was induced via activation of the ERK-dependent signaling pathway in A549 and MLE12. Another ER stress-inducing reagent thapsigargin induced the expression of OPN mRNA as well as the subsequent production of OPN in A549 and MLE12. Furthermore, OPN promoted the proliferation of A549 and the migration of normal human lung fibroblasts. Inhibition of OPN by small interference RNA or neutralizing antibody suppressed both of these responses. The results of this study suggest that cell stress induces the upregulation of OPN in AEC II by signaling through the ERK pathway, and that upregulated OPN may play a role in fibrogenesis of the lung.

  7. TGF-β1 up-regulates cadherin-11 expression through Snail: A potential mechanism for human trophoblast cell differentiation.

    Science.gov (United States)

    Cheng, Jung-Chien; Yi, Yuyin; Chang, Hsun-Ming; Leung, Peter C K

    2018-03-01

    Cadherins are transmembrane proteins that mediate cell-cell adhesion by promoting the formation of adherens junctions. The regulated expression of cadherins is thought to play important roles in both normal and diseased placental development. Cadherin-11, also known as OB-cadherin, is expressed in human placenta and has been shown to be involved in regulation of trophoblast cell differentiation. We have demonstrated that transforming growth factor-beta1 (TGF-β1) promotes human trophoblast cell differentiation. In addition, cadherin-11 can be up-regulated by TGF-β1 treatment. However, the underlying molecular mechanisms that mediate TGF-β1-induced cadherin-11 expression remain unknown. In this study, we demonstrate that TGF-β1 up-regulates cadherin-11 expression in human trophoblast cells. TGF-β1 treatment activates SMAD2/3 signaling pathways. Knockdown of SMAD2 or SMAD3 attenuates the stimulatory effect of TGF-β1 on cadherin-11 expression. In addition, the transcription factors, Snail and Slug, are up-regulated by the TGF-β1 treatment. Interestingly, only knockdown of Snail abolishes the TGF-β1-induced up-regulation of cadherin-11 expression. Our results suggest that TGFβ1-SMAD2/3-Snail signaling could contribute to the human trophoblast cell differentiation by up-regulating cadherin-11 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Rck1 up-regulates pseudohyphal growth by activating the Ras2 and MAP kinase pathways independently in Saccharomyces cerevisiae.

    Science.gov (United States)

    Chang, Miwha; Kang, Chang-Min; Park, Yong-Sung; Yun, Cheol-Won

    2014-02-21

    Previously, we reported that Rck1 regulates Hog1 and Slt2 activities and affects MAP kinase activity in Saccharomyces cerevisiae. Recently, we found that Rck1 up-regulates phospho-Kss1 and phospho-Fus3. Kss1 has been known as a component in the pseudohyphal growth pathway, and we attempted to identify the function of Rck1 in pseudohyphal growth. Rck1 up-regulated Ras2 at the protein level, not the transcriptional level. Additionally, FLO11 transcription was up-regulated by RCK1 over-expression. RCK1 expression was up-regulated during growth on SLAD+1% butanol medium. On nitrogen starvation agar plates, RCK1 over-expression induced pseudohyphal growth of colonies, and cells over-expressing RCK1 showed a filamentous morphology when grown in SLAD medium. Furthermore, 1-butanol greatly induced filamentous growth when RCK1 was over-expressed. Moreover, invasive growth was activated in haploid cells when RCK1 was over-expressed. The growth defect of cells observed on 1-butanol medium was recovered when RCK1 was over-expressed. Interestingly, Ras2 and phospho-Kss1 were up-regulated by Rck1 independently. Together, these results suggest that Rck1 promotes pseudohyphal growth by activating Ras2 and Kss1 via independent pathways in S. cerevisiae. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Bioefficacy of Graviola leaf extracts in scavenging free radicals and upregulating antioxidant genes.

    Science.gov (United States)

    Son, Yu-Ra; Choi, Eun-Hye; Kim, Goon-Tae; Park, Tae-Sik; Shim, Soon-Mi

    2016-02-01

    The aims of this study were to determine bioactive components of Graviola leaf extracts and to examine the radical scavenging capacity, gene expression and transcription factors of antioxidant enzymes. Rutin, kaempferol-rutinoside, and vitamin U were identified from the steaming and 50% EtOH extracts of Graviola leaves. Graviola leaf extracts effectively scavenged peroxy and nitrogen radicals. 50% EtOH of Graviola leaves provided a 1-2.9 times higher trolox equivalent than the steaming extract. It also had a higher VCEAC. Graviola leaf extracts reduced the generation of reactive oxygen species (ROS) induced by H2O2 in a dose-dependent manner. The 50% EtOH extract of Graviola leaves upregulated SOD1 and Nrf2, but catalase and HMOX1 were not altered by the 50% EtOH extract of Graviola leaves.

  10. Fetal nicotine exposure produces postnatal up-regulation of adenylate cyclase activity in peripheral tissues

    Energy Technology Data Exchange (ETDEWEB)

    Slotkin, T.A.; Navarro, H.A.; McCook, E.C.; Seidler, F.J. (Duke Univ. Medical Center, Durham, NC (USA))

    1990-01-01

    Gestational exposure to nicotine has been shown to affect development of noradrenergic activity in both the central and peripheral nervous systems. In the current study, pregnant rats received nicotine infusions of 6 mg/kg/day throughout gestation, administered by osmotic minipump implants. After birth, offspring of the nicotine-infused dams exhibited marked increases in basal adenylate cyclase activity in membranes prepared from kidney and heart, as well as supersensitivity to stimulation by either a {beta}-adrenergic agonist, isoproterenol, or by forskolin. The altered responses were not accompanied by up-regulation of {beta}-adrenergic receptors: in fact, ({sup 125}I)pindolol binding was significantly decreased in the nicotine group. These results indicate that fetal nicotine exposure affects enzymes involved in membrane receptor signal transduction, leading to altered responsiveness independently of changes at the receptor level.

  11. Lipopolysaccharide-induced Pulpitis Up-regulates TRPV1 in Trigeminal Ganglia

    Science.gov (United States)

    Chung, M.-K.; Lee, J.; Duraes, G.; Ro, J.Y.

    2011-01-01

    Tooth pain often accompanies pulpitis. Accumulation of lipopolysaccharides (LPS), a product of Gram-negative bacteria, is associated with painful clinical symptoms. However, the mechanisms underlying LPS-induced tooth pain are not clearly understood. TRPV1 is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and hyperalgesia under inflammation or injury. Although TRPV1 is expressed in pulpal afferents, it is not known whether the application of LPS to teeth modulates TRPV1 in trigeminal nociceptors. By assessing the levels of protein and transcript of TRPV1 in mouse trigeminal ganglia, we demonstrate that dentinal application of LPS increases the expression of TRPV1. Our results suggest that the up-regulation of TRPV1 in trigeminal nociceptors following bacterial infection could contribute to hyperalgesia under pulpitis conditions. PMID:21712529

  12. Fetal nicotine exposure produces postnatal up-regulation of adenylate cyclase activity in peripheral tissues

    International Nuclear Information System (INIS)

    Slotkin, T.A.; Navarro, H.A.; McCook, E.C.; Seidler, F.J.

