Sample records for alphav beta3 aggravates

  1. RPTP-alpha acts as a transducer of mechanical force on alphav/beta3-integrin-cytoskeleton linkages

    DEFF Research Database (Denmark)

    von Wichert, Gotz; Jiang, Guoying; Kostic, Ana


    of alphav/beta3-integrin-cytoskeleton connections during the initial phase of ECM contact. These observations indicate that Src family kinases have distinct functions during adhesion site assembly, and that RPTPalpha is an early component in force-dependent signal transduction pathways leading......Cell motility on ECM critically depends on the cellular response to force from the matrix. We find that force-dependent reinforcement of alphav/beta3-integrin-mediated cell-matrix connections requires the receptor-like tyrosine phosphatase alpha (RPTPalpha). RPTPalpha colocalizes with alphav......-integrins at the leading edge during early spreading, and coimmunoprecipitates with alphav-integrins during spreading on fibronectin and vitronectin. RPTPalpha-dependent activation of Src family kinases, in particular activation of Fyn, is required for the force-dependent formation of focal complexes and strengthening...

  2. Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors

    DEFF Research Database (Denmark)

    Oxboel, Jytte; Binderup, Tina; Knigge, Ulrich;


    Anti-angiogenesis treatment is a promising new therapy for cancer that recently has also been suggested for patients with neuroendocrine tumors. The aim of the present study was therefore to investigate the level of tumor angiogenesis, and thereby the molecular basis for anti-angiogenesis treatment......, in neuroendocrine tumors. We used quantitative real-time PCR for measuring mRNA gene-expression of vascular endothelial growth factor (VEGF), integrin alphaV, and integrin beta3, and CD34 for a group of patients with neuroendocrine tumors (n=13). Tissue from patients with colorectal cancer liver metastases (n=14......) and normal liver tissues (n=16) was used as control. We found a lower mRNA level of VEGF in neuroendocrine tumors compared to both colorectal liver metastases (ptumors...

  3. Functional Interactions Between Laminin-10, alphaV beta3 Integrin and Matrix Metalloproteinase-9 in Promoting Breast Cancer Metastasis to Bone (United States)


    Slavin, J., and Anderson, R. L. (1999) Clin Exp Metastasis 17, 163-170 3. Eckhardt, B. L., Parker, B. S., van Laar, R. K., Restall , C. M., Natoli, A. L...Medecine Science, supplement no2 (99) p.36A. Meeting Presentations: 1. Pouliot N., E. Sloan, A.L. Natoli, B. Eckhardt, C.M. Restall , B. Parker, L...Australia. 2. Pouliot N., C.M. Restall , A.L. Natoli, 0. Narayan and R.L. Anderson (2003). The role of MMP-9 and its regulation by tumour/stromal

  4. [Beta 3 adrenergic receptor polymorphism and obesity]. (United States)

    Yoshida, T; Umekawa, T


    The beta 3-adrenoceptor plays a significant role in the control of lipolysis and thermogenesis in the brown adipose tissue of rodents and humans. In human beta 3-adrenoceptor, a Trp to Arg replacement has recently been discovered. This change which occurs at position 64, in the first coding exon, has been correlated with increased weight gain, difficulty in losing weight, insulin resistance syndrome, and worsened diabetic situation. Higher percentages of this mutation are observed in Pima Indians (over 30%) and Japanese (20%). The possible functional mechanism of Trp54Arg is reported using human HEK293 cell line stably expressing the wild type and the [Arg64] beta 3-adrenoceptor type. Beta 3-adrenoceptor agonists available for humans are been also developing. In this paper we describe these points up-to-date.

  5. Genetics Home Reference: potassium-aggravated myotonia (United States)

    ... structure and function of sodium channels. The altered channels cannot properly regulate ion flow, increasing the movement of sodium ions into ... area? Other Names for This Condition PAM sodium channel ... and Rare Diseases Information Center (1 link) Potassium aggravated myotonia Additional ...

  6. Role of Jumonji c-domain containing protein 6 (JMJD6) in infectivity of foot-and-mouth disease virus (United States)

    Foot-and-mouth disease virus (FMDV) can utilize as many as three distinct groups of receptor molecules to attach and enter a susceptible host cell. Four integrin heterodimers (alphavBeta1, alphavBeta3, alphavBeta6, and alphavBeta8) can function as the primary receptor for FMDV field strains. FMDV ...

  7. Role of human GABA(A) receptor beta3 subunit in insecticide toxicity. (United States)

    Ratra, G S; Kamita, S G; Casida, J E


    The gamma-aminobutyric acid type A (GABA(A)) receptor is the target for the major insecticides alpha-endosulfan, lindane, and fipronil and for many analogs. Their action as chloride channel blockers is directly measured by binding studies with [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB). This study tests the hypothesis that GABA(A) receptor subunit composition determines the sensitivity and selectivity of insecticide toxicity. Human receptor subtypes were expressed individually (alpha1, alpha6, beta1, beta3, and gamma2) and in combination in insect Sf9 cells. Binding parameters were similar for [(3)H]EBOB in the beta3 homooligomer, alpha1beta3gamma2 heterooligomer, and native brain membranes, but toxicological profiles were very different. Surprisingly, alpha-endosulfan, lindane, and fipronil were all remarkably potent on the recombinant beta3 homooligomeric receptor (IC50 values of 0.5-2.4 nM), whereas they were similar in potency on the alpha1beta3gamma2 subtype (IC50 values of 16-33 nM) and highly selective on the native receptor (IC50 values of 7.3, 306, and 2470 nM, respectively). The selectivity order for 29 insecticides and convulsants as IC50 ratios for native/beta3 or alpha1beta3gamma2/beta3 was as follows: fipronil > lindane > 19 other insecticides including alpha-endosulfan and picrotoxinin > 4 trioxabicyclooctanes and dithianes (almost nonselective) > tetramethylenedisulfotetramine, 4-chlorophenylsilatrane, or alpha-thujone. Specificity between mammals and insects at the target site (fipronil > lindane > alpha-endosulfan) paralleled that for toxicity. Potency at the native receptor is more predictive for inhibition of GABA-stimulated chloride uptake than that at the beta3 or alpha1beta3gamma2 receptors. Therefore, the beta3 subunit contains the insecticide target and other subunits differentially modulate the binding to confer compound-dependent specificity and selective toxicity.

  8. Pregnancy aggravates proteinuria in subclinical glomerulonephritis in the rat

    NARCIS (Netherlands)

    Faas, MM; Bakker, WW; Poelman, RT; Schuiling, GA


    Because subclinical renal disease may be aggravated during pregnancy-as reflected in the occurrence of proteinuria, for example-we investigated whether a subclinical glomerulonephritis (SG) in the non-pregnant rat (passive Heymann nephritis), a condition without proteinuria, is aggravated when the a

  9. The TF1-ATPase and ATPase activities of assembled alpha 3 beta 3 gamma, alpha 3 beta 3 gamma delta, and alpha 3 beta 3 gamma epsilon complexes are stimulated by low and inhibited by high concentrations of rhodamine 6G whereas the dye only inhibits the alpha 3 beta 3, and alpha 3 beta 3 delta complexes. (United States)

    Paik, S R; Yokoyama, K; Yoshida, M; Ohta, T; Kagawa, Y; Allison, W S


    The ATPase activity of the F1-ATPase from the thermophilic bacterium PS3 is stimulated at concentrations of rhodamine 6G up to about 10 microM where 70% stimulation is observed at 36 degrees C. Half maximal stimulation is observed at about 3 microM dye. At rhodamine 6G concentrations greater than 10 microM, ATPase activity declines with 50% inhibition observed at about 75 microM dye. The ATPase activities of the alpha 3 beta 3 gamma and alpha 3 beta 3 gamma delta complexes assembled from isolated subunits of TF1 expressed in E. coli deleted of the unc operon respond to increasing concentrations of rhodamine 6G nearly identically to the response of TF1. In contrast, the ATPase activities of the alpha 3 beta 3 and alpha 3 beta 3 delta complexes are only inhibited by rhodamine 6G with 50% inhibition observed, respectively, at 35 and 75 microM dye at 36 degrees C. The ATPase activity of TF1 is stimulated up to 4-fold by the neutral detergent, LDAO. In the presence of stimulating concentrations of LDAO, the ATPase activity of TF1 is no longer stimulated by rhodamine 6G, but rather, it is inhibited with 50% inhibition observed at about 30 microM dye at 30 degrees C. One interpretation of these results is that binding of rhodamine 6G to a high-affinity site on TF1 stimulates ATPase activity and unmasks a low-affinity, inhibitory site for the dye which is also exposed by LDAO.

  10. [Keeping dogs indoor aggravates infantile atopic dermatitis]. (United States)

    Endo, K; Hizawa, T; Fukuzumi, T; Kataoka, Y


    We had a two-month-old girl with severe dermatitis since birth. Her serum RAST to HD, Df and Dp were 1.06, 0.03 and 0.01 Ua/ml respectively. A Yorkshire terrier were kept at her mother's parents' home where the patient had lived for a month since birth. Her eczema, which became markedly aggravated whenever she visited there, improved after the elimination of the dog. We investigated the relationship between keeping dogs and infantile atopic dermatitis. We studied 368 patients under the age of two years (211 boys and 157 girls). Skin symptoms were graded globally mild, moderate or severe. Total serum IgE and specific antibody titer to dog dander were measured. We asked them whether they kept dogs and specifically, where they kept dogs, outdoor, indoor, in their own house, or in their grandparents' house. 197 patients had no contact with dogs, 90 patients kept dogs outdoor and 81 patients did indoor. The positive rate of RAST (> or = 0.7 Ua/ml) to dog dander was 6.1%, 17.8% and 46.9% respectively in these three groups. There were strong statistical differences between three groups. On the other hand, among the 81 patients who kept indoor, the RAST positive rates were almost same regarding where the dogs were kept, in their own house or their grandparents' house. Interestingly this difference happens only with patients under the age of 3 months. Patients older than 4 months showed no significant differences in the positive RAST rates, whether they kept dogs indoor or outdoor. This suggests the sensitization occurs before the age of 3 months. Speaking of symptoms, patients who kept dogs indoor showed significantly more severe symptoms than patients who had no contact with dogs and patients who kept dogs outdoor. There was no significant difference between the symptoms of patients who had no contact with dogs and those of patients who kept dogs outdoor. This implies the patient's symptom will improve only by moving the dog out of the house.

  11. [Beta-3 adrenergic receptor--structure and role in obesity and metabolic disorders]. (United States)

    Wiejak, J; Wyroba, E


    Structure and essential motifs of beta 3-adrenergic receptor (known previously as atypical beta-AR), which plays a central role in regulation of lipid metabolism have been described. Obesity results from an imbalance between caloric intake and energy expenditure. The consequence of catecholamine activation of beta 3-AR is increased mobilization of fatty acids from triglyceride stores (lipolysis) in brown and white adipose tissue as well as increased fatty acid beta-oxidation and heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg mutation in beta 3-AR gene in obesity and another metabolic disorders have been discussed.

  12. [Aggravation after Diagnosis of Sudden Sensorineural Hearing Loss]. (United States)

    Fukumoto, Ichiro; Nemoto, Toshimitsu; Tsukuda, Tomoko; Koshizuka, Keiichi


    Among 95 patients with sudden sensorineural hearing loss who received inpatient treatment at our hospital within the 27-month period between October 2009 and December 2011, those in whom hearing loss was aggravated after diagnosis were compared with a control group. Hearing loss aggravation was defined as a decrease by 10 dB or more in the mean hearing threshold at 5 frequencies from 250 to 4,000 Hz or decrease of 15 dB or more in the hearing threshold at 2 consecutive frequencies. Hearing loss was aggravated after diagnosis in 22 (23.2%) of the 95 patients, showing a similar tendency to that previously reported. Although the grades of hearing loss in these patients were higher than those in 73 control group patients, according to the sudden hearing loss severity classification, their outcomes were favorable. The hearing loss aggravation group consisted of those with steroid-dependent hearing loss (6) and those who had undergone perilymphatic fistula repair (4), in addition to a large number of patients with idiopathic hearing loss, including suspicious perilymphatic fistula (10). When hearing loss becomes aggravated after the diagnosis of sudden sensorineural hearing loss, it may be important to determine the most appropriate approach in each case, such as a careful and gradual decrease in the adenocortical steroid dose and the consideration of perilymphatic fistula repair.

  13. Aggravation of symptomatic occipital epilepsy of childhood by carbamazepine

    Directory of Open Access Journals (Sweden)

    Škrijelj Fadil E.


    Full Text Available Introduction. Carbamazepine can lead to aggravation of epileptic seizures in generalized epilepsies (primary or secondary with clinical manifestations of absence (typical or atypical and/or myoclonic seizures. However, some focal epilepsies can be also aggravated by the introduction of carbamazepine. Case report. We presented a 10-year-old boy born after a complicated and prolonged delivery completed by vacuum extraction, of early psychomotor development within normal limits. At the age of 8 years he had the first epileptic seizure of simple occipital type with generalization and urination. Brain magnetic resonance imaging (MRI showed focal cortical reductions in the left parietal and occipital regions. Interictal EEG recorded slowed basic activities above the posterior regions of the left hemisphere, with intermittent occurrence of occipital sharp waves and bioccipital sharp and slow-wave complexes. Initially, treatment with valproate was administered; however, the addition of carbamazepine into therapy induced aggravation of seizures and EEG findings, changed behavior and poor performance at school. By withdrawal of carbamazepine the condition improved both clinically and in EEG findings. Conclusion. Childhood occipital epilepsy lesions show deterioration due to carbamazepine, which if administered induces aggravation of seizures, behavior changes, cognition with occurrence of long-term bilateral discharges, and posterior sharp and slow wave high amplitude complexes recorded by EEG.