    1990-01-01

    Gestational exposure to nicotine has been shown to affect development of noradrenergic activity in both the central and peripheral nervous systems. In the current study, pregnant rats received nicotine infusions of 6 mg/kg/day throughout gestation, administered by osmotic minipump implants. After birth, offspring of the nicotine-infused dams exhibited marked increases in basal adenylate cyclase activity in membranes prepared from kidney and heart, as well as supersensitivity to stimulation by either a β-adrenergic agonist, isoproterenol, or by forskolin. The altered responses were not accompanied by up-regulation of β-adrenergic receptors: in fact, [ 125 I]pindolol binding was significantly decreased in the nicotine group. These results indicate that fetal nicotine exposure affects enzymes involved in membrane receptor signal transduction, leading to altered responsiveness independently of changes at the receptor level

  13. Fascaplysin sensitizes cells to TRAIL-induced apoptosis through upregulating DR5 expression

    Science.gov (United States)

    Wang, Feng; Chen, Haimin; Yan, Xiaojun; Zheng, Yanling

    2013-05-01

    This study investigated the molecular mechanism of anti-tumor effect of fascaplysin, a nitrogenous red pigment firstly isolated from a marine sponge. Microarray analysis show that the TNF and TNF receptor superfamily in human umbilical vein endothelial cells (HUVEC) and human hepatocarcinoma cells (BEL-7402) were significantly regulated by fascaplysin. Western Blot results reveal that fascaplysin increased the expression of cleaved caspase-9, active caspase-3, and decreased the level of procaspase-8 and Bid. Flow cytometry and cytotoxicity tests indicate that fascaplysin sensitized cells to tumor necrosis-related apoptosisinducing ligand-(TRAIL) induced apoptosis, which was markedly blocked by TRAIL R2/Fc chimera, a dominant negative form of TRAIL receptor DR5. Therefore, our results demonstrate that fascaplysin promotes apoptosis through the activation of TRAIL signaling pathway by upregulating DR5 expression.

  14. Up-regulation of β-adrenoreceptors by drugs which cause depression

    International Nuclear Information System (INIS)

    Brand, L.; Van Rooyen, J.M.; Offermeier, J.

    1988-01-01

    A number of drugs associated with depressive episodes in man were investigated for their effects on rat cortical β-adrenoceptors, in view of the down-regulation of β-adrenoceptors caused by chronic administration of anti-depressant drugs. Scatchard analyses of [ 3 H]dihydro-alprenolol binding data provided B max and K D values for the cortical β-adrenoceptors. Up-regulation of the receptors occurred after daily injections of phenobarbitone for seven days (by 55%), pentobarbitone (by 143%), reserpine (by 82%) and propranolol (by 64%). β-adrenoceptors were not affected by daily injections of clonidine, chlorpromazine and flupenthixol for seven days. This work confirms the up-regulatory effect on β-adrenoceptors of certain drugs which produce depressions in man

  15. SPARC is up-regulated during skeletal muscle regeneration and inhibits myoblast differentiation

    DEFF Research Database (Denmark)

    Petersson, Stine Juhl; Jørgensen, Louise Helskov; Andersen, Ditte C

    2013-01-01

    Skeletal muscle repair is mediated primarily by the muscle stem cell, the satellite cell. Several factors, including extracellular matrix, are known to regulate satellite cell function and regeneration. One factor, the matricellular Secreted Protein Acidic and Rich in Cysteine (SPARC) is highly up......-regulated during skeletal muscle disease, but its function remains elusive. In the present study, we demonstrate a prominent yet transient increase in SPARC mRNA and protein content during skeletal muscle regeneration that correlates with the expression profile of specific muscle factors like MyoD, Myf5, Myf6......, Myogenin, NCAM, CD34, and M-Cadherin, all known to be implicated in satellite cell activation/proliferation following muscle damage. This up regulation was detected in more cell types. Ectopic expression of SPARC in the muscle progenitor cell line C2C12 was performed to mimic the high levels of SPARC seen...

  16. Upregulation of nestin in proximal tubules may participate in cell migration during renal repair.

    Science.gov (United States)

    Wen, Donghai; Ni, Li; You, Li; Zhang, Liying; Gu, Yong; Hao, Chuan-Ming; Chen, Jing

    2012-12-01

    The characteristics of renal tubular progenitor/precursor cells and the role of renal tubule regeneration in the repair of remnant kidneys (RKs) after nephrectomy are not well known. In the present study of a murine model of subtotal nephrectomy, we used immunofluorescence (IF), immunoblot analysis, and in situ hybridization methods to demonstrate that nestin expression was transiently upregulated in tubule cells near the incision edges of RKs. The nestin-positive tubules were immature proximal tubules that colabeled with lotus tetragonolobus agglutinin but not with markers of mature tubules (aquaporin-1, Tamm-Horsfall protein, and aquaporin-2). In addition, many of the nestin-expressing tubule cells were actively proliferative cells, as indicated by colabeling with bromodeoxyuridine. Double-label IF and immunoblot analysis also showed that the upregulation of tubular nestin was associated with enhanced transforming growth factor-β1 (TGF-β1) expression in the incision edge of RKs but not α-smooth muscle actin, which is a marker of fibrosis. In cultured human kidney proximal tubule cells (HKC), immunoblot analysis indicated that TGF-β1 induced nestin expression and loss of E-cadherin expression, suggesting an association of nestin expression and cellular dedifferentiation. Knockdown of nestin expression by a short hairpin RNA-containing plasmid led to decreased migration of HKC cells that were induced by TGF-β1. Taken together, our results suggest that the tubule repair that occurs during the recovery process following nephrectomy may involve TGF-β1-induced nestin expression in immature renal proximal tubule cells and the promotion of renal cell migration.