  14. 38 CFR 3.306 - Aggravation of preservice disability. (United States)


    ... disability. 3.306 Section 3.306 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... Connection § 3.306 Aggravation of preservice disability. (a) General. A preexisting injury or disease will be... disability during such service, unless there is a specific finding that the increase in disability is due...

  15. Inducing and Aggravating Factors of Gastroesophageal Reflux Symptoms

    Directory of Open Access Journals (Sweden)

    Radhiyatam Mardhiyah


    Full Text Available Gastroesophageal reflux disease (subsequently abbreviated as GERD is a disease commonly found in the community. Several factors have been recognized as inducing and aggravating factors of GERD symptoms such as older age, female gender, obesity, smoking habit, alcohol consumption, certain diet and poor eating habit like eating fatty, spicy, and acid food.

  16. The pharmacology of spontaneously open alpha 1 beta 3 epsilon GABA A receptor-ionophores. (United States)

    Maksay, Gábor; Thompson, Sally A; Wafford, Keith A


    Human alpha(1)beta(3) epsilon GABA(A) receptors were expressed in Xenopus oocytes and examined using the conventional two-electrode voltage-clamp technique and compared to alpha(1)beta(3)gamma(2) receptors. The effects of several GABA(A) agonists were studied, and the allosteric modulation of the channel by a number of GABAergic modulators investigated. The presence of the epsilon subunit increased the potency and efficacy of direct activation by partial GABA(A) agonists (piperidine-4-sulphonic acid and thio-4-PIOL), pentobarbital and neuro-steroids. Direct activation by 3-hydroxylated neurosteroids was restricted to 3alpha epimers, while chirality at C5 was indifferent. The 3beta-sulfate esters of pregnenolone and dehydroepiandrosterone inhibited the spontaneous currents with efficacies higher, while bicuculline methiodide and SR 95531 did so lower than picrotoxin and TBPS. Furosemide, fipronil, triphenylcyanoborate and Zn(2+) blocked the spontaneous currents of alpha(1)beta(3) epsilon receptors with different efficacies. Flunitrazepam and 4'-chlorodiazepam inhibited the spontaneous currents with micromolar potencies. In conclusion, spontaneously active alpha(1)beta(3) epsilon GABA(A) receptors can be potentiated and blocked by GABAergic agents within a broad range of efficacy.

  17. Fipronil-based photoaffinity probe for Drosophila and human beta 3 GABA receptors. (United States)

    Sirisoma, N S; Ratra, G S; Tomizawa, M; Casida, J E


    Modification of the major insecticide fipronil (1) by replacing three pyrazole substituents (hydrogen for both cyano and amino and trifluoromethyldiazirinyl for trifluoromethylsulfinyl) gives a candidate photoaffinity probe (3) of high potency (IC(50) 2-28 nM) in blocking the chloride channel of Drosophila and human beta 3 GABA receptors.

  18. Rat beta(3)-adrenoceptor protein expression : antibody validation and distribution in rat gastrointestinal and urogenital tissues

    NARCIS (Netherlands)

    Cernecka, Hana; Pradidarcheep, Wisuit; Lamers, Wouter H.; Schmidt, Martina; Michel, Martin C.


    beta(3)-Adrenoceptors play important roles in the regulation of urogenital and probably gastrointestinal function. However, despite recent progress, their detection at the protein level has remained difficult due to a lack of sufficiently validated selective antibodies. Therefore, we have explored t

  19. Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. (United States)

    Carpéné, C; Galitzky, J; Fontana, E; Atgié, C; Lafontan, M; Berlan, M


    Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1

  20. Differential regulation of chemoattractant-stimulated beta 2, beta 3, and beta 7 integrin activity. (United States)

    Sadhu, C; Masinovsky, B; Staunton, D E


    Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattractants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation of three integrins, alpha 4 beta 7, alpha L beta 2, and alpha V beta 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in alpha L beta 2- and alpha V beta 3-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of alpha 4 beta 7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We also demonstrate that alpha 4 beta 7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While alpha V beta 3- and alpha L beta 2-mediated cell adhesion was significantly reduced by cytochalasin D, alpha 4 beta 7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of alpha L beta 2 and alpha V beta 3. In contrast, inducible alpha 4 beta 7 activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of alpha 4 beta 7 regulation by chemoattractants is different from that of alpha L beta 2 and alpha V beta 3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion.

  1. Aggravating andmitigating factors associated with cyclist injury severity in Denmark

    DEFF Research Database (Denmark)

    Kaplan, Sigal; Vavatsoulas,, Konstantinos; Prato, Carlo Giacomo


    Denmark is one of the leading cycling nations, where cycling trips constitute a large share of the total trips, and cycling safety assumes a top priority position in the agenda of policy makers. The current study sheds light on the aggravating and mitigating factors associated with cyclist injury...... severity on Danish roads by examining a comprehensive set of accidents involving a cyclist and a collision partner between 2007 and 2011. Method: This study estimates a generalized ordered logit model of the severity of cyclist injuries because of its ability to accommodate the ordered-response nature...... of severity while relaxing the proportional odds assumption. Results: Model estimates show that cyclist fragility (children under 10 years old and elderly cyclists over 60 years of age) and cyclist intoxication are aggravating individual factors,while helmet use is a mitigating factor. Speed limits above 70...

  2. DMPD: Immunoreceptor-like signaling by beta 2 and beta 3 integrins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17913496 Immunoreceptor-like signaling by beta 2 and beta 3 integrins. Jakus Z, Fod...or S, Abram CL, Lowell CA, Mocsai A. Trends Cell Biol. 2007 Oct;17(10):493-501. (.png) (.svg) (.html) (.csml) Show Immunore...ceptor-like signaling by beta 2 and beta 3 integrins. PubmedID 17913496 Title Immunoreceptor-

  3. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles. (United States)

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D


    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  4. Aggravated neuromuscular symptoms of mercury exposure from dental amalgam fillings. (United States)

    Akbal, Ayla; Yılmaz, Hınç; Tutkun, Engin; Köş, Durdu Mehmet


    Dental amalgam fillings are widely used all over the world. However, their mercury content can lead to various side effects and clinical problems. Acute or chronic mercury exposure can cause several side effects on the central nerve system, renal and hepatic functions, immune system, fetal development and it can play a role on exacerbation of neuromuscular diseases. In this case, we will present a patient with vacuolar myopathy whose symptoms were started and aggravated with her dental amalgam fillings.

  5. Beta(3)-adrenergic signaling acutely down regulates adipose triglyceride lipase in brown adipocytes. (United States)

    Deiuliis, Jeffrey A; Liu, Li-Fen; Belury, Martha A; Rim, Jong S; Shin, Sangsu; Lee, Kichoon


    Mice exposed to cold rely upon brown adipose tissue (BAT)-mediated nonshivering thermogenesis to generate body heat using dietary glucose and lipids from the liver and white adipose tissue. In this report, we investigate how cold exposure affects the PI3 K/Akt signaling cascade and the expression of genes involved in lipid metabolism and trafficking in BAT. Cold exposure at an early time point led to the activation of the PI3 K/Akt, insulin-like signaling cascade followed by a transient decrease in adipose triglyceride lipase (ATGL) gene and protein expression in BAT. To further investigate how cold exposure-induced signaling altered ATGL expression, cultured primary brown adipocytes were treated with the beta(3)-adrenergic receptor (beta(3)AR) agonist CL 316,243 (CL) resulting in activation of PI3 K/Akt, ERK 1/2, and p38 signaling pathways and significantly decreased ATGL protein levels. ATGL protein levels decreased significantly 30 min post CL treatment suggesting protein degradation. Inhibition of PKA signaling by H89 rescued ATGL levels. The effects of PKA signaling on ATGL were shown to be independent of relevant pathways downstream of PKA such as PI3 K/Akt, ERK 1/2, and p38. However, CL treatment in 3T3-L1 adipocytes did not decrease ATGL protein and mRNA expression, suggesting a distinct response in WAT to beta3-adrenergic agonism. Transitory effects, possibly attributed to acute Akt activation during the early recruitment phase, were noted as well as stable changes in gene expression which may be attributed to beta3-adrenergic signaling in BAT.

  6. Structure of the integrin beta3 transmembrane segment in phospholipid bicelles and detergent micelles. (United States)

    Lau, Tong-Lay; Partridge, Anthony W; Ginsberg, Mark H; Ulmer, Tobias S


    Integrin adhesion receptors transduce bidirectional signals across the plasma membrane, with the integrin transmembrane domains acting as conduits in this process. Here, we report the first high-resolution structure of an integrin transmembrane domain. To assess the influence of the membrane model system, structure determinations of the beta3 integrin transmembrane segment and flanking sequences were carried out in both phospholipid bicelles and detergent micelles. In bicelles, a 30-residue linear alpha-helix, encompassing residues I693-H772, is adopted, of which I693-I721 appear embedded in the hydrophobic bicelle core. This relatively long transmembrane helix implies a pronounced helix tilt within a typical lipid bilayer, which facilitates the snorkeling of K716's charged side chain out of the lipid core while simultaneously immersing hydrophobic L717-I721 in the membrane. A shortening of bicelle lipid hydrocarbon tails does not lead to the transfer of L717-I721 into the aqueous phase, suggesting that the reported embedding represents the preferred beta3 state. The nature of the lipid headgroup affected only the intracellular part of the transmembrane helix, indicating that an asymmetric lipid distribution is not required for studying the beta3 transmembrane segment. In the micelle, residues L717-I721 are also embedded but deviate from linear alpha-helical conformation in contrast to I693-K716, which closely resemble the bicelle structure.

  7. High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs. (United States)

    Pelat, Michel; Verwaerde, Patrick; Galitzky, Jean; Lafontan, Max; Berlan, Michel; Senard, Jean-Michel; Montastruc, Jean-Louis


    The "in vivo" conditions for beta3-adrenoceptors (beta-AR) activation by isoproterenol were investigated in dog. Experiments were carried out in anesthetized dogs using isoproterenol as a nonselective beta-AR agonist. Intravenous infusion of isoproterenol (0.4 nmol/kg/min) induced arterial hypotension and tachycardia with a slight decrease in cutaneous blood flow. At this dose, isoproterenol increased glucose, glycerol, and nonesterified fatty acid plasma levels. The changes in cardiovascular and endocrine-metabolic parameters, induced by the low dose of isoproterenol, were suppressed by pretreatment with nadolol (1 mg/kg, i.v.). After nadolol administration, however, a 10-fold higher dose (4 nmol/kg/min) of isoproterenol was able to induce a decrease in arterial blood pressure with a slight tachycardia and an increase in cutaneous blood flow. This high dose of isoproterenol increased nonesterified fatty acid and glycerol plasma levels but failed to change glucose plasma levels. All these effects were abolished by a pretreatment with nadolol (1 mg/kg, i.v.) plus SR59230A [a selective beta3-adrenoceptor antagonist; (3-(2-ethylphenoxy)-1(1S)-1,2,3,4-tetrahydronaphth-1-ylaminol-(2S)2-propanol oxalate); 1 mg/kg, i.v.]. Moreover, as observed with the high dose of isoproterenol under nadolol pretreatment, an infusion of SR58611A [a selective beta3-adrenoceptor agonist; ((N2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl-(2R)-2-hydroxy-2-chlorophenyl) ethanamine hydrochloride] induces a decrease in mean arterial blood pressure associated with an increase in heart rate, cutaneous blood flow, and nonesterified fatty acid and glycerol plasma levels. These results demonstrate that the in vivo activation of beta3-adrenoceptors requires higher doses of catecholamine than those necessary for beta1- and/or beta2-adrenoceptor stimulation. These results also argue for the lack of a beta3-AR involvement in the control of heart rate and glycogenolysis in dogs.

  8. Aldosterone aggravates glucose intolerance induced by high fructose. (United States)

    Sherajee, Shamshad J; Rafiq, Kazi; Nakano, Daisuke; Mori, Hirohito; Kobara, Hideki; Hitomi, Hirofumi; Fujisawa, Yoshihide; Kobori, Hiroyuki; Masaki, Tsutomu; Nishiyama, Akira


    We previously reported that aldosterone impaired vascular insulin signaling in vivo and in vitro. Fructose-enriched diet induces metabolic syndrome including hypertension, insulin resistance, hyperlipidemia and diabetes in animal. In the current study, we hypothesized that aldosterone aggravated fructose feeding-induced glucose intolerance in vivo. Rats were divided into five groups for six-week treatment; uninephrectomy (Unx, n=8), Unx+aldosterone (aldo, 0.75 µg/h, s.c., n=8), Unx+fructose (fruc, 10% in drinking water, n=8), Unx+aldo+fruc, (aldo+fruc, n=8), and Unx+aldo+fruc+spironolactone, a mineralocorticoid receptor antagonist (aldo+fruc+spiro, 20mg/kg/day, p.o., n=8). Aldo+fruc rats manifested the hypertension, and induced glucose intolerance compared to fruc intake rats assessed by oral glucose tolerance test, homeostasis model assessment of insulin resistance and hyperinsulinemic-euglycemic clamp study. Spironolactone, significantly improved the aldosterone-accelerated glucose intolerance. Along with improvement in insulin resistance, spironolactone suppressed upregulated mineralocorticoid receptor (MR) target gene, serum and glucocorticoid-regulated kinases-1 mRNA expression in skeletal muscle in aldo+fruc rats. In conclusion, these data suggested that aldosterone aggravates fructose feeding-induced glucose intolerance through MR activation.