  17. Lutein Induces Autophagy via Beclin-1 Upregulation in IEC-6 Rat Intestinal Epithelial Cells.

    Science.gov (United States)

    Chang, Chi-Jen; Lin, Ji-Fan; Hsiao, Chien-Yu; Chang, Hsun-Hao; Li, Hsin-Ju; Chang, Hsun-Hsien; Lee, Gon-Ann; Hung, Chi-Feng

    2017-01-01

    Lutein is a carotenoid with anti-oxidant properties. Autophagy, an evolutionarily conserved catabolic cellular pathway for coping with stress conditions, is responsive to reactive oxygen species (ROS) and degrades damaged organelles. We previously demonstrated that lutein can induce anti-oxidant enzymes to relieve methotrexate-induced ROS stress. We therefore hypothesized that lutein, which activates ROS-scavenging enzymes, can also induce autophagy for cell survival. In this study, we demonstrated that lutein treatment attenuated the reduction in cell viability caused by H 2 O 2 . Lutein dose-dependently induced the processing of microtubule-associated protein light chain 3 (LC3)-II, an autophagy marker protein, and accumulation of LC3-positive puncta in rat intestinal IEC-6 cells. Furthermore, (a) direct observation of autophagosome formation through transmission electron microscopy, (b) upregulation of autophagy-related genes including ATG4A, ATG5, ATG7, ATG12, and beclin-1 (BENC1), and (c) increased BECN1/Bcl-2 ratio confirmed the induction of autophagy by lutein. The results revealed that bafilomycin-A1-induced inhibition of autophagy reduced cell viability and increased apoptosis in lutein-treated cells, indicating a protective role of lutein-induced autophagy. Lutein treatment also activated adenosine monophosphate-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK), and p-38, but had no effects on the induction of extracellular signal-related kinase or inhibition of mTOR; however, the inhibition of activated AMPK, JNK, or p-38 did not attenuate lutein-induced autophagy. Finally, increased BECN1 expression levels were detected in lutein-treated cells, and BECN1 knockdown abolished autophagy induction. These results suggest that lutein-induced autophagy was mediated by the upregulation of BECN1 in IEC-6 cells. We are the first to demonstrate that lutein induces autophagy. Elevated autophagy in lutein-treated IEC-6 cells may have a protective role

  18. MMP-15 is upregulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin.

    Directory of Open Access Journals (Sweden)

    Tu'uhevaha J Kaitu'u-Lino

    Full Text Available Preeclampsia is a major pregnancy complication, characterized by severe endothelial dysfunction, hypertension and maternal end-organ damage. Soluble endoglin is an anti-angiogenic protein released from placenta and thought to play a central role in causing the endothelial dysfunction and maternal organ injury seen in severe preeclampsia. We recently reported MMP-14 was the protease producing placentally-derived soluble endoglin by cleaving full-length endoglin present on the syncytiotrophoblast surface. This find identifies a specific drug target for severe preeclampsia; interfering with MMP-14 mediated cleavage of endoglin could decrease soluble endoglin production, ameliorating clinical disease. However, experimental MMP-14 inhibition alone only partially repressed soluble endoglin production, implying other proteases might have a role in producing soluble endoglin. Here we investigated whether MMP-15--phylogenetically the closest MMP relative to MMP-14 with 66% sequence similarity--also cleaves endoglin to produce soluble endoglin. MMP-15 was localized to the syncytiotrophoblast layer of the placenta, the same site where endoglin was localized. Interestingly, it was significantly (p = 0.03 up-regulated in placentas from severe early-onset preeclamptic pregnancies (n = 8 compared to gestationally matched preterm controls (n = 8. However, siRNA knockdown of MMP-15 yielded no significant decrease of soluble endoglin production from either HUVECs or syncytialised BeWo cells in vitro. Importantly, concurrent siRNA knockdown of both MMP-14 and MMP-15 in HUVECS did not yield further decrease in soluble endoglin production compared to MMP-14 siRNA alone. We conclude MMP-15 is up-regulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin.

  19. Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-κB-dependent pathway

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Chi-Chih [Department of Research, Taichung Veterans General Hospital, Taichung, Taiwan (China); Hsueh, Chi-Mei [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chen, Chiu-Yuan [Graduate Institute of Natural Healing Sciences, Nanhua University, Chiayi, Taiwan (China); Chen, Tzu-Hsiu, E-mail: hsiu@mail.chna.edu.tw [Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan (China); Hsu, Shih-Lan, E-mail: h2326@vghtc.gov.tw [Department of Research, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan (China)

    2013-07-19

    Highlights: •IL-6 could induce PON1 gene expression. •IL-6 increased NF-κB protein expression and NF-κB-p50 and -p65 subunits nuclear translocation. •IL-6-induced PON1 up-regulation was through an AKT/NF-κB pathway. -- Abstract: The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro-inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-α and IL-1β, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-induced PON1 expression occurred at the transcriptional level. Increase of IκB kinase activity and IκB phosphorylation, and reduction of IκB protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-κB-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-κB. Furthermore, pharmacological inhibition of NF-κB activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/IκB/NF-κB signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-κB signaling axis in human hepatocyte-derived HepG2 cell line.

  20. Upregulation of distinct collagen transcripts in post-surgery scar tissue: a study of conjunctival fibrosis.

    Science.gov (United States)

    Seet, Li-Fong; Toh, Li Zhen; Chu, Stephanie W L; Finger, Sharon N; Chua, Jocelyn L L; Wong, Tina T

    2017-06-01

    Excessive accumulation of collagen is often used to assess the development of fibrosis. This study aims to identify collagen genes that define fibrosis in the conjunctiva following glaucoma filtration surgery (GFS). Using the mouse model of GFS, we have identified collagen transcripts that were upregulated in the fibrotic phase of wound healing via RNA-seq. The collagen transcripts that were increased the most were encoded by Col8a1 , Col11a1 and Col8a2 Further analysis of the Col8a1 , Col11a1 and Col8a2 transcripts revealed their increase by 67-, 54- and 18-fold, respectively, in the fibrotic phase, compared with 12-fold for Col1a1 , the most commonly evaluated collagen gene for fibrosis. However, only type I collagen was significantly upregulated at the protein level in the fibrotic phase. Type VIII and type I collagens colocalized in fibrous structures and in ACTA2-positive pericytes, and appeared to compensate for each other in expression levels. Type XI collagen showed low colocalization with both type VIII and type I collagens but can be found in association with macrophages. Furthermore, we show that both mouse and human conjunctival fibroblasts expressed elevated levels of the most highly expressed collagen genes in response to TGFβ2 treatment. Importantly, conjunctival tissues from individuals whose GF surgeries have failed due to scarring showed 3.60- and 2.78-fold increases in type VIII and I collagen transcripts, respectively, compared with those from individuals with no prior surgeries. These data demonstrate that distinct collagen transcripts are expressed at high levels in the conjunctiva after surgery and their unique expression profiles may imply differential influences on the fibrotic outcome. © 2017. Published by The Company of Biologists Ltd.

  1. Upregulation of CPE promotes cell proliferation and tumorigenicity in colorectal cancer

    International Nuclear Information System (INIS)

    Liang, Xing-Hua; He, Wen-guang; Huang, Yan-Nian; Zeng, Xian-Cheng; Li, Ling-ling; Wu, Geng-Gang; Xie, Yi-Cheng; Zhang, Guang-Xian; Chen, Wei; Yang, Hai-Feng; Liu, Qi-Long; Li, Wen-Hong

    2013-01-01

    Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of cancer related death. Although the mortality rate of CRC is decreasing, finding novel targets for its therapy remains urgent. Carboxypeptidase E (CPE), a member of the pro-protein convertases, which are involved in the maturation of protein precursors, has recently been reported as elevated in many types of cancer. However, its role and mechanisms in tumor progression are poorly understood. In the present study, we investigated expression of CPE in CRC cell lines and tumor tissues using Western blot and real-time qRT-PCR. Plasmids for overexpression and depletion of CPE were constructed and analyzed by Western blot, MTT and colony formation assays and bromodeoxyuridine incorporation assays. The relative expression of p21, p27, and cyclin D1 were analyzed by Real-time qRT-PCR in the indicated cells. Our study showed that CPE was significantly upregulated in CRC cell lines and tumor tissues. MTT and colony formation assays indicated that overexpression of CPE enhanced cell growth rates. BrdU incorporation and flow-cytometry assays showed that ectopic expression of CPE increased the S-phase fraction cells. Soft agar assay proved enhanced tumorigenicity activity in CPE over-expressing CRC cells. Further studies of the molecular mechanisms of CPE indicated that is promoted cell proliferation and tumorigenicity through downregulation of p21 and p27, and upregulation of cyclin D1. Taken together, these data suggest that CPE plays an important role in cell cycle regulation and tumorigenicity, and may serve as a potential target for CRC therapeutics

  2. Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish.

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    Brenda M Geiger

    Full Text Available BACKGROUND: Melanin-concentrating hormone (MCH, an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD. Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. METHODS: In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. RESULTS: Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. CONCLUSIONS: Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.

  3. Low-level laser irradiation stimulates tenocyte migration with up-regulation of dynamin II expression.

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    Wen-Chung Tsai

    Full Text Available Low-level laser therapy (LLLT is commonly used to treat sports-related tendinopathy or tendon injury. Tendon healing requires tenocyte migration to the repair site, followed by proliferation and synthesis of the extracellular matrix. This study was designed to determine the effect of laser on tenocyte migration. Furthermore, the correlation between this effect and expression of dynamin 2, a positive regulator of cell motility, was also investigated. Tenocytes intrinsic to rat Achilles tendon were treated with low-level laser (660 nm with energy density at 1.0, 1.5, and 2.0 J/cm(2. Tenocyte migration was evaluated by an in vitro wound healing model and by transwell filter migration assay. The messenger RNA (mRNA and protein expressions of dynamin 2 were determined by reverse transcription/real-time polymerase chain reaction (real-time PCR and Western blot analysis respectively. Immunofluorescence staining was used to evaluate the dynamin 2 expression in tenocytes. Tenocytes with or without laser irradiation was treated with dynasore, a dynamin competitor and then underwent transwell filter migration assay. In vitro wound model revealed that more tenocytes with laser irradiation migrated across the wound border to the cell-free zone. Transwell filter migration assay confirmed that tenocyte migration was enhanced dose-dependently by laser. Real-time PCR and Western-blot analysis demonstrated that mRNA and protein expressions of dynamin 2 were up-regulated by laser irradiation dose-dependently. Confocal microscopy showed that laser enhanced the expression of dynamin 2 in cytoplasm of tenocytes. The stimulation effect of laser on tenocytes migration was suppressed by dynasore. In conclusion, low-level laser irradiation stimulates tenocyte migration in a process that is mediated by up-regulation of dynamin 2, which can be suppressed by dynasore.

  4. Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

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    Hongming Lv

    2018-03-01

    Full Text Available Acetaminophen (APAP overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2 is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These

  5. saRNA guided iNOS up-regulation improves erectile function of diabetic rats.

    Science.gov (United States)

    Wang, Tao; Li, Mingchao; Yuan, Huixin; Zhan, Yin; Xu, Hua; Wang, Shaogang; Yang, Weiming; Liu, Jihong; Ye, Zhangqun; Li, Long-Cheng

    2013-08-01

    Promoter targeted saRNAs mediate sequence specific up-regulation of gene expression. We explored the therapeutic effect of RNA activation mediated iNOS gene activation on improving erectile function in a rat model of diabetes mellitus. An optimal saRNA sequence specific for iNOS promoter was cloned into an adenoviral vector, resulting in AdU6/shiNOS and AdU6/shControl. The corresponding viruses were used to transduce cultured rat cavernous smooth muscle cells. Streptozotocin induced diabetes models were established in rats and used to test the effects of intracavernous delivery of iNOS saRNA viruses on erectile function. iNOS expression in the cavernous smooth muscle cells or penile tissue of treated rats was assessed by reverse transcriptase-polymerase chain reaction and Western blot. Cyclic guanosine monophosphate was analyzed by enzyme-linked immunosorbent assay. Intracavernous pressure in response to cavernous nerve stimulation was measured using a data acquisition system on post-injection days 1, 3, 5, 7, 10 and 14. Adenovirus mediated expression of iNOS saRNA caused sustained up-regulation of iNOS in cavernous smooth muscle cells. Intracavernous injection of AdU6/shiNOS activated iNOS expression in vivo and significantly increased peak intracavernous pressure in streptozotocin induced diabetic rats via nitric oxide/intracellular cyclic guanosine monophosphate activation. Results show that saRNA mediated iNOS over expression in the penis can restore erectile function in streptozocin diabetic rats via the nitric oxide-cyclic guanosine monophosphate pathway. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  6. Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response.

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    Michael A Flierl

    Full Text Available Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFkappaB in macrophages, causing enhanced release of proinflammatory cytokines (TNFalpha, IL-1beta, IL-6. Both adrenal-intact (AD+ and adrenalectomized (ADX rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-beta-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI. Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to alpha(2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of alpha(2-adrenoceptors.

  7. To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses.

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    Rafik Terra

    Full Text Available Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6 was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1 in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2 STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3 STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.

  8. Identification of actin beta-like 2 (ACTBL2) as novel, upregulated protein in colorectal cancer.

    Science.gov (United States)

    Ghazanfar, Saba; Fatima, Iram; Aslam, Muhammad; Musharraf, Syed Ghulam; Sherman, Nicholas E; Moskaluk, Christopher; Fox, Jay W; Akhtar, M Waheed; Sadaf, Saima

    2017-01-30

    Early diagnosis of colorectal cancer (CRC) can be of value for increasing the survival rate of patients. Recently, proteomic strategies to identify markers for the diagnosis of cancer at an early stage have been employed with noteworthy results. To extend these studies, we utilized two dimensional gel electrophoresis and mass spectrometry for expression profiling of proteins extracted from the freshly frozen human colorectal cancer tissue specimens and the comparable regions of adjacent normal mucosa (serving as controls). Four gel spots were determined to be differentially stained between the tumor and the control samples on a consistent basis. Following mass spectrometric analysis of these spots, six proteins were identified; five of these had previously been reported to be associated with colorectal cancer. One protein actin beta-like 2 (ACTBL2), not linked with colorectal cancer in the earlier reports, was however found to be at higher abundance in colorectal tumor samples both by proteomics and immunohistochemistry analysis. Thus ACTBL2 association and differential upregulation in colorectal cancer is novel, and as such may contribute to our understanding of the colorectal carcinogenesis and potentially serve a function in developing markers for colorectal cancer. Colorectal cancer (CRC) is a major cause of death world-wide and good markers for early detection are lacking. In this study we conducted a proteomic analysis of tumor vs. normal tissue. We corroborated the finding of a number of previously identified proteins associated with CRC and more importantly identified a novel protein, ACTBL2, which we demonstrated to be upregulated in CRC. As additional proteins associated with CRC are identified the potential for developing panels of markers may be realized with better outcomes in early cancer detection. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Green tea diet decreases PCB 126-induced oxidative stress in mice by upregulating antioxidant enzymes