  9. Aggravation of viral hepatitis by platelet-derived serotonin. (United States)

    Lang, Philipp A; Contaldo, Claudio; Georgiev, Panco; El-Badry, Ashraf Mohammad; Recher, Mike; Kurrer, Michael; Cervantes-Barragan, Luisa; Ludewig, Burkhard; Calzascia, Thomas; Bolinger, Beatrice; Merkler, Doron; Odermatt, Bernhard; Bader, Michael; Graf, Rolf; Clavien, Pierre-Alain; Hegazy, Ahmed N; Löhning, Max; Harris, Nicola L; Ohashi, Pamela S; Hengartner, Hans; Zinkernagel, Rolf M; Lang, Karl S


    More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.

  10. Beyond bullying: Aggravating elements of peer victimization episodes. (United States)

    Turner, Heather A; Finkelhor, David; Shattuck, Anne; Hamby, Sherry; Mitchell, Kimberly


    This study sought to identify features of peer victimization that aggravate negative outcomes in children. The features that were assessed include "power imbalance," a commonly used criterion in defining bullying, and 5 other characteristics: injury, weapon involvement, Internet involvement, sexual content, and bias content. Three outcomes were assessed: level of fear, missing school, and trauma symptoms. A nationally representative sample of 3,164 children and youth ages 6-17 (51.8% male; 68.4% white, 12.5% black, 13.5% Hispanic, 5.7% other race) was obtained through Random Digit Dial and supplemented with an address-based sample to capture cell-phone-only households. One child was randomly selected from each household. Interviews were conducted with parents of children age 6-9 and with the youths themselves if they were age 10-17. Peer victimization was assessed with the Juvenile Victimization Questionnaire (JVQ). Almost half (48.4%) of the entire sample of school-age children experienced at least 1 form of peer victimization in the past year. Injury and power imbalance independently increased the impact on children for all 3 outcomes. Additionally, weapon involvement and sexual content were associated with trauma symptoms, with sexual content having the strongest effect (B = .23, p bullying with its exclusionary power imbalance definition as the central focus for prevention and intervention. We recommend a broader focus on peer victimization along with more research to identify the aggravating features that signal the greatest need for intervention.

  11. Andes virus recognition of human and Syrian hamster beta3 integrins is determined by an L33P substitution in the PSI domain. (United States)

    Matthys, Valery S; Gorbunova, Elena E; Gavrilovskaya, Irina N; Mackow, Erich R


    Andes virus (ANDV) causes a fatal hantavirus pulmonary syndrome (HPS) in humans and Syrian hamsters. Human alpha(v)beta(3) integrins are receptors for several pathogenic hantaviruses, and the function of alpha(v)beta(3) integrins on endothelial cells suggests a role for alpha(v)beta(3) in hantavirus directed vascular permeability. We determined here that ANDV infection of human endothelial cells or Syrian hamster-derived BHK-21 cells was selectively inhibited by the high-affinity alpha(v)beta(3) integrin ligand vitronectin and by antibodies to alpha(v)beta(3) integrins. Further, antibodies to the beta(3) integrin PSI domain, as well as PSI domain polypeptides derived from human and Syrian hamster beta(3) subunits, but not murine or bovine beta(3), inhibited ANDV infection of both BHK-21 and human endothelial cells. These findings suggest that ANDV interacts with beta(3) subunits through PSI domain residues conserved in both Syrian hamster and human beta(3) integrins. Sequencing the Syrian hamster beta(3) integrin PSI domain revealed eight differences between Syrian hamster and human beta(3) integrins. Analysis of residues within the PSI domains of human, Syrian hamster, murine, and bovine beta(3) integrins identified unique proline substitutions at residues 32 and 33 of murine and bovine PSI domains that could determine ANDV recognition. Mutagenizing the human beta(3) PSI domain to contain the L33P substitution present in bovine beta(3) integrin abolished the ability of the PSI domain to inhibit ANDV infectivity. Conversely, mutagenizing either the bovine PSI domain, P33L, or the murine PSI domain, S32P, to the residue present human beta(3) permitted PSI mutants to inhibit ANDV infection. Similarly, CHO cells transfected with the full-length bovine beta(3) integrin containing the P33L mutation permitted infection by ANDV. These findings indicate that human and Syrian hamster alpha(v)beta(3) integrins are key receptors for ANDV and that specific residues within the

  12. Structural policy in the context of international competition aggravation

    Directory of Open Access Journals (Sweden)

    Volodymyr Bodrov


    Full Text Available This article researches the essence and peculiarities of the structural policy, performs classification of its models and determines possibilities of their use in the context of increasing international competition. It discovers the main components of the economic structure and trends of the state policy regarding their modernization. Measures on improvement of state regulation instruments are offered, factors of influence upon improvement of the Ukrainian economy structure are analyzed and priority goals are systematized which require urgent implementation in the terms of competitive struggle aggravation at the global markets. The article also researches the matter of importance of performing a complex of state functional and selective measures in the form of matrix policy for the purpose of protecting national interests of the country in the context of global challenges

  13. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats.

    Directory of Open Access Journals (Sweden)

    Jie Wu

    Full Text Available Aortocaval fistula (AV in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX rats.Adult male Sprague-Dawley (SD rats were divided into Sham (n = 10, UNX (right kidney remove, n = 10, AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18 and UNX+AV (AV at one week after UNX, n = 22, respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements.UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats.Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals.

  14. Two-Dimensional Infrared (2DIR) Spectroscopy of the Peptide Beta3s Folding (United States)

    Lai, Zaizhi; Preketes, Nicholas K; Jiang, Jun; Mukamel, Shaul; Wang, Jin


    Probing underlying free energy landscape, pathways, and mechanism is the key for understanding protein folding in theory and experiment. Recently time-resolved two-dimensional infrared (2DIR) with femtosecond laser pulses, has emerged as a promising tool for investigating the protein folding dynamics on faster timescales than possible by NMR. We have employed molecular dynamics simulations to compute 2DIR spectra of the folding process of a peptide, Beta3s. Simulated non-chiral and chiral 2DIR signals illustrate the variation of the spectra as the peptide conformation evolves along the free energy landscape. Chiral spectra show stronger changes than the non-chiral signals because cross peaks caused by the formation of the β-sheet are clearly resolved. Chirality-induced 2DIR may be used to detect the folding of β-sheet proteins with high spectral and temporal resolution. PMID:23956818

  15. Integrin-beta3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force (United States)

    Yu, Cheng-han; Rafiq, Nisha Bte Mohd; Cao, Fakun; Zhou, Yuhuan; Krishnasamy, Anitha; Biswas, Kabir Hassan; Ravasio, Andrea; Chen, Zhongwen; Wang, Yu-Hsiu; Kawauchi, Keiko; Jones, Gareth E.; Sheetz, Michael P.


    The turnover of integrin receptors is critical for cell migration and adhesion dynamics. Here we find that force development at integrins regulates adaptor protein recruitment and endocytosis. Using mobile RGD (Arg-Gly-Asp) ligands on supported lipid membranes (RGD membranes) and rigid RGD ligands on glass (RGD-glass), we find that matrix force-dependent integrin signals block endocytosis. Dab2, an adaptor protein of clathrin-mediated endocytosis, is not recruited to activated integrin-beta3 clusters on RGD-glass; however, it is recruited to integrin-mediated adhesions on RGD membranes. Further, when force generation is inhibited on RGD-glass, Dab2 binds to integrin-beta3 clusters. Dab2 binding to integrin-beta3 excludes other adhesion-related adaptor proteins, such as talin. The clathrin-mediated endocytic machinery combines with Dab2 to facilitate the endocytosis of RGD-integrin-beta3 clusters. From these observations, we propose that loss of traction force on ligand-bound integrin-beta3 causes recruitment of Dab2/clathrin, resulting in endocytosis of integrins. PMID:26507506

  16. Vitamin D depletion aggravates hypertension and target-organ damage

    DEFF Research Database (Denmark)

    Andersen, Louise Bjørkholt; Przybyl, Lukasz; Haase, Nadine;


    BACKGROUND: We tested the controversial hypothesis that vitamin D depletion aggravates hypertension and target-organ damage by influencing renin. METHODS AND RESULTS: Four-week-old double-transgenic rats (dTGR) with excess angiotensin (Ang) II production due to overexpression of the human renin (h......REN) and angiotensinogen (hAGT) genes received vitamin D-depleted (n=18) or standard chow (n=15) for 3 weeks. The depleted group had very low serum 25-hydroxyvitamin D levels (mean±SEM; 3.8±0.29 versus 40.6±1.19 nmol/L) and had higher mean systolic BP at week 5 (158±3.5 versus 134.6±3.7 mm Hg, P....6±3.3 versus 162.3±3.8 mm Hg, PVitamin D depletion led to increased relative heart weights and increased serum creatinine concentrations. Furthermore, the mRNAs of natriuretic peptides, neutrophil gelatinase-associated lipocalin, hREN, and r...

  17. Pain in Breast Cancer Treatment: Aggravating Factors and Coping Mechanisms

    Directory of Open Access Journals (Sweden)

    Maria de Fatima Guerreiro Godoy


    Full Text Available The objective of this study was to evaluate pain in women with breast cancer-related lymphedema and the characteristics of aggravating factors and coping mechanisms. The study was conducted in the Clinica Godoy, São Jose do Rio Preto, with a group of 46 women who had undergone surgery for the treatment of breast cancer. The following variables were evaluated: type and length of surgery; number of radiotherapy and chemotherapy sessions; continued feeling of the removed breast (phantom limb, infection, intensity of pain, and factors that improve and worsen the pain. The percentage of events was used for statistical analysis. About half the participants (52.1% performed modified radical surgery, with 91.3% removing only one breast; 82.6% of the participants did not perform breast reconstruction surgery. Insignificant pain was reported by 32.60% of the women and 67.3% said they suffered pain; it was mild in 28.8% of the cases (scale 1–5, moderate in 34.8% (scale 6–9, and severe in 4.3%. The main mechanisms used to cope with pain were painkillers in 41.30% of participants, rest in 21.73%, religious ceremonies in 17.39%, and chatting with friends in 8.69%. In conclusion, many mastectomized patients with lymphedema complain of pain, but pain is often underrecognized and undertreated.

  18. Seawater Immersion Aggravates Burn Injury Causing Severe Blood Coagulation Dysfunction

    Directory of Open Access Journals (Sweden)

    Hong Yan


    Full Text Available This study aimed to investigate the endothelial function in a canine model of burn injury combined with seawater immersion. The model of burn injury was established. The dogs were randomly divided into four groups including dogs with burn injury (B group, or burn injury combined with seawater immersion (BI group, or only immersion in seawater (I group, or control animals with no injury or immersion (C group. The circulating endothelial cell (CEC count and coagulation-fibrinolysis parameters were measured. The CEC count in B group increased at 4 h, 7 h, and 10 h after injury and then reduced, whereas it continuously increased to a greater extent in BI group (P<0.05. The von Willebrand factor (vWF activity, plasminogen activator inhibitor (PAI-1, and the ratio of thromboxane B2 (TXB2 to 6-keto-prostaglandin F1α (6-K-PGF1α in BI group had a marked increase after injury, and the tissue-type plasminogen activator (tPA in the BI group decreased. Microscope observations revealed thrombus formation in lungs of the animals in BI group, but not in C, I, or B groups. Burn injury causes endothelial dysfunction, and seawater immersion lastingly aggravates this injury, leading to a higher risk of developing thrombosis.

  19. Tolbutamide attenuates diazoxide-induced aggravation of hypoxic cell injury. (United States)

    Pissarek, M; Reichelt, C; Krauss, G J; Illes, P


    ATP-dependent potassium (KATP) channels of neurons are closed in the presence of physiological levels of intracellular ATP and open when ATP is depleted during hypoxia or metabolic damage. The present study investigates hypoxic alterations of purine and pyrimidine nucleotide levels supposed to intracellularly modulate KATP channels. In addition, the effects of the KATP channel activator diazoxide and its antagonist tolbutamide were investigated on ATP, GTP, CTP and UTP levels in slices of the parietal cortex. Hypoxia was evoked by saturation of the medium with 95% N2-5% CO2 instead of 95% O2-5% CO2 for 5 min. Nucleotide contents were measured by anion-exchange HPLC in neutralized perchloric acid extracts obtained from slices frozen immediately at the end of incubation. Hypoxia per se decreased purine and pyrimidine nucleoside triphosphate contents. Thus, ATP and GTP contents were reduced to 69.9 and 77.6% of the respective normoxic levels. UTP and CTP contents were even more decreased (to 60.9 and 41.6%),, probably because the salvage pathway of these pyrimidine nucleotides is less effective than that of the purine nucleotides ATP and GTP. While tolbutamide (30 microM) had no effect on the hypoxia-induced decrease of nucleotides, diazoxide at 300, but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 MicroM). Nucleoside diphosphate (ADP, GDP and UDP) levels were uniformly increased by hypoxia. There was no hypoxia-induced increase of ADP contents in the presence of tolbutamide (300 microM). The ATP

  20. Dietary hypercholesterolemia aggravates contrast media-induced nephropathy

    Institute of Scientific and Technical Information of China (English)

    杨定位; 贾汝汉; 杨定平; 丁国华; 黄从新


    Background Contrast media administration can result in severe nephrotoxicity under pathological conditions such as diabetic nephropathy, congestive heart failure, dehydration, et al. The purpose of this study was to evaluate the effects of dietary hypercholesterolemia on contrast media-induced changes in renal function, blood flow, and histopathology.Methods Rats were fed either on a normal rodent diet (group N) or a high-cholesterol supplemented diet (group H; 4% cholesterol and 1% cholic acid) for 8 weeks. Half of the animals (n =6) from each diet group were then given a tail vein injection of 60% diatrizoate (6 ml/kg; group NC and group HC)and the other half were administered saline. Total serum cholesterol, triglyceride, serum creatinine,creatinine clearance rate, fractional excretion of sodium and potassium, and cortical nitric oxide production were determined one day following contrast media administration. Renal blood flow was determined by color Doppler flow imaging and pulsed-mode Doppler. Renal histopathology was observed by light microscopy.Results Total serum cholesterol and resistance indices of renal blood vessels increased significantly,while creatinine clearance rate and production of nitric oxide in the renal cortex decreased markedly in group HC and group H when compared to group N and group NC. The creatinine clearance rate decreased significantly in group HC compared to group H. Serum creatinine levels and fractional excretion of sodium and potassium in group HC were significantly higher than those in the other three groups. Severe tubular degeneration and necrosis, protein cast accumulation, and medullary congestion were found in group HC.Conclusion Hypercholesterolemia is a risk factor for contrast media-induced nephropathy.Hypercholesterolemia aggravates contrast media-induced nephrotoxicity through the reduced production of nitric oxide.

  1. Imprecise methods may both obscure and aggravate a relation between fat and breast cancer

    DEFF Research Database (Denmark)

    Heitmann, B L; Frederiksen, Peder


    Bias in diet reporting may be both random and non-random, and may be found with simpler as well as more advanced dietary instruments. A random bias will contribute to obscure relations between diet and disease. A systematic bias may obscure or aggravate such associations. Underreporting of non......-protein energy has been found to be substantial, particularly among those who are obese or have high dietary intakes. Such a non-random bias on the group level would tend to aggravate associations between dietary non-protein and disease. Whether the net result of the random and non-random bias aggravates...

  2. Aggravation of excessive daytime sleepiness concurrent with aggravation of an injured ascending reticular activating system in a patient with mild traumatic brain injury (United States)

    Jang, Sung Ho; Kwon, Hyeok Gyu


    Abstract Background: We report on a patient who developed aggravation of excessive daytime sleepiness (EDS) concurrent with aggravation of an injured ascending reticular activating system (ARAS) following mild traumatic brain injury (TBI), demonstrated by follow-up diffusion tensor tractographies (DTTs). Methods: A 42-year-old male patient experienced head trauma resulting from flexion-hyperextension injury after collision with another vehicle from behind while stopped at an intersection. The patient lost consciousness for approximately 10 seconds and experienced no post-traumatic amnesia following the accident. The patient's Glasgow Coma Scale score was 15. No specific lesion was observed on the conventional brain MRI performed at 10 weeks after onset. The patient complained of EDS after the head trauma and aggravation of EDS with passage of time. The Epworth Sleepiness Scale indicated abnormality with a score of 12 at 10 weeks after onset (cut-off: 10 points full mark: 24 score) and it was aggravated with a score of 18 at 16 months. Results: On 10-week DTT, decreased neural connectivity of the intralaminar thalamic nucleus to the prefrontal cortex and basal forebrain was observed in both hemispheres. However, no significant abnormality was observed in the dorsal and ventral lower ARAS. On 16-month DTT, the upper portion of the left dorsal lower ARAS showed partial tearing and the ventral lower ARAS showed thinning (both sides) and partial tearing (right side). Conclusions: Aggravation of EDS concurrent with aggravation of an injured ARAS was demonstrated in a patient with mild TBI using DTT. PMID:28121943

  3. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China); Peng, Shuangqing [Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071 (China); Wang, Weidong, E-mail: [Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Li, Rong, E-mail: [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China)


    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  4. Involvement of PLC-beta3 in the effect of morphine on memory retrieval in passive avoidance task. (United States)

    Bianchi, E; Lehmann, D; Vivoli, E; Norcini, M; Ghelardini, C


    Phospholipase C (PLC) is one signalling effector enzyme whose activity is directly modulated by opioids. Several physiological studies have implicated PLC-linked pathways in in-vivo pain regulation and opioid tolerance. Co-administration of PLC-beta(2/3) activity blocker M119 with morphine resulted in a dramatic increase in morphine-induced amnesic effect in mice, proving a role for beta subunit of PLC enzyme in these processes. Administration of morphine to mice at amnesic dose increased PLC-beta(3) activity, with respect to basal value, in the membrane-soluble material from anterior cortex and hippocampal formation in brain areas. PLC-beta(3) appears to be simultaneously implicated in both analgesic and amnesic effects induced by administration of morphine to mice suggesting a commonality in the molecular mechanisms of morphine-induced analgesia and memory impairment.

  5. Sleep-related hypoxemia aggravates systematic inflammation in emphysematous rats

    Institute of Scientific and Technical Information of China (English)

    FENG Jing; Ambrose An-Po Chiang; WU Qi; CHEN Bao-yuan; CUI Lin-yang; LIANG Dong-chun; ZHANG Ze-li; YAO Wo


    mean linear intercept (MLI) and mean alveolar number (MAN) values than SRHCtrl group. MLI values in SRHStand group were the highest (ail P <0.05). O2Sat in SRHStand rats when SRH exposure was (83.45±1.76)%. Histological scores of lung, liver, pancreas and right carotid artery were higher in emphysematous groups than SRHCtrl group, and SRHStand group were the highest (all P <0.05) (SOD and CAT values were lower and MDA values were higher in groups with emphysema than without and in SRHStand group than in ECtrl group (all P <0.05)). MDA values were the highest in SRHStand group (all P <0.05). Total cellular score in BALF and White blood cell (WBC) in whole blood were the highest in SRHStand group (all P <0.05). Lymphocyte ratios were the highest in SRHStand group both in BALF and blood (all P <0.05). Red blood cell (RBC) and hemoglobin in emphysematous groups were higher than that in SRHCtrl group, and SRHStand group were higher than ECtrl group (all P <0.05).Conclusions With a proper novo model of SRHIE with Wistar rats, we have demonstrated SRH may aggravate the degree of emphysematous changes, polycythemia,oxidative stress and systematic inflammation. SRH and emphysema may have a synergistic action in causing systematic damages, and lymphocyte may be playing a central role in this process. Longer duration and more severe extent of SRHIE exposure also seem to result in more serious systematic damages. The mechanisms of all these concerned processes remain to be studied.

  6. Peripheral cardiovascular actions of SR 58611 A, a beta 3-adrenoceptor agonist, in the dog: lack of central effect. (United States)

    Montastruc, J L; Verwaerde, P; Pelat, M; Galitzky, J; Langin, D; Lafontan, M; Berlan, M


    In order to investigate the putative role of beta3-adrenoceptors in central and peripheral cardiovascular regulations, the effects of intracisternal (i.c.) and intravenous (i.v.) injections of SR 58611 A (10, 50, 100 and 200 nmol kg-1), a selective beta3-adrenoceptor agonist, were investigated in chloralose anaesthetized dogs. In normal dogs, i.v. SR 58611 A (100 and 200 nmol kg-1) induced a dose-dependent increase in heart rate with no change in blood pressure. After i.c. injection, SR 58611 A failed to modify blood pressure and heart rate (except at the highest dose 200 nmol kg-1 which induced a positive chronotropic effect). The positive chronotropic effect of SR 58611 A (200 nmol kg-1) appeared earlier and was significantly more pronounced after i.v. than i.c. administration. The positive chronotropic effect of i.v. SR 58611 A (200 nmol kg-1) was reduced by pretreatment with beta-adrenoceptor antagonists [propranolol, nadolol, bupranolol or the beta3-adrenoceptor selective antagonist, SR 59230 A (2 mg kg-1 i.v.)] and suppressed after sinoaortic denervation (i.e. after removal of vagal tone to the heart). These experiments do not show evidence for a primary central cardiovascular effect of SR 58611 A. The positive chronotropic effect of i.v. SR 58611 A is mainly of peripheral origin and can be attributed to a baroreceptor-mediated reflex due to the beta3-adrenoceptor mediated vasodilation with an increase in sympathetic tone and a reduction in vagal tone to the heart.

  7. Investigation of the causes of clinical symptom aggravation in process of intravenous thrombolysis with alteplase

    Directory of Open Access Journals (Sweden)

    LI Chen-hua


    Full Text Available Objective To explore the causes of aggravation of microcirculation disorders in the process of intravenous thrombolysis with alteplase and the clinical outcomes. Methods The clinical data of the aggravated signs and symptoms of 13 cases treated by alteplase were reported, and the onset characteristics and clinical outcomes were analysed to summarize emergency experiences. Results There were 13 patients with stenosis of intracranial large arteries occurred perforating branch infarctions caused by the blocking of carried arteries (8 cases in internal carotid system, 5 cases in vertebral-basilar system. In the process of thrombolytic therapy, main aggravated presentations including cortical ischemic symptom, quadriplegia, exacerbated disturbance of consciousness were seen. Imaging examinations showed multiple new petechial ischemic foci in cortex and watershed region or increasing of infarct foci in cerebellum and brain stem. The prognosis was favorable after expectant treatment. NIHSS score was 8.69 ± 3.42 at 24 h after treatment, and mRS score was 0.94 ±0.37 at 3 month-follow-up. Neurologic deficit and quality of life were evidently improved. Conclusion In the course of intravenous thrombolytic therapy with alteplase. Aggravated clinical signs and symptoms may be related to various factors. Emboli disintegration inducing microcirculation disorder is inferred to be the main cause. For patients presenting aggravated signs and symptoms in thrombolysis process, favorable outcomes may occur as long as intensive care and timely treatment are performed.

  8. Moderate alcohol consumption aggravates high fat-diet induced steatohepatitis in rats (United States)

    Background: Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Methods: Sprague-Dawley rats were first fed ad libitum...

  9. Aggravation and Stress in Parenting: Associations with Coparenting and Father Engagement among Resident Fathers (United States)

    Bronte-Tinkew, Jacinta; Horowitz, Allison; Carrano, Jennifer


    This study uses a sample of 2,139 resident biological fathers from the Fragile Families and Child Wellbeing surveys (baseline and 12-month follow-up), to examine whether paternal aggravation and stress in parenting is associated with father engagement and coparenting and whether this association differs by father's socioeconomic status. Results of…

  10. Metabolic response to various beta-adrenoceptor agonists in beta3-adrenoceptor knockout mice: evidence for a new beta-adrenergic receptor in brown adipose tissue. (United States)

    Preitner, F; Muzzin, P; Revelli, J P; Seydoux, J; Galitzky, J; Berlan, M; Lafontan, M; Giacobino, J P


    The beta3-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to beta-adrenoceptor stimulation were compared in adipose tissues of beta3-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. In BAT of wild type mice (-)-norepinephrine maximally stimulated MO2 4.1+/-0.8 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (dobutamine 5.1+/-0.3, terbutaline 5.3+/-0.3 and CL 316,243 4.8+/-0.9 fold, respectively); in BAT of beta3-adrenoceptor knockout mice, the beta1- and beta2-responses were fully conserved. In BAT of wild type mice, the beta1/beta2-antagonist and beta3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7+/-0.4 fold). In beta3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical beta-adrenoceptor, distinct from the beta1-, beta2- and beta3-subtypes and referred to as a putative beta4-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. In isolated white adipocytes of wild type mice, (-)-epinephrine maximally stimulated lipolysis 12.1+/-2.6 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (TO509 12+/-2, procaterol 11+/-3, CL 316,243 11+/-3 fold, respectively) or with CGP 12177 (7.1+/-1.5 fold). In isolated white adipocytes of beta3-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the beta1-, beta2-, beta3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.

  11. Immunohistochemical localization of integrin alpha V beta 3 and osteopontin suggests that they do not interact during embryo implantation in ruminants

    Directory of Open Access Journals (Sweden)

    MacLaren Leslie A


    Full Text Available Abstract Background It has been suggested that trophoblast attachment requires co-expression of integrin alpha V beta 3 and its ligand osteopontin at the fetal-maternal interface. Until now the expression patterns of integrin alpha V beta 3 and osteopontin in the pregnant bovine uterus were unknown. The objectives of this study were to localize integrin alpha V beta 3 and osteopontin in bovine and sheep endometrium during the periimplantation period and to compare the distribution patterns using antibodies that had not yet been tested in sheep. Methods Cell compartments within endometrial tissue sections were scored for immunohistochemical staining intensity and data were analyzed to determine the effects of day of pregnancy or cycle. Results In pregnant bovine endometrium, integrin alpha V beta 3 was detected in luminal epithelium, stroma, myometrium and smooth muscle. A strong band of immunoreactivity was observed in the subepithelial stroma of intercaruncular regions, but there was reduced reactivity in the caruncles and glands. Bovine trophoblast did not express integrin alpha V beta 3 at any stage of pregnancy. In ovine endometrium a different pattern of staining for integrin alpha V beta 3 was observed. Reactivity was not present in the luminal epithelium or trophoblast. There was strong staining of the deep glands and no reactivity in the superficial glands. Osteopontin distribution was similar for sheep and cattle. For both species, apical staining was present on the luminal epithelium and glands and on embryonic tissues. Conclusion In ruminants, integrin alpha V beta 3 and osteopontin do not co-localize at the fetal-maternal interface indicating that these proteins could not interact to facilitate embryo attachment as has been proposed in other species.