    Science.gov (United States)

    Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu; Murphy, Margaret O; Eske, Katryn E; Sunkara, Manjula; Morris, Andrew J; Hennig, Bernhard

    2013-01-01

    Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the upregulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-Isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited five-fold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both mRNA and protein analyses, and it was determined that many genes transcriptionally controlled by AhR and Nrf2 proteins were upregulated in PCB-exposed mice fed the green tea supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126 which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants. PMID:24378064

  10. VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation

    Science.gov (United States)

    Soo, Isaac; Madsen, Karen L; Tejpar, Qassim; Sydora, Beate C; Sherbaniuk, Richard; Cinque, Benedetta; Di Marzio, Luisa; Cifone, Maria Grazia; Desimone, Claudio; Fedorak, Richard N

    2008-01-01

    BACKGROUND: Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE: To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS: Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (109 colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS: Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (± SEM) ulcerative colitis disease activity index scores from 5.3±1.8946 to 0.70±0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION: Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity. PMID:18354751

  11. Targeting of slug sensitizes anaplastic thyroid carcinoma SW1736 cells to doxorubicin via PUMA upregulation.

    Science.gov (United States)

    Dong, Anbing; Jiao, Xuelong; Chen, Dong; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers and often shows resistance to multimodal therapeutic approaches. It has been shown that the transcriptional repressor Slug inhibits the chemotherapeutic agent-induced apoptosis of cancer cells. We evaluated whether targeting of Slug could augment doxorubicin (DOX)-induced apoptosis of ATC cells. We also determined changes in PUMA (p53-upregulated modulator of apoptosis) expression levels to identify possible mechanisms of their combined actions. Methods SW1736 cells were transfected with Slug siRNA or/and PUMA siRNA and then exposed to DOX (0.1, 1, and 5 mM) for selected times. Scrambled siRNA was used as a control. The effects on cell viability were determined via MTT assay. Apoptosis was assessed using TUNEL assays and annexin V staining, and was confirmed by flow cytometry analyses. Slug and PUMA levels were determined using western blotting and immunofluorescence analyses. We used a subcutaneous implanted tumor model of SW1736 cells in nude mice to assess the effects of Slug silencing in combination with DOX on tumor development. Apoptosis was assessed via TUNEL assay. Results Targeting of Slug using siRNA combined with DOX led to lower cell viability than treatment with DOX alone in SW1736 cells. TUNEL and flow cytometry analyses showed that targeting of Slug enhanced DOX-induced apoptosis of SW1736 cells. In addition, targeting of Slug increased PUMA expression, and targeting of PUMA restored the chemoresistance of SW1736/Slug siRNA cells to DOX. Conclusions Knockdown of Slug enhanced the antitumor activity of DOX in SW1736 cells via induction of PUMA upregulation. Our results suggest that targeting of Slug has good potential for the development of new therapeutic strategies for ATC.

  12. Cervical cancer stem cells manifest radioresistance: Association with upregulated AP-1 activity.

    Science.gov (United States)

    Tyagi, Abhishek; Vishnoi, Kanchan; Kaur, Harsimrut; Srivastava, Yogesh; Roy, Bal Gangadhar; Das, Bhudev C; Bharti, Alok C

    2017-07-06

    Transcription factor AP-1 plays a central role in HPV-mediated cervical carcinogenesis. AP-1 has also been implicated in chemo-radio-resistance but the mechanism(s) remained unexplored. In the present study, cervical cancer stem-like cells (CaCxSLCs) isolated and enriched from cervical cancer cell lines SiHa and C33a demonstrated an elevated AP-1 DNA-binding activity in comparison to non-stem cervical cancer cells. Upon UV-irradiation, CaCxSLCs showed a UV exposure duration-dependent higher proliferation and highly increased AP-1 activity whereas it was completely abolished in non-stem cancer cells. CaCxSLCs also showed differential overexpression of c-Fos and c-Jun at transcript as well as in protein level. The loss of AP-1 activity and expression was accompanied by decrease in cell viability and proliferation in UV-irradiated non-stem cancer cells. Interestingly, CaCxSLCs treated with curcumin prior to UV-irradiation abolished AP-1 activity and a concomitant reduction in SP cells leading to abrogation of sphere forming ability, loss of proliferation, induction of apoptosis and the cells were poorly tumorigenic. The curcumin pre-treatment abolished the expression of c-Fos and c-Jun but upregulated Fra-1 expression in UV-irradiated CaCxSLCs. Thus, the study suggests a critical role of AP-1 protein in the manifestation of radioresistance but targeting with curcumin helps in radiosensitizing CaCxSLCs through upregulation of Fra-1.

  13. γ-Tocotrienol upregulates aryl hydrocarbon receptor expression and enhances the anticancer effect of baicalein

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Shuya; Baba, Kiwako; Makio, Akiko; Kumazoe, Motofumi; Huang, Yuhui; Lin, I-Chian; Bae, Jaehoon; Murata, Motoki; Yamada, Shuhei; Tachibana, Hirofumi, E-mail: tatibana@agr.kyushu-u.ac.jp

    2016-05-13

    Previous studies have identified biomolecules that mediate the physiological actions of food factors, such as amino acids, vitamins, fatty acids, minerals, plant polyphenols, and lactobacilli, suggesting that our bodies are equipped with an innate system that senses which food factors are required to maintain our health. However, the effects of environmental factors on food factor sensing (FFS) remains largely unknown. Tocotorienols (T3s), which belongs to the vitamin E family, possess several physiological functions, including cholesterol lowering and neuroprotective effects. Here, we investigated the effects of naturally abundant γ-T3 on FFS-related gene expressions in melanoma using a DNA chip. Our results showed that γ-T3 increased the expression level of aryl hydrocarbon receptor (AhR), a sensing molecule to plant polyphenol baicalein. The co-treatment with γ-T3 and baicalein enhanced the anti-proliferative activity of baicalein, accompanied by the downstream events of AhR-activation induced by baicalein. These data suggest that γ-T3 upregulates AhR expression and enhances its sensitivity to baicalein. - Highlights: • γ-T3 upregulated the expression of AhR in mouse melanoma. • Promotion of the binding activity of Sp1 is associated with the increasing effect of γ-T3 on AhR expression. • γ-T3 enhanced the anti-proliferative activity of baicalein that has an AhR ligand activity. • γ-T3 enhanced the inducing activity of baicalein on the expression of AhR target genes.