  12. Polymorphism at the ovine beta3-adrenergic receptor locus: associations with birth weight, growth rate, carcass composition and cold survival. (United States)

    Forrest, R H; Hickford, J G H; Hogan, A; Frampton, C


    The beta3-adrenergic receptors (ADRB3s) are predominantly found on the surface of adipocytes and are the major mediators of the lipolytic and thermogenic effects of high catecholamine concentrations. Polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of part of the ovine beta3-adrenergic receptor gene (ADRB3) intron was used to screen 12 large Merino half-sib families for sequence variation. Six different alleles that segregated in a Mendelian fashion were observed. The genetic basis for the allelic differences were identified by sequencing the ADRB3 (coding and non-coding regions) from animals that were homozygous for each of the alleles. Five sire lines (two Merino x Merino, two Merino x Coopworth, one Dorset Down x Coopworth) provided phenotypic and genotypic data used to ascertain the effects of allelic variation at the ADRB3 locus on birth weight, weaning weight, growth rate (up until weaning), carcass composition at 63 days post-weaning and cold survival. Statistical analyses within each half-sib family showed that in some sire lines (S13, S15, and S17) the inheritance of a particular allele was associated with increased birth weights and/or increased growth rates up until weaning. The inheritance of a particular sire allele was associated with fatter carcasses in sire line S16. Chi-squared analysis revealed the association of the E allele with cold survival and the D allele with cold-related mortality in sire line S14. Such associations support the hypothesis that ADRB3s are involved in energy homeostasis. With more research, the variation detected at the ADRB3 locus may assist in the genetic selection for desirable animal production traits.

  13. Residential characteristics aggravating infestation by Culex quinquefasciatus in a region of Northeastern Brazil

    Directory of Open Access Journals (Sweden)

    Juliana Cavalcanti Correia


    Full Text Available OBJECTIVE: Analyse how basic sanitation conditions, water supply and housing conditions affect the concentration of Culex quinquefasciatus METHODS: Populations of C. quinquefasciatus in 61 houses in the municipality of Olinda, PE, were monitored between October 2009 and October 2010. Observations were carried out in homes without the presence of preferred breeding sites in order to identify characteristics that may be aggravating factors for the development of the mosquito. Five aggravating factors were analysed: vegetation cover surrounding the home, number of residents/home, water storage, sewage drainage and water drainage. These characteristics were analysed in terms of presence or absence and as indicators of the degree of infestation, which was estimated through monitoring the concentration of eggs (oviposition traps - BR-OVT and adults (CDC light traps. RESULTS: Sewage drainage to a rudimentary septic tank or to the open air was the most frequent aggravating factor in the homes (91.8%, although the presence of vegetation was the only characteristic that significantly influenced the increase in the number of egg rafts (p = 0.02. The BR-OVT achieved positive results in 95.1% of the evaluations, with the presence of at least one egg raft per month. A total of 2,366 adults were caught, with a mosquito/room/night ratio of 32.9. No significant difference was found in the number of mosquitoes caught in the homes. CONCLUSIONS: Although the sanitation and water supply influence the population density of C. quinquefasciatus, residence features that are not usually considered in control measures can be aggravating factors in sustaining the mosquito population.

  14. Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene

    DEFF Research Database (Denmark)

    Højlund, K; Christiansen, C; Bjørnsbo, K S;


    and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.......AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin......-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild...

  15. Aggravation of nonalcoholic steatohepatitis by moderate alcohol consumption is associated with decreased SIRT1 activity in rats (United States)

    Chronic alcohol intake decreases adiponectin and sirtuin 1 (SIRT1) expressions, both of which have been implicated in various biological processes including inflammation, apoptosis and metabolism. We have previously shown that moderate consumption of alcohol aggravates liver inflammation and apoptos...

  16. Rhodamine-labeled 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)tropane analogues as high-affinity fluorescent probes for the dopamine transporter

    DEFF Research Database (Denmark)

    Cha, Joo Hwan; Zou, Mu-Fa; Adkins, Erika M


    Novel fluorescent ligands were synthesized to identify a high-affinity probe that would enable visualization of the dopamine transporter (DAT) in living cells. Fluorescent tags were extended from the N- or 2-position of 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)tropane, using an ethylamino lin...

  17. Lack of associations between serum leptin, a polymorphism in the gene for the beta(3)-adrenergic receptor and glucose tolerance in the Dutch population.

    NARCIS (Netherlands)

    Janssen, JAMJL; Koper, JW; Stolk, RP; Englaro, P; Uitterlinden, AG; Huang, Q; van Leeuwen, JPTM; Blum, WF; Attanasio, AMF; Pols, HAP; Grobbee, DE; de Jong, FH; Lamberts, SWJ


    BACKGROUND The associations between leptin levels and the prevalence of a polymorphism in the beta(3)-adrenergic receptor were studied in a cross-sectional analysis of 600 participants in a population-based study, which were stratified for glucose tolerance by an oral glucose tolerance test. METHODS

  18. Leptin upregulates beta3-integrin expression and interleukin-1beta, upregulates leptin and leptin receptor expression in human endometrial epithelial cell cultures. (United States)

    Gonzalez, R R; Leavis, P


    Human endometrium and endometrial epithelial cells (EECs) either cultured alone or cocultured with human embryos express leptin and leptin receptor. This study compares the effect of leptin with that of interleukin-1beta (IL-1beta) on the expression of beta3-EEC integrin, a marker of endometrial receptivity. Both cytokines increased the expression of beta3-EEC at concentrations in the range of 0.06-3 nM; however, leptin exhibited a significantly greater effect than IL-1beta. We also determined the regulatory effects of IL-1beta on leptin secretion and on the expression of leptin and leptin receptor at the protein level in both EEC and endometrial stromal cell (ESC) cultures. In EEC cultures, IL-1beta upregulated secretion of leptin and expression of both leptin and leptin receptors. No effect of IL-1beta was found in the ESC cultures. However, leptin exhibited marginal upregulation of leptin receptor. The upregulation of beta3-integrin and leptin/leptin receptor expression by IL-1beta in EEC cultures indicates that both cytokines may be implicated in embryonic-maternal cross-talk during the early phase of human implantation. Our present data also raise the possibility that leptin is an endometrial molecular effector of IL-1beta action on beta3-integrin upregulation. Thus, a new role for leptin in human reproduction as an autocrine/paracrine regulator of endometrial receptivity is proposed.

  19. Expression of the wild-type and the Cys-/Trp-less alpha 3 beta 3 gamma complex of thermophilic F1-ATPase in Escherichia coli. (United States)

    Matsui, T; Yoshida, M


    The alpha, beta and gamma subunits of F1-ATPase from thermophilic Bacillus PS3 were expressed in Escherichia coli cells simultaneously in large amounts. Most of the expressed subunits assembled into a form of alpha 3 beta 3 gamma complex in E. coli cells and this complex was easily purified to homogeneity. The recombinant alpha 3 beta 3 gamma complex thus obtained showed similar enzymatic properties to the alpha 3 beta 3 gamma complex obtained by in vitro reconstitution from individual subunits (Yokoyama, K. et al. (1989) J. Biol. Chem. 264, 21837-21841) except that the former had several-fold higher ATPase activity than the latter. Using this expression system, a mutant alpha 3 beta 3 gamma complex with no Trp and Cys was generated by replacing alpha Cys193 and alpha Trp463 with Ser and Phe, respectively. This mutant complex was functionally intact, indicating both residues are not essential for catalysis. The Cys-/Trp-less complex is a convenient 'second wild type' enzyme from which one can generate mutants with Trp (as a fluorescent probe) or Cys (as an acceptor of a variety of probes) at desired positions without concern for 'background' Trp and Cys residues.

  20. Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil. (United States)

    Cheng, Jin; Ju, Xiu-Lian; Chen, Xiang-Yang; Liu, Gen-Yan


    To further explore the mechanism of selective binding of the representative gamma-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human alpha 1 beta 2 gamma 2 and house fly beta 3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly beta 3 GABAR than with human alpha 1 beta 2 gamma 2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABARs may result in differential selectivity for fipronil.

  1. Role of beta-adrenoceptors in memory consolidation: beta3-adrenoceptors act on glucose uptake and beta2-adrenoceptors on glycogenolysis. (United States)

    Gibbs, Marie E; Hutchinson, Dana S; Summers, Roger J


    Noradrenaline, acting via beta(2)- and beta(3)-adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated beta(3)- rather than beta(2)-ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na(+)/energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with beta(3)-AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with beta(2)-AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) beta(2)- and beta(3)-ARs consolidate memory by different mechanisms; beta(3)-ARs stimulate central glucose transport, whereas beta(2)-ARs stimulate central glycogenolysis.

  2. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. (United States)

    Hucke, Stephanie; Eschborn, Melanie; Liebmann, Marie; Herold, Martin; Freise, Nicole; Engbers, Annika; Ehling, Petra; Meuth, Sven G; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa


    The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro-inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity.

  3. Viola Playing May Be a Strong Aggravating Factor for Temporomandibular Disorder

    Directory of Open Access Journals (Sweden)

    Mahmut Alpayci


    Full Text Available Temporomandibular disorder (TMD is the general term used to describe the symptoms originated from temporomandibular joint region. The most common symptom of the disorder is pain during mandibular movement. Etiology of TMD is multifactorial. Several factors such as trauma, occlusal discrepancies, stress, parafunctions, hypermobility, and heredity can make one more vulnerable to this disorder. It has been reported that viola playing might be a predisposing factor for TMD. In this article, we present a 24 year old male patient suffering from TMD symptoms exacerbated by viola playing and emphasize that viola playing may be a powerful aggravating factor for TMD.

  4. Environmental air pollution is an aggravating event for sudden unexpected death in epilepsy

    Directory of Open Access Journals (Sweden)

    Carla A. Scorza


    Full Text Available It is extremely difficult to estimate the occurrence of sudden unexpected death in epilepsy (SUDEP. On the other hand, discovering and carefully evaluating new risk factors that may contribute to the onset of cardiovascular abnormalities in people with refractory epilepsy may prevent fatal events in these individuals. In this context, we should not ignore that urban air pollution is a leading problem for environmental health and is able to cause serious cardiovascular dysfunctions that culminate in sudden death. In this regard, we aimed to determine whether environmental exposure to air pollution is an aggravating event for SUDEP.

  5. Hyperglycemia Aggravates Hepatic Ischemia Reperfusion Injury by Inducing Chronic Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Yihan Zhang


    Full Text Available Aim. To investigate whether hyperglycemia will aggravate hepatic ischemia reperfusion injury (HIRI and the underlying mechanisms. Methods. Control and streptozotocin-induced diabetic Sprague-Dawley rats were subjected to partial hepatic ischemia reperfusion. Liver histology, transferase, inflammatory cytokines, and oxidative stress were assessed accordingly. Similarly, BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R after high (25 mM or low (5.5 mM glucose culture. Cell viability, reactive oxygen species (ROS, and activation of nuclear factor-erythroid 2-related factor 2 (Nrf2 and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB were determined. Results. Compared with control, diabetic rats presented more severe hepatic injury and increased hepatic inflammatory cytokines and oxidative stress. HIRI in diabetic rats could be ameliorated by pretreatment of N-acetyl-L-cysteine (NAC or apocynin. Excessive ROS generation and consequent Nrf2 and NF-κB translocation were determined after high glucose exposure. NF-κB translocation and its downstream cytokines were further increased in high glucose cultured group after H/R. While proper regulation of Nrf2 to its downstream antioxidases was observed in low glucose cultured group, no further induction of Nrf2 pathway by H/R after high glucose culture was identified. Conclusion. Hyperglycemia aggravates HIRI, which might be attributed to chronic oxidative stress and inflammation and potential malfunction of antioxidative system.

  6. Orally delivered β-glucans aggravate dextran sulfate sodium (DSS)-induced intestinal inflammation. (United States)

    Heinsbroek, Sigrid E M; Williams, David L; Welting, Olaf; Meijer, Sybren L; Gordon, Siamon; de Jonge, Wouter J


    β-Glucans have beneficial health effects due to their immune modulatory properties. Oral administration of β-glucans affects tumour growth, microbial infection, sepsis, and wound healing. We hypothesized that pre-treatment with orally delivered soluble and particulate β-glucans could ameliorate the development of aggravate dextran sulfate sodium (DSS) induced intestinal inflammation. To study this, mice were orally pre-treated with β-glucans for 14 days. We tested curdlan (a particulate β-(1,3)-glucan), glucan phosphate (a soluble β-(1,3)-glucan), and zymosan (a particle made from Saccharomyces cerevisiae, which contains around 55% β-glucans). Weight loss, colon weight, and feces score did not differ between β-glucan and vehicle treated groups. However, histology scores indicated that β-glucan-treated mice had increased inflammation at a microscopic level suggesting that β-glucan treatment worsened intestinal inflammation. Furthermore, curdlan and zymosan treatment led to increased colonic levels of inflammatory cytokines and chemokines, compared to vehicle. Glucan phosphate treatment did not significantly affect cytokine and chemokine levels. These data suggest that particulate and soluble β-glucans differentially affect the intestinal immune responses. However, no significant differences in other clinical colitis scores between soluble and particulate β-glucans were found in this study. In summary, β-glucans aggravate the course of dextran sulfate sodium (DSS)-induced intestinal inflammation at the level of the mucosa.