  14. Up-regulation of Intracellular Calcium Handling Underlies the Recovery of Endotoxemic Cardiomyopathy in Mice.

    Science.gov (United States)

    Morse, Justin C; Huang, Joanne; Khona, Natasha; Miller, Edward J; Siwik, Deborah A; Colucci, Wilson S; Hobai, Ion A

    2017-06-01

    In surviving patients, sepsis-induced cardiomyopathy is spontaneously reversible. In the absence of any experimental data, it is generally thought that cardiac recovery in sepsis simply follows the remission of systemic inflammation. Here the authors aimed to identify the myocardial mechanisms underlying cardiac recovery in endotoxemic mice. Male C57BL/6 mice were challenged with lipopolysaccharide (7 μg/g, intraperitoneally) and followed for 12 days. The authors assessed survival, cardiac function by echocardiography, sarcomere shortening, and calcium transients (with fura-2-acetoxymethyl ester) in electrically paced cardiomyocytes (5 Hz, 37°C) and myocardial protein expression by immunoblotting. Left ventricular ejection fraction, cardiomyocyte sarcomere shortening, and calcium transients were depressed 12 h after lipopolysaccharide challenge, started to recover by 24 h (day 1), and were back to baseline at day 3. The recovery of calcium transients at day 3 was associated with the up-regulation of the sarcoplasmic reticulum calcium pump to 139 ± 19% (mean ± SD) of baseline and phospholamban down-regulation to 35 ± 20% of baseline. At day 6, calcium transients were increased to 123 ± 31% of baseline, associated with increased sarcoplasmic reticulum calcium load (to 126 ± 32% of baseline, as measured with caffeine) and inhibition of sodium/calcium exchange (to 48 ± 12% of baseline). In mice surviving lipopolysaccharide challenge, the natural recovery of cardiac contractility was associated with the up-regulation of cardiomyocyte calcium handling above baseline levels, indicating the presence of an active myocardial recovery process, which included sarcoplasmic reticulum calcium pump activation, the down-regulation of phospholamban, and sodium/calcium exchange inhibition.

  15. Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals.

    Science.gov (United States)

    Heesen, Ludwig; Peitz, Michael; Torres-Benito, Laura; Hölker, Irmgard; Hupperich, Kristina; Dobrindt, Kristina; Jungverdorben, Johannes; Ritzenhofen, Swetlana; Weykopf, Beatrice; Eckert, Daniela; Hosseini-Barkooie, Seyyed Mohsen; Storbeck, Markus; Fusaki, Noemi; Lonigro, Renata; Heller, Raoul; Kye, Min Jeong; Brüstle, Oliver; Wirth, Brunhilde

    2016-05-01

    Spinal muscular atrophy (SMA) is a devastating motoneuron (MN) disorder caused by homozygous loss of SMN1. Rarely, SMN1-deleted individuals are fully asymptomatic despite carrying identical SMN2 copies as their SMA III-affected siblings suggesting protection by genetic modifiers other than SMN2. High plastin 3 (PLS3) expression has previously been found in lymphoblastoid cells but not in fibroblasts of asymptomatic compared to symptomatic siblings. To find out whether PLS3 is also upregulated in MNs of asymptomatic individuals and thus a convincing SMA protective modifier, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of three asymptomatic and three SMA III-affected siblings from two families and compared these to iPSCs from a SMA I patient and control individuals. MNs were differentiated from iPSC-derived small molecule neural precursor cells (smNPCs). All four genotype classes showed similar capacity to differentiate into MNs at day 8. However, SMA I-derived MN survival was significantly decreased while SMA III- and asymptomatic-derived MN survival was moderately reduced compared to controls at day 27. SMN expression levels and concomitant gem numbers broadly matched SMN2 copy number distribution; SMA I presented the lowest levels, whereas SMA III and asymptomatic showed similar levels. In contrast, PLS3 was significantly upregulated in mixed MN cultures from asymptomatic individuals pinpointing a tissue-specific regulation. Evidence for strong PLS3 accumulation in shaft and rim of growth cones in MN cultures from asymptomatic individuals implies an important role in neuromuscular synapse formation and maintenance. These findings provide strong evidence that PLS3 is a genuine SMA protective modifier.

  16. Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis.

    Science.gov (United States)

    Xie, Yan; Jiang, Haihong; Zhang, Qian; Mehrotra, Suneet; Abel, Peter W; Toews, Myron L; Wolff, Dennis W; Rennard, Stephen; Panettieri, Reynold A; Casale, Thomas B; Tu, Yaping

    2016-08-22

    Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

  17. Up-regulated expression of extracellular matrix remodeling genes in phagocytically challenged trabecular meshwork cells.

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    Kristine M Porter

    Full Text Available Cells in the trabecular meshwork (TM, the tissue responsible for draining aqueous humor out of the eye, are known to be highly phagocytic. Phagocytic function in TM cells is thought to play an important role in the normal functioning of the outflow pathway. Dysfunction of phagocytosis could lead to abnormalities of outflow resistance and increased intraocular pressure (IOP. However, the molecular mechanisms triggered by phagocytosis in TM cells are completely unknown.Gene expression profile analysis of human TM cells phagocytically challenged to E. coli or pigment under physiological and oxidative stress environment were performed using Affymetrix U133 plus 2.0 array and analyzed with Genespring GX. Despite the differential biological response elicited by E. coli and pigment particles, a number of genes, including MMP1, MMP3, TNFSF11, DIO2, KYNU, and KCCN2 showed differential expression with both phagocytic ligands in all conditions. Data was confirmed by qPCR in both human and porcine TM cells. Metacore pathway analysis and the usage of recombinant adenovirus encoding the dominant negative mutant of IkB identified NF-κB as a transcription factor mediating the up-regulation of at least MMP1 and MMP3 in TM cells with phagocytosis. In-gel zymography demonstrated increased collagenolytic and caseinolytic activities in the culture media of TM cells challenge to E. coli. In addition, collagenolytic I activity was further confirmed using the self-quenched fluorescent substrate DQ-Collagen I.Here we report for the first time the differential gene expression profile of TM cells phagocytically challenged with either E. coli or pigment. Our data indicate a potential role of phagocytosis in outflow pathway tissue homeostasis through the up-regulation and/or proteolytic activation of extracellular matrix remodeling genes.