  7. Consumption of Mercury-contaminated Rice Induces Oxidative Stress and Free Radical Aggravation in Rats

    Institute of Scientific and Technical Information of China (English)



    Objective To study the oxidative stress induced by consumption of mercury-contaminated rice in rats, and to assess the possible public health risk of mercury contamination in Wanshan mining area. Methods Sprague Dawley rats were fed the mercury-contaminated rice produced from Wanshan area for 90 days. The antioxidant status and the free radicals in rat serum were evaluated. Results High mercury accumulation in organs of rats fed the mercury-contaminated rice confirmed the server pollution of mercury in Wanshan mining area. The intensity of electron spin resonance (ESR) signal increased by 87.38% in rats fed the rice from Wanshan compared with that in the control rats fed the rice from Shanghai, suggesting that chronic dietary consumption of rice from mercury mining area could induce an aggravation of free radicals. Feeding the mercury-contaminated rice was associated with significant decreases in the antioxidant enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and concentration of serum nitric oxide (NO), but it had no effect on serum nitric oxide synthase (NOS) activity. Feeding the mercury-contaminated rice raised the level of serum malonyldialdehyde (MDA), indicating the occurrence of oxidative stress. Conclusion The long-term dietary consumption of mercury-contaminated rice induces the aggravation of free radicals and exerts oxidative stress.

  8. Chronic hypertension aggravates heat stress-induced brain damage: possible neuroprotection by cerebrolysin. (United States)

    Muresanu, Dafin Fior; Zimmermann-Meinzingen, Sibilla; Sharma, Hari Shanker


    Whole body hyperthermia (WBH) aggravates brain edema formation and cell damage in chronic hypertensive rats compared with normotensive animals. In this investigation, we examined the influence of cerebrolysin on WBH-induced edema formation and brain pathology in hypertensive and normotensive rats. Rats subjected to 4 h WBH at 38 degrees C in a biological oxygen demand (BOD) incubator showed breakdown of the blood-brain barrier (BBB), reduced cerebral blood flow (CBF), edema formation and cell injuries in several parts of the brain. These effects were further aggravated in chronic hypertensive rats (two-kidney one clip model (2K1C), for 4 weeks) subjected to WBH. Pretreatment with cerebrolysin (5 mL/kg, 24 h and 30 min before heat stress) markedly attenuated the BBB dysfunction and brain pathology in normal animals. However, in hypertensive animals, a high dose of cerebrolysin (10 mL/kg, 24 h and 30 min before heat stress) was needed to attenuate WBH-induced BBB dysfunction and brain pathology. These observations indicate that heat stress could affect differently in normal and hypertensive conditions. Furthermore, our results suggest that patients suffering from various chronic cardiovascular diseases may respond differently to hyperthermia and to neuroprotective drugs, e.g., cerebrolysin not reported earlier.

  9. Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy (United States)

    Guo, Rui; Lin, Bin; Pan, Jing Fei; Liong, Emily C.; Xu, Ai Min; Youdim, Moussa; Fung, Man Lung; So, Kwok Fai; Tipoe, George L.


    Acute liver disease is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long term clinical outcome and lead to liver failure or cancer. Here, we initially demonstrated the beneficial role of caspase-9-dependent autophagy in acute liver injury. Treatment with caspase-9 inhibitor z-LEHD-FMK in HepG2 cells, AML12 cells and C57BL/b6N mice exacerbated CCl4-induced acute hepatocellular damage, and also down-regulated autophagy markers expression levels, indicating that caspase-9 inhibition may aggravate acute liver damage by suppressing cytoprotective autophagy. CCl4 was used as an acute liver injury inducer which caused oxidative stress and apoptosis through up-regulation of HIF-1α, as well as triggered hepatic inflammation and necroptosis via TLR4/NF-κB pathway. Caspase-9 Thr125 site was firstly phosphorylated by ERK1/2 which subsequently activated the cytoprotective autophagy process to attenuate acute CCl4 injury. Caspase-9 inhibition further aggravated hepatic necroptosis through NF-κB expression, leading to increased pro-inflammatory mediators levels, suggesting a protective role of caspase-9-dependent autophagy in the inflammatory process as well as its possibility being a new therapeutic target for the treatment of acute liver injury. PMID:27580936

  10. An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats.

    Directory of Open Access Journals (Sweden)

    Masanori Nozako

    Full Text Available Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment.

  11. An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats (United States)

    Nozako, Masanori; Koyama, Takashi; Nagano, Chifumi; Sato, Makoto; Matsumoto, Satoshi; Mitani, Kiminobu; Yasufuku, Reiko; Kohashi, Masayuki; Yoshikawa, Tomohiro


    Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment. PMID:26606054

  12. Mesenchymal stromal cell implantation for stimulation of long bone healing aggravates Staphylococcus aureus induced osteomyelitis. (United States)

    Seebach, Elisabeth; Holschbach, Jeannine; Buchta, Nicole; Bitsch, Rudi Georg; Kleinschmidt, Kerstin; Richter, Wiltrud


    Large bone defects requiring long-term osteosynthetic stabilization or repeated surgeries show a considerable rate of infection. Mesenchymal stromal cells (MSCs) have been successfully used to enhance bone regeneration, but their powerful immunomodulatory effects may impose an enhanced risk for osteomyelitis development. In order to unravel whether implantation of MSCs aggravates a simultaneous bone infection, a hydrogel-supported osteomyelitis ostectomy model was developed in which rats received a femoral bone defect with rigid plate-fixation. After fibrin-assisted transfer of Staphylococcus aureus (SA), effects of MSC implantation on osteomyelitis development were quantified over 3-4 weeks. All SA-infected animals developed an acute local osteomyelitis with significantly increased blood neutrophil count, abscess formation and bone destruction. MSC-treatment of infected defects aggravated osteomyelitis according to a significantly elevated osteomyelitis score and enhanced distal bone loss with spongy alteration of cortical bone architecture. Increased attraction of macrophages, osteoclasts and regulation of pro- and anti-inflammatory mediators were potential MSC actions. Overall trophic actions of MSCs implanted into non-sterile bone defects may enhance an infection and/or exacerbate osteomyelitis. Studies on antibiotic carrier augmentation or antibiotic treatment are warranted to decide whether MSC implantation is a safe and promising therapy for orthopedic implant-stabilized bone defects at high risk for development of infection.

  13. Serotonin Transporter (5-HTT) and gamma-Aminobutyric Acid Receptor Subunit beta3 (GABRB3) Gene Polymorphisms are not Associated with Autism in the IMGSA Families

    DEFF Research Database (Denmark)

    Maestrini, E.; Lai, C.; Marlow, A.;


    Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study...... and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set....

  14. Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis. (United States)

    Hazelgrove, Krystina B; Flynn, Robert S; Qiao, Li-Ya; Grider, John R; Kuemmerle, John F


    Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the alpha(v)beta(3) integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although alpha(v)beta(3) integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 +/- 10% and 90 +/- 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 +/- 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3beta phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 +/- 15% and decreased apoptosis by 20 +/- 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an alpha(v)beta(3) integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of alpha(v)beta(3) integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

  15. Effects of the perfusion of beta-, beta2-, or beta3-adrenergic agonists or epinephrine on in situ adipose tissue lipolysis measured by microdialysis in underfed ewes. (United States)

    Ferlay, A; Charret, C; Galitzky, J; Berlan, M; Chilliard, Y


    The effects of isoproterenol (ISO, a non-selective beta-agonist), terbutaline (TER, a selective beta2-agonist), CL316243 (CL, a selective beta3-agonist), and epinephrine (EPI, beta- and alpha2-agonist) on in situ lipolytic response of s.c. adipose tissue were investigated in vivo, using a microdialysis method to measure glycerol release, in 12 adult nonlactating and ovariectomized, underfed Lacaune ewes. All the adrenergic compounds were perfused for 120 min at 10(-6), 10(-5), and 10(-4) M. They had no lipolytic effect at 10(-6) M. Isoproterenol and EPI at 10(-5) and 10(-4) M enhanced, in the same way, maximal response and area under the concentration curve (AUC) of dialysate glycerol, thus suggesting that involvement of alpha2-adrenoceptors in the control of in situ lipolysis is of minor importance in underfed ewes. Terbutaline had only a slight lipolytic effect at 10(-5) M. This low effect could be due to a lower affinity of TER than of ISO for the beta2-adrenoceptors. The beta3-agonist, CL, had no lipolytic effect whatever the concentration perfused. Further studies are needed to prove the putative presence of beta3-adrenoceptors and their possible role in the ovine adipose tissue.

  16. Acute patellofemoral pain: aggravating activities, clinical examination, MRI and ultrasound findings

    DEFF Research Database (Denmark)

    Brushoj, C.; Holmich, P.; Nielsen, M.B.;


    Objective: To investigate acute anterior knee pain caused by overuse in terms of pain location, aggravating activities, findings on clinical examination and ultrasound/MRI examination. To determine if acute anterior knee pain caused by overuse should be classified as a subgroup of patellofemoral...... pain syndrome (PFPS). Methods: In a observational study design 30 army recruits with anterior knee pain (mean duration of pain 4 weeks) were examined using the PFPS pain severity scale (PSS), knee pain diagrams, standardised clinical examination, ultrasound and MRI examinations. Results: On PSS typical......%)), but other synovial covered structures including the fat pad of Hoffa (12 patients (40%)), the medial plica and the joint line (12 patients (40%)) were also involved. Only eight patients (27%) experienced pain on the patellofemoral compression test. Only discrete changes was detected on MRI...

  17. Obesity does not aggravate vitrification injury in mouse embryos: a prospective study

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    Ma Wenhong


    Full Text Available Abstract Background Obesity is associated with poor reproductive outcomes, but few reports have examined thawed embryo transfer in obese women. Many studies have shown that increased lipid accumulation aggravates vitrification injury in porcine and bovine embryos, but oocytes of these species have high lipid contents (63 ng and 161 ng, respectively. Almost nothing is known about lipids in human oocytes except that these cells are anecdotally known to be relatively lipid poor. In this regard, human oocytes are considered to be similar to those of the mouse, which contain approximately 4 ng total lipids/oocyte. To date, no available data show the impact of obesity on vitrification in mouse embryos. The aim of this study was to establish a murine model of maternal diet-induced obesity and to characterize the effect of obesity on vitrification by investigating the survival rate and embryo developmental competence after thawing. Methods Prospective comparisons were performed between six–eight-cell embryos from obese and normal-weight mice and between fresh and vitrified embryos. Female C57BL/6 mice were fed standard rodent chow (normal-weight group or a high-fat diet (obese group for 6 weeks. The mice were mated, zygotes were collected from oviducts and cultured for 3 days, and six–eight-cell embryos were then selected to assess lipid content in fresh embryos and to evaluate differences in apoptosis, survival, and development rates in response to vitrification. Results In fresh embryos from obese mice, the lipid content (0.044 vs 0.030, Pvs.9.3%, Pvs. 93.1%, P Conclusions This study demonstrated that differences in survival and developmental rates between embryos from obese and normal-weight mice were eliminated after vitrification. Thus, maternal obesity does not aggravate vitrification injury, but obesity alone greatly impairs pre-implantation embryo survival and development.

  18. Calreticulin Translocation Aggravates Endoplasmic Reticulum Stress-associated Apoptosis during Cardiomyocyte Hypoxia/Reoxygenation

    Institute of Scientific and Technical Information of China (English)

    Fei-Fei Xu; Xiu-Hua Liu


    Background:Calreticulin (CRT) is major Ca2+-binding chaperone mainly resident in the endoplasmic reticulum (ER) lumen.Recently,it has been shown that non-ER CRT regulates a wide array of cellular responses.We previously found that CRT was up-regulated during hypoxia/reoxygenation (H/R) and this study was aimed to investigate whether CRT nuclear translocation aggravates ER stress (ERS)-associated apoptosis during H/R injury in neonatal rat cardiomyocytes.Methods:Apoptosis rate and lactate dehydrogenase (LDH) leakage in culture medium were measured as indices of cell injury.Immunofluorescence staining showed the morphological changes of ER and intracellular translocation of CRT.Western blotting or reverse transcription polymerase chain reaction was used to detect the expression of target molecules.Results:Compared with control,H/R increased apoptosis rate and LDH activity.The ER became condensed and bubbled,and CRT translocated to the nucleus.Western blotting showed up-regulation of CRT,Nrf2,activating transcription factor 4 (ATF4),CHOP and caspase-12 expression after H/R.Exogenous CRT overexpression induced by plasmid transfection before H/R increased cell apoptosis,LDH leakage,ER disorder,CRT nuclear translocation and the expression of ERS-associated molecules.However,administration of the ERS inhibitor,taurine,or CRT siRNA alleviated cell injury,ER disorder,and inhibited ERS-associated apoptosis.Conclusions:Our results indicated that during H/R stress,CRT translocation increases cell apoptosis and LDH leakage,aggravates ER disorder,up-regulates expression of nuclear transcription factors,Nrf2 and ATF4,and activates ERS-associated apoptosis.