  18. Smoking-mediated up-regulation of GAD67 expression in the human airway epithelium.

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    Wang, Guoqing; Wang, Rui; Ferris, Barbara; Salit, Jacqueline; Strulovici-Barel, Yael; Hackett, Neil R; Crystal, Ronald G

    2010-10-29

    The production of gamma-amino butyric acid (GABA) is dependent on glutamate decarboxylases (GAD65 and GAD67), the enzymes that catalyze the decarboxylation of glutamate to GABA. Based on studies suggesting a role of the airway epithelial GABAergic system in asthma-related mucus overproduction, we hypothesized that cigarette smoking, another disorder associated with increased mucus production, may modulate GABAergic system-related gene expression levels in the airway epithelium. We assessed expression of the GABAergic system in human airway epithelium obtained using bronchoscopy to sample the epithelium and microarrays to evaluate gene expression. RT-PCR was used to confirm gene expression of GABAergic system gene in large and small airway epithelium from heathy nonsmokers and healthy smokers. The differences in the GABAergic system gene was further confirmed by TaqMan, immunohistochemistry and Western analysis. The data demonstrate there is a complete GABAergic system expressed in the large and small human airway epithelium, including glutamate decarboxylase, GABA receptors, transporters and catabolism enzymes. Interestingly, of the entire GABAergic system, smoking modified only the expression of GAD67, with marked up-regulation of GAD67 gene expression in both large (4.1-fold increase, p smoking. In the context that GAD67 is the rate limiting enzyme in GABA synthesis, the correlation of GAD67 gene expression with MUC5AC expressions suggests that the up-regulation of airway epithelium expression of GAD67 may contribute to the increase in mucus production observed in association with cigarette smoking. NCT00224198; NCT00224185.

  19. Pro-inflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat

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    Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua; Felder, Robert B.

    2015-01-01

    Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne pro-inflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating pro-inflammatory cytokines remain unclear. We hypothesized that pro-inflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of TNF-α (25 ng) or IL-1β (25 ng) into SFO increased mean blood pressure, heart rate and renal sympathetic nerve activity within 15–20 minutes, mimicking the response to systemically administered pro-inflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type 1 receptor (AT1R) blocker losartan (1 µg), angiotensin-converting enzyme (ACE) inhibitor captopril (1 µg) or cyclooxygenase (COX)-2 inhibitor NS-398 (2 µg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for ACE, AT1R, TNF-α and the p55 TNF-α receptor TNFR1, IL-1β and the IL-1R receptor, and COX-2 had increased in SFO, and mRNA for ACE, AT1R and COX-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for TNFR1 and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, co-localized with ACE, AT1R-like, COX-2 and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that pro-inflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation. PMID:25776070

  20. Cardiorespiratory upregulation during seawater acclimation in rainbow trout: effects on gastrointestinal perfusion and postprandial responses.

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    Brijs, Jeroen; Gräns, Albin; Ekström, Andreas; Olsson, Catharina; Axelsson, Michael; Sandblom, Erik

    2016-05-01

    Increased gastrointestinal blood flow is essential for euryhaline fishes to maintain osmotic homeostasis during the initial phase of a transition from freshwater to seawater. However, the cardiorespiratory responses and hemodynamic changes required for a successful long-term transition to seawater remain largely unknown. In the present study, we simultaneously measured oxygen consumption rate (ṀO2), cardiac output (CO), heart rate (HR), and gastrointestinal blood flow (GBF) in rainbow trout (Oncorhynchus mykiss) acclimated to either freshwater or seawater for at least 6 wk. Seawater-acclimated trout displayed significantly elevated ṀO2 (day: 18%, night: 19%), CO (day: 22%, night: 48%), and GBF (day: 96%, night: 147%), demonstrating that an overall cardiorespiratory upregulation occurs during seawater acclimation. The elevated GBF was achieved via a combination of increased CO, mediated through elevated stroke volume (SV), and a redistribution of blood flow to the gastrointestinal tract. Interestingly, virtually all of the increase in CO of seawater-acclimated trout was directed to the gastrointestinal tract. Although unfed seawater-acclimated trout displayed substantially elevated cardiorespiratory activity, the ingestion of a meal resulted in a similar specific dynamic action (SDA) and postprandial GBF response as in freshwater-acclimated fish. This indicates that the capacity for the transportation of absorbed nutrients, gastrointestinal tissue oxygen delivery, and acid-base regulation is maintained during digestion in seawater. The novel findings presented in this study clearly demonstrate that euryhaline fish upregulate cardiovascular function when in seawater, while retaining sufficient capacity for the metabolic and cardiovascular changes associated with the postprandial response. Copyright © 2016 the American Physiological Society.

  1. Up-regulation of microRNA-1290 impairs cytokinesis and affects the reprogramming of colon cancer cells.

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    Wu, Jia; Ji, Xiaowei; Zhu, Linlin; Jiang, Qiaoli; Wen, Zhenzhen; Xu, Song; Shao, Wei; Cai, Jianting; Du, Qin; Zhu, Yongliang; Mao, Jianshan

    2013-02-28

    Abnormal cytokinesis increases the possibility of nuclear fusion in tumor cells. However, the role of microRNAs (miRNAs) in abnormal cytokinesis is unclear. Here, we found that miR-1290 was significantly up-regulated in clinical colon cancer tissues. Up-regulation of miR-1290 postponed cytokinesis and led to the formation of multinucleated cells. KIF13B was a target of miR-1290 that was involved in aberrant cytokinesis. Furthermore, enforced expression of miR-1290 activated the Wnt pathway and increased the reprogramming-related transcript factors c-Myc and Nanog. Our results suggest that up-regulation of miR-1290 in colon cancer cells impaired cytokinesis and affected reprogramming. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

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    Yong-lin Zhao

    2016-01-01

    Full Text Available Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser 404 (p-tau (S 404 , and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S 404 levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.

  3. Acute Ethanol Administration Upregulates Synaptic α4-Subunit of Neuronal Nicotinic Acetylcholine Receptors within the Nucleus Accumbens and Amygdala

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    Josephine R. Tarren

    2017-10-01

    Full Text Available Alcohol and nicotine are two of the most frequently abused drugs, with their comorbidity well described. Previous data show that chronic exposure to nicotine upregulates high-affinity nicotinic acetylcholine receptors (nAChRs in several brain areas. Effects of ethanol on specific brain nAChR subtypes within the mesolimbic dopaminergic (DA pathway may be a key element in the comorbidity of ethanol and nicotine. However, it is unknown how alcohol affects the abundance of these receptor proteins. In the present study, we measured the effect of acute binge ethanol on nAChR α4 subunit levels in the prefrontal cortex (PFC, nucleus accumbens (NAc, ventral tegmental area (VTA, and amygdala (Amg by western blot analysis using a knock-in mouse line, generated with a normally functioning α4 nAChR subunit tagged with yellow fluorescent protein (YFP. We observed a robust increase in α4-YFP subunit levels in the NAc and the Amg following acute ethanol, with no changes in the PFC and VTA. To further investigate whether this upregulation was mediated by increased local mRNA transcription, we quantified mRNA levels of the Chrna4 gene using qRT-PCR. We found no effect of ethanol on α4 mRNA expression, suggesting that the upregulation of α4 protein rather occurs post-translationally. The quantitative counting of YFP immunoreactive puncta further revealed that α4-YFP protein is upregulated in presynaptic boutons of the dopaminergic axons projecting to the shell and the core regions of the NAc as well as to the basolateral amygdala (BLA, but not to the central or lateral Amg. Together, our results demonstrate that a single exposure to binge ethanol upregulates level of synaptic α4∗ nAChRs in dopaminergic inputs to the NAc and BLA. This upregulation could be linked to the functional dysregulation of dopaminergic signalling observed during the development of alcohol dependence.