  19. Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis.

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    Keisuke Mishiro

    Full Text Available Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO in streptozotocin (STZ -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells. Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP-9 activity, but not reactive oxygen species production. Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption. A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.

  20. Aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats. (United States)

    Jia, Ling-ling; Zhong, Ze-yu; Li, Feng; Ling, Zhao-li; Chen, Yang; Zhao, Wei-man; Li, Ying; Jiang, Shu-wen; Xu, Ping; Yang, Yang; Hu, Meng-yue; Liu, Li; Liu, Xiao-dong


    Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZ-induced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZ-induced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (nor-CLZ) and clozapine N-oxide (CLZ N-oxide). The results in vivo showed that 7-day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in γ-glutamyl transpeptidase (γ-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, γ-GT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of nor-CLZ and CLZ N-oxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of nor-CLZ and CLZ N-oxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QT-PCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZ-induced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

  1. Noninvasive visualization and quantification of tumor {alpha}{sub V{beta}3} integrin expression using a novel positron emission tomography probe, {sup 64}Cu-cyclam-RAFT-c(-RGDfK-){sub 4}

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    Jin, Zhao-Hui [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Furukawa, Takako, E-mail: tfuru@nirs.go.j [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Galibert, Mathieu; Boturyn, Didier [Departement de Chimie Moleculaire, UMR 5250, CNRS-Universite Joseph Fourier, 38041 Grenoble Cedex 9 (France); Coll, Jean-Luc [INSERM U823, Institut Albert Bonniot and Universite Joseph Fourier, 38706 La Tronche Cedex, Grenoble (France); Fukumura, Toshimitsu; Saga, Tsuneo [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Dumy, Pascal [Departement de Chimie Moleculaire, UMR 5250, CNRS-Universite Joseph Fourier, 38041 Grenoble Cedex 9 (France); Fujibayashi, Yasuhisa [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan)


    Introduction: The {alpha}{sub V{beta}3} integrin is a well-known transmembrane receptor involved in tumor invasion, angiogenesis and metastasis. Our aim was to evaluate a novel positron emission tomography (PET) probe, {sup 64}Cu-cyclam-RAFT-c(-RGDfK-){sub 4}, for noninvasive visualization and quantification of {alpha}{sub V{beta}3} integrin expression. Methods: RAFT-c(-RGDfK-){sub 4}, a tetrameric cyclic Arg-Gly-Asp (RGD)-based peptide, was conjugated with a bifunctional chelator, 1,4,8,11-tetraazacyclotetradecane (cyclam), radiolabeled with the positron emitter {sup 64}Cu and evaluated in vitro by cell binding and competitive inhibition assays and in vivo by biodistribution and receptor blocking studies, and PET imaging. The following cell lines, human embryonic kidney HEK293({beta}{sub 1}) [{alpha}{sub V{beta}3}-negative] and HEK293({beta}{sub 3}) [{alpha}{sub V{beta}3}-overexpressing] and human glioblastoma U87MG [naturally expressing {alpha}{sub V{beta}3}], together with their subcutaneous xenografts in athymic nude mice, were used for the present study. The expression levels of {alpha}{sub V{beta}3} on these cell lines and tumor xenografts were analyzed by flow cytometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography, respectively. Results: {sup 64}Cu-cyclam-RAFT-c(-RGDfK-){sub 4} demonstrated the in vitro and in vivo specificity for the {alpha}{sub V{beta}3} integrin and displayed rapid blood clearance, predominantly renal excretion and low uptake in nontumor tissues. Tumor uptake of {sup 64}Cu-cyclam-RAFT-c(-RGDfK-){sub 4} (3 h postinjection) in HEK293({beta}{sub 3}) (high levels of {alpha}{sub V{beta}3}), U87MG (moderate levels of {alpha}{sub V{beta}3}) and HEK293({beta}{sub 1}) (undetectable levels of {alpha}{sub V{beta}3}) tumors was 9.35%{+-}1.19%, 3.46%{+-}0.45% and 1.18%{+-}0.30% injected dose per gram, respectively, with a strong and positive correlation with the tumor {alpha}{sub V{beta}3} expression levels

  2. Manganese-induced integrin affinity maturation promotes recruitment of alpha V beta 3 integrin to focal adhesions in endothelial cells: evidence for a role of phosphatidylinositol 3-kinase and Src. (United States)

    Dormond, Olivier; Ponsonnet, Lionel; Hasmim, Meriem; Foletti, Alessandro; Rüegg, Curzio


    Integrin activity is controlled by changes in affinity (i.e. ligand binding) and avidity (i.e. receptor clustering). Little is known, however, about the effect of affinity maturation on integrin avidity and on the associated signaling pathways. To study the effect of affinity maturation on integrin avidity, we stimulated human umbilical vein endothelial cells (HUVEC) with MnCl(2) to increase integrin affinity and monitored clustering of beta 1 and beta 3 integrins. In unstimulated HUVEC, beta 1 integrins were present in fibrillar adhesions, while alpha V beta 3 was detected in peripheral focal adhesions. Clustered beta 1 and beta 3 integrins expressed high affinity/ligand-induced binding site (LIBS) epitopes. MnCl(2)-stimulation promoted focal adhesion and actin stress fiber formation at the basal surface of the cells, and strongly enhanced mAb LM609 staining and expression of beta 3 high affinity/LIBS epitopes at focal adhesions. MnCl(2)-induced alpha V beta 3 clustering was blocked by a soluble RGD peptide, by wortmannin and LY294002, two pharmacological inhibitors of phosphatidylinositol 3-kinase (PI 3-K), and by over-expressing a dominant negative PI 3-K mutant protein. Conversely, over-expression of active PI 3-K and pharmacological inhibiton of Src with PP2 and CGP77675, enhanced basal and manganese-induced alpha V beta 3 clustering. Transient increased phosphorylation of protein kinase B/Akt, a direct target of PI 3K, occurred upon manganese stimulation. MnCl(2) did not alter beta 1 integrin distribution or beta1 high-affinity/LIBS epitope expression. Based on these results, we conclude that MnCl(2)-induced alpha V beta 3 integrin affinity maturation stimulates focal adhesion and actin stress fiber formation, and promotes recruitment of high affinity alpha V beta 3 to focal adhesions. Affinity-modulated alpha V beta 3 clustering requires PI3-K signaling and is negatively regulate by Src.

  3. Effect of lysozyme chloride on betel quid chewing aggravated gastric oxidative stress and hemorrhagic ulcer in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Chen-Road Hung


    AIM: To evaluate the protective effect of lysozyme chloride on betel quid chewing (BQC) aggravated gastric oxidative stress and hemorrhagic ulcer in rats with diabetes mellitus (DM).METHODS: Male Wistar rats were challenged intravenously with streptozotocin (65 mg/kg) to induce DM. Rats were fed with regular pellet food or BQC-containing diets. After 90 d, rats were deprived of food for 24 h. Rat stomachs were irrigated for 3 h with normal saline or simulated gastric juice. Rats were killed and gastric specimens were harvested.RESULTS: An enhancement of various gastric ulcerogenic parameters, including acid back-diffusion, mucosal lipid peroxide generation, as well as decreased glutathione levels and mucus content, were observed in DM rats. After feeding DM rats with BQC, an exacerbation of these ulcerogenic parameters was achieved. Gastric juice caused a further aggravation of these ulcerogenic parameters. Daily intragastric lysozyme chloride dose-dependently inhibited exacerbation of various ulcerogenic parameters in those BQC-fed DM rats.CONCLUSION: (1) Gastric juice could aggravate both DM and BQC-fed DM rat hemorrhagic ulcer; (2) BQC exacerbated gastric hemorrhagic ulcer in DM rats via enhancing oxidative stress and reducing defensive factors; (3) lysozyme chloride effectively protected BQC aggravated gastric damage in DM rats.

  4. Aggravation of Risk and Precautionary Measures in Non-Life Insurance: A Tricky Scope for the Insurer?

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    Olavi-Jüri Luik


    Full Text Available Aggravation of risk and failure to take precautionary measures are focal issues in non-life insurance in terms of potential partial or full release of the insurer from the duty to perform. Not infrequently, it is difficult to draw a line between the aggravation of risk on the one hand, and non-compliance with precautionary measures on the other, since a particular action by a policyholder may present both situations. At the same time, the legal remedies available to the insurer regarding these two situations are different in scope. The aggravation of risk and non-compliance with precautionary measures are precisely the bases on which insurers actually reduce indemnity or refuse to compensate for damages. This article explores the differences between insurance laws in the Baltic states—specifically, the Estonian Law of Obligations Act, the Latvian Insurance Contract Law and Lithuanian rules contained in the Civil Code and Insurance Law. The article explores the differences between the Baltic states’ insurance laws and the Principles of European Insurance Contract Law (PEICL with regard to a policyholder’s duty in relation to aggravation of risk and precautionary measures, as the rights and obligations of policyholders do change where the optional instrument is applied. The article also includes comparisons to German, Finnish and Russian insurance law.

  5. Contributions of Streptococcus mutans Cnm and PA antigens to aggravation of non-alcoholic steatohepatitis in mice (United States)

    Naka, Shuhei; Hatakeyama, Rina; Takashima, Yukiko; Matsumoto-Nakano, Michiyo; Nomura, Ryota; Nakano, Kazuhiko


    Streptococcus mutans, a major pathogen of dental caries, can cause infective endocarditis after invading the bloodstream. Recently, intravenous administration of specific S. mutans strains was shown to aggravate non-alcoholic steatohepatitis (NASH) in a mouse model fed a high-fat diet. Here, we investigated the mechanism of this aggravation in a NASH mouse model by focusing on the S. mutans cell surface collagen-binding protein (Cnm) and the 190-kDa protein antigen (PA). Mice that were intravenously administered a S. mutans strain with a defect in Cnm (TW871CND) or PA (TW871PD) did not show clinical or histopathological signs of NASH aggravation, in contrast to those administered the parent strain TW871. The immunochemical analyses demonstrated higher levels of interferon-γ and metallothionein expression in the TW871 group than in the TW871CND and TW871PD groups. Analysis of bacterial affinity to cultured hepatic cells in the presence of unsaturated fatty acids revealed that the incorporation rate of TW871 was significantly higher than those of TW871CND and TW871PD. Together, our results suggest that Cnm and PA are important cell surface proteins for the NASH aggravation caused by S. mutans adhesion and affinity for hepatic cells. PMID:27833139

  6. Neuronal chloride accumulation and excitatory GABA underlie aggravation of neonatal epileptiform activities by phenobarbital. (United States)

    Nardou, Romain; Yamamoto, Sumii; Chazal, Geneviève; Bhar, Asma; Ferrand, Nadine; Dulac, Olivier; Ben-Ari, Yehezkel; Khalilov, Ilgam


    Phenobarbital produces its anti-epileptic actions by increasing the inhibitory drive of γ-aminobutyric acid. However, following recurrent seizures, γ-aminobutyric acid excites neurons because of a persistent increase of chloride raising the important issue of whether phenobarbital could aggravate persistent seizures. Here we compared the actions of phenobarbital on initial and established ictal-like events in an in vitro model of mirror focus. Using the in vitro three-compartment chamber preparation with the two hippocampi and their commissural fibres placed in three different chambers, kainate was applied to one hippocampus and phenobarbital contralaterally, either after one ictal-like event or after many recurrent ictal-like events that produce an epileptogenic mirror focus. Field, perforated patch and single-channel recordings were used to determine the effects of γ-aminobutyric acid and their modulation by phenobarbital, and alterations of the chloride cotransporters were investigated using sodium-potassium-chloride cotransporter 1 and potassium chloride cotransporter 2 antagonists, potassium chloride cotransporter 2 immunocytochemistry and sodium-potassium-chloride cotransporter 1 knockouts. Phenobarbital reduced initial ictal-like events and prevented the formation of a mirror focus when applied from the start. In contrast, phenobarbital aggravated epileptiform activities when applied after many ictal-like events by enhancing the excitatory actions of γ-aminobutyric acid due to increased chloride. The accumulation of chloride and the excitatory actions of γ-aminobutyric acid in mirror foci neurons are mediated by the sodium-potassium-chloride cotransporter 1 chloride importer and by downregulation and internalization of the chloride-exporter potassium-chloride cotransporter 2. Finally, concomitant applications of the sodium-potassium-chloride cotransporter 1 antagonist bumetanide and phenobarbital decreased excitatory actions of γ-aminobutyric acid and

  7. ERK5 knock down aggravates detrimental effects of hypothermal stimulation on cardiomyocytes via Bim upregulation. (United States)

    Wang, Yao-Sheng; Zhou, Jing; Liang, Chun; Hong, Kui; Cheng, Xiao-Shu; Wu, Zong-Gui


    Mechanism of cold induced myocardial injury remained unclear. Our study investigated the role of ERK5/Bim pathway in hypothermal stimulation-induced apoptosis or damage of cardiomyocytes (CMs). Results showed that in CMs which under hypothermal stimulation, ERK5 siRNA promoted expression of Bim protein. Bim siRNA did not influence ERK5 expression but attenuated production of p-ERK5. ERK5 siRNA induced higher apoptosis rate; intracellular Ca(2+) overload; ROS activity; ΔΨm damage in hypothermia stimulated CMs, when compared with hypothermal stimulation solely treated group, while Bim siRNA effected oppositely and canceled pro-apoptotic effect of ERK5 siRNA. In conclusion, ERK5 knock down releases inhibition to Bim expression, induces aggravated apoptosis in CMs under hypothermal stimulation, which related to higher intracellular Ca(2+) overload, ROS activity, and more severe ΔΨm damage. Results revealed regulative role of ERK5/Bim pathway in hypothermal stimulation-induced injure or apoptosis of cardiomyocytes.