  4. The effect of an educational program based on the PRECEDE Model on the level of academic consultants' ability and students' satisfaction

    Directory of Open Access Journals (Sweden)

    Hazavehei SMM

    2003-07-01

    Full Text Available Background: Universities have important responsibilities to prevent physical, emotional, social and academic problems during the course of their study. To achieve this goal, it is necessary that universities offer effective academic advising services to the students. Purpose: To investigate the effectiveness of programs offered for developing academic consultants (AC ability by assessing students’ satisfaction with the consultation they recieve. Methods: From a total of 90 ACs and 2,500 students in the Hamadan University of Medical Sciences, 72 AC and 445 students from four colleges (Medicine, Health Sciences, Dentistry, Nursing and Midwifery voluntarily participated in the pretest. 87 ACs were randomly assigned into two groups (Group Bf participated in a workshop designed based on PRECEDE model; Group Cf was offered material relevant to academic consultation. According to the AC groups, the students were divided into groupBs(n=363; their AC have participated in workshop, group Cs (n=408; their AC received Educational Material, and groupDs (n= 190; the student have no active AC. Data collection was conducted by questionnaires, pre-test and post-test (after one academic semester prior to the intervention. Results: Mean scores of knowledge (M=14.77, SD=3.01 (especially in the College of Medicine and Dentistry and attitude (M=61.79, SD=5.78 of AC about offering effective academic advising to the students was improved significantly in both intervention groups, but this effect was more pronounced in group Bf compared with group Cf (M= 1 1.54,SD=2.76; M=59.23,SD=8.6 (n=44, and group Af (the pre-test group (M=10.67,SD=4.2; M=57.2,SD=1 1.6. Students in group Bf significantly were more satisfied with consultation they received and more willing to use consultation services of their ACs. Conclusion: The PRECEDE model's educational workshop program was more effective in modifying the AC ability in offering effective academic advising, guiding, and

  5. National Aeronautics and Space Administration "threat and error" model applied to pediatric cardiac surgery: error cycles precede ∼85% of patient deaths.

    Science.gov (United States)

    Hickey, Edward J; Nosikova, Yaroslavna; Pham-Hung, Eric; Gritti, Michael; Schwartz, Steven; Caldarone, Christopher A; Redington, Andrew; Van Arsdell, Glen S

    2015-02-01

    We hypothesized that the National Aeronautics and Space Administration "threat and error" model (which is derived from analyzing >30,000 commercial flights, and explains >90% of crashes) is directly applicable to pediatric cardiac surgery. We implemented a unit-wide performance initiative, whereby every surgical admission constitutes a "flight" and is tracked in real time, with the aim of identifying errors. The first 500 consecutive patients (524 flights) were analyzed, with an emphasis on the relationship between error cycles and permanent harmful outcomes. Among 524 patient flights (risk adjustment for congenital heart surgery category: 1-6; median: 2) 68 (13%) involved residual hemodynamic lesions, 13 (2.5%) permanent end-organ injuries, and 7 deaths (1.3%). Preoperatively, 763 threats were identified in 379 (72%) flights. Only 51% of patient flights (267) were error free. In the remaining 257 flights, 430 errors occurred, most commonly related to proficiency (280; 65%) or judgment (69, 16%). In most flights with errors (173 of 257; 67%), an unintended clinical state resulted, ie, the error was consequential. In 60% of consequential errors (n = 110; 21% of total), subsequent cycles of additional error/unintended states occurred. Cycles, particularly those containing multiple errors, were very significantly associated with permanent harmful end-states, including residual hemodynamic lesions (P < .0001), end-organ injury (P < .0001), and death (P < .0001). Deaths were almost always preceded by cycles (6 of 7; P < .0001). Human error, if not mitigated, often leads to cycles of error and unintended patient states, which are dangerous and precede the majority of harmful outcomes. Efforts to manage threats and error cycles (through crew resource management techniques) are likely to yield large increases in patient safety. Copyright © 2015. Published by Elsevier Inc.

  6. Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats.

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    Medina, Anya; Parween, Saba; Ullsten, Sara; Vishnu, Neelanjan; Siu, Yuk Ting; Quach, My; Bennet, Hedvig; Balhuizen, Alexander; Åkesson, Lina; Wierup, Nils; Carlsson, Per Ola; Ahlgren, Ulf; Lernmark, Åke; Fex, Malin

    2018-04-01

    Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 ± 121.3 vs 633.3 ± 148.7; p beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

  7. Association of Parkinsonism or Parkinson Disease with Polypharmacy in the Year Preceding Diagnosis: A Nested Case-Control Study in South Korea.

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    Park, Hae-Young; Park, Ji-Won; Sohn, Hyun Soon; Kwon, Jin-Won

    2017-11-01

    Published studies on the association between polypharmacy and parkinsonism or Parkinson disease are very limited. The objective of this study was to investigate whether polypharmacy is associated with parkinsonism or Parkinson disease in elderly patients. From a South Korean national health insurance sample cohort database for 2002-2013, we matched parkinsonism cases (defined by diagnosis codes for parkinsonism/Parkinson disease) and Parkinson disease cases (patients who had records for both Parkinson disease diagnosis and anti-Parkinson disease drug prescriptions) with controls. Logistic regression analysis evaluated the associations of parkinsonism/Parkinson disease with polypharmacy (i.e., five or more prescribed daily drugs) during the year preceding parkinsonism/Parkinson disease diagnosis, medications potentially associated with parkinsonism, and comorbidity status (using the Charlson Comorbidity Index score and hospitalization records). The study population included 6209 cases and 24,836 controls for parkinsonism and 1331 cases and 5324 controls for Parkinson disease. In univariate logistic regression, odds ratios for parkinsonism/Parkinson disease increased significantly with increased polypharmacy, medications potentially associated with parkinsonism, Charlson Comorbidity Index score, or prior hospitalizations. In multiple logistic regression, odds ratios for parkinsonism/Parkinson disease (adjusted for medications potentially associated with parkinsonism and comorbidities) also increased with increased polypharmacy. Odds ratios (95% confidence interval) for Parkinson disease were higher than those for parkinsonism with stronger statistical significance: 1.41 (1.28-1.55) and 2.17 (1.84-2.57) for parkinsonism and 2.87 (2.30-3.58) and 4.75 (3.39-6.66) for Parkinson disease for between five and ten prescribed daily drugs and ten or more