  8. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. (United States)

    Shahzad, Khurrum; Bock, Fabian; Dong, Wei; Wang, Hongjie; Kopf, Stefan; Kohli, Shrey; Al-Dabet, Moh'd Mohanad; Ranjan, Satish; Wolter, Juliane; Wacker, Christian; Biemann, Ronald; Stoyanov, Stoyan; Reymann, Klaus; Söderkvist, Peter; Groß, Olaf; Schwenger, Vedat; Pahernik, Sascha; Nawroth, Peter P; Gröne, Herman-Josef; Madhusudhan, Thati; Isermann, Berend


    Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

  9. Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway (United States)

    Reboul, Cyril; Boissière, Julien; André, Lucas; Meyer, Gregory; Bideaux, Patrice; Fouret, Gilles; Feillet-Coudray, Christine; Obert, Philippe; Lacampagne, Alain; Thireau, Jérôme; Cazorla, Olivier; Richard, Sylvain


    Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac β–adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca2+ cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality. PMID:28045070

  10. Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. (United States)

    Chen, Xin; Zhang, Ke-Li; Yang, Shu-Yuan; Dong, Jing-Fei; Zhang, Jian-Ning


    Administration of glucocorticoid to patients with head injury has previously been demonstrated to impair memory. We hypothesize that glucocorticoids promote post-traumatic hippocampal apoptosis, resulting in retrograde memory deficiency associated with traumatic brain injury (TBI). In the present study, we tested this hypothesis by measuring spatial memory deficiency in rats subjected to fluid percussion injury (FPI) and receiving dexamethasone (DXM at 0.5-10 mg/kg) or methylprednisolone (MP at 5-30 mg/kg); we also examined neuronal apoptosis in hippocampus. Adult male Wistar rats were trained for the acquisition of spatial memory, then subjected to FPI and tested for spatial reference memory on post-injury days 7 and 14 using the Morris Water Maze. Brain tissue from injured rats was examined 24 h to 2 weeks after injury. The percent time in the goal quadrant, which measures spatial reference memory, was significantly lower in injured rats receiving either high-dose DXM or MP than in control groups. TUNEL-positive cells in hippocampus were first detected 24 h post-injury, plateauing at 48h. The number of TUNEL-positive cells was significantly higher in injured rats treated with either DXM or MP. The data suggest that glucocorticoid therapy for TBI may increase neuronal apoptosis in hippocampus and, as a result, aggravate retrograde memory deficits induced by TBI.

  11. Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway.

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    Parag Kundu


    Full Text Available To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2. Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.

  12. Cedar Pollen Aggravates Atopic Dermatitis in Childhood Monozygotic Twin Patients with Allergic Rhino Conjunctivitis

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    Yukako Murakami


    Full Text Available We report a case of 7-year-old monozygotic twin patients with atopic dermatitis. The HLA haplotypes were HLA A2, A11, B27, B61, DR1, and DR4. Both serum IgE levels and cedar pollen radioallergosorbent test (RAST scores were high in the twins (elder/younger sister: IgE: 5170/3980 IU/ml and Japansese cedar pollen: >100/64.0 in contrast to low mite and food RAST scores (Dermatophagoides Pterygonium; 0.59/0.4 and egg white 9.24/4.6. The patients showed positive immediate (20 min in both sisters and delayed (24 hours in elder sister, 24, 48, 72 hours in younger sister reactions to a scratch test with Japanese cedar pollen. Skin lesions on the face were aggravated and extended to the trunk and extremities during the Japanese cedar pollen season and gradually subsided in summer. Oral provocation with egg white or cow milk showed no exacerbations, and topical corticosteroid did not improve the eczema. In contrast, successful protection from severe scratching behaviors was achieved by use of topical anti-allergic eye drops and wearing nightgowns made by the mother.

  13. Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity. (United States)

    Agrawal, Rahul; Noble, Emily; Vergnes, Laurent; Ying, Zhe; Reue, Karen; Gomez-Pinilla, Fernando


    Fructose consumption has been on the rise for the last two decades and is starting to be recognized as being responsible for metabolic diseases. Metabolic disorders pose a particular threat for brain conditions characterized by energy dysfunction, such as traumatic brain injury. Traumatic brain injury patients experience sudden abnormalities in the control of brain metabolism and cognitive function, which may worsen the prospect of brain plasticity and function. The mechanisms involved are poorly understood. Here we report that fructose consumption disrupts hippocampal energy homeostasis as evidenced by a decline in functional mitochondria bioenergetics (oxygen consumption rate and cytochrome C oxidase activity) and an aggravation of the effects of traumatic brain injury on molecular systems engaged in cell energy homeostasis (sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1alpha) and synaptic plasticity (brain-derived neurotrophic factor, tropomyosin receptor kinase B, cyclic adenosine monophosphate response element binding, synaptophysin signaling). Fructose also worsened the effects of traumatic brain injury on spatial memory, which disruption was associated with a decrease in hippocampal insulin receptor signaling. Additionally, fructose consumption and traumatic brain injury promoted plasma membrane lipid peroxidation, measured by elevated protein and phenotypic expression of 4-hydroxynonenal. These data imply that high fructose consumption exacerbates the pathology of brain trauma by further disrupting energy metabolism and brain plasticity, highlighting the impact of diet on the resilience to neurological disorders.

  14. 147 Mitigating and Aggravating Circumstances. Their Impact on Judicial Individualization of Punishment

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    Cosmin Peonaşu


    Full Text Available For an act to fall under criminal law it is sufficient for it to meet the minimum conditions to achieve constitutive content of the offense. However, committing a criminal act takes place, in most cases, in a complex set of variables specific to each case, variables that, without characterizing the act as an offense or the perpetrator's person as subject of that offence, helps determining, on one hand, the social danger of the committed crime and, on the other hand, knowing the offender as an individual and its social dangerousness. Mitigating and aggravating circumstances are such variables and they have a specific impact on criminal responsibility of the perpetrator. These circumstances have a major influence on judicial individualization of punishment because their effect is preset by the Law and acts separately on the length or amount of punishment. This study aims both students and practitioners or academics and highlights on one hand, the legislative solutions of the new Criminal Code and on the other hand, the differences between the old and the new Criminal Code.

  15. Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

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    Yaqian Zhao


    Full Text Available Elevated homocysteine (Hcy levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE staining and TdT-mediated dUTP Nick-End Labeling (TUNEL staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG. Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO. Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive and hardly in astrocytes (GFAP-positive. 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA. Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level.

  16. Cardiac Fibroblasts Aggravate Viral Myocarditis: Cell Specific Coxsackievirus B3 Replication

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    Diana Lindner


    Full Text Available Myocarditis is an inflammatory disease caused by viral infection. Different subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inflammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: fibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3 and detected increased gene expression of anti-inflammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac fibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-α, IL-6, MCP-1, and IFN-β was significantly increased in cardiac fibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac fibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase compared to cardiomyocytes (14-fold increase between 6 and 24 hours after infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. Therefore, we suggest that cardiac fibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis.

  17. Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke. (United States)

    Inácio, Ana R; Ruscher, Karsten; Leng, Lin; Bucala, Richard; Deierborg, Tomas


    Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif(-/-) mice does not affect interleukin-1β protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.

  18. Cardiomyocyte Overexpression of FABP4 Aggravates Pressure Overload-Induced Heart Hypertrophy.

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    Ji Zhang

    Full Text Available Fatty acid binding protein 4 (FABP4 is a member of the intracellular lipid-binding protein family, responsible for the transportation of fatty acids. It is considered to express mainly in adipose tissues, and be strongly associated with inflammation, obesity, diabetes and cardiovasculardiseases. Here we report that FABP4 is also expressed in cardiomyocytes and plays an important role in regulating heart function under pressure overload. We generated heart-specific transgenic FABP4 (FABP4-TG mice using α myosin-heavy chain (α-MHC promoter and human FABP4 sequence, resulting in over-expression of FABP4 in cardiomyocytes. The FABP4-TG mice displayed normal cardiac morphology and contractile function. When they were subjected to the transverse aorta constriction (TAC procedure, the FABP4-TG mice developed more cardiac hypertrophy correlated with significantly increased ERK phosphorylation, compared with wild type controls. FABP4 over-expression in cardiomyocytes activated phosphor-ERK signal and up-regulate the expression of cardiac hypertrophic marker genes. Conversely, FABP4 induced phosphor-ERK signal and hypertrophic gene expressions can be markedly inhibited by an ERK inhibitor PD098059 as well as the FABP4 inhibitor BMS309403. These results suggest that FABP4 over-expression in cardiomyocytes can aggravate the development of cardiac hypertrophy through the activation of ERK signal pathway.

  19. Feed exposure to FB1 can aggravate pneumonic damages in pigs provoked by P. multocida. (United States)

    Kovács, Melinda; Pósa, Roland; Tuboly, Tamás; Donkó, Tamás; Repa, Imre; Tossenberger, János; Szabó-Fodor, Judit; Stoev, Stoycho; Magyar, Tibor


    The possible interaction between Pasteurella multocida and the mycotoxin fumonisin B1 (FB1), recognised as one of the most often food/feed contaminant, was studied with the aim to evaluate whether and how FB1 can influence and/or complicate the development and severity of various pathological damages provoked by Pasteurella multocida in some internal organs of pigs. Heavier lung pathology was seen in pigs experimentally infected with Pasteurella multocida, when the same were exposed to 20ppm dietary levels of fumonisin B1 (FB1) as was assessed by gross pathology, pathomorphological examinations, clinical biochemistry and some immunological investigations. The most typical damages in FB1 treated pigs were the strong oedema in the lung and the slight oedema in the other internal organs and mild degenerative changes in the kidneys, whereas the typical pathomorphological findings in pigs infected with Pasteurella multocida was broncho-interstitial pneumonia. FB1 was found to aggravate pneumonic changes provoked by P. multocida in the cranial lobes of the lung and to complicate pneumonic damages with interstitial oedema in the lung. No macroscopic damages were observed in the pigs infected only with Pasteurella multocida. It can be concluded that the feed intake of FB1 in pigs may complicate or exacerbate the course of P. multocida serotype A infection.

  20. Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

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    Natalia Nuño-Lámbarri


    Full Text Available Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress.

  1. Norepinephrine as a Potential Aggravator of Symptomatic Cerebral Vasospasm: Two Cases and Argument for Milrinone Therapy

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    F. A. Zeiler


    Full Text Available Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140–150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130–140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.

  2. Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway. (United States)

    Reboul, Cyril; Boissière, Julien; André, Lucas; Meyer, Gregory; Bideaux, Patrice; Fouret, Gilles; Feillet-Coudray, Christine; Obert, Philippe; Lacampagne, Alain; Thireau, Jérôme; Cazorla, Olivier; Richard, Sylvain


    Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac β-adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca(2+) cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality.

  3. Polymorphism Trp64Arg of beta 3 adrenoreceptor gene: allelic frequencies and influence on insulin resistance in a multicenter study of Castilla-León Polimorfismo TRP64ARG del gen receptor beta 3: frecuencia alélica e influencia en la resistencia a la insulina en un estudio multicéntrico de Castilla y León

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    D. A. de Luis


    Full Text Available Background and objective: The genetic variant (Trp64Arg is a missense mutation located within the beta3 adrenoreceptor (Beta3AR. The aim of our study was to investigate the influence of Trp64Arg polymorphism in the Beta3AR gene on insulin resistance in obese patients and the allelic distribution of this polymorphismin a geographic area of Spain. Design: A population of 264 obese patients was analyzed. A bioimpedance, blood pressure, an assessment of nutritional intake, and biochemical parameters were measured. The beta 3 adrenoreceptor gene polymorphism(Trp64Arg was genotyped. Results: Two hundred and twenty six patients (77 males/149 females (85.6% had the genotype Trp64/Trp64 (wild type group with and average age of 41.12 ± 13.1 years and 38 patients (16 males/22 females Trp64/Arg64 (14.4% (mutant type group with an average age of 40.5 ± 12.7 years. High frequencies of Arg64 allele were observed in Salamanca and Valladolid. In the mutant type group, HOMA (3.75 ± 2.77 vs 5.27 ± 5.4; p Introducción y objetivos: La variante genética (Trp64Arg es una mutación localizada en el adrenoreceptor Beta 3 (Beta3AR. El objetivo de nuestro trabajo es evaluar la influencia de el polimorfismo Trp64Arg del gen de Beta3AR sobre la resistencia a la insulina en pacientes obesos, así como la distribución alélica de este polimorfismo en un área geográfica de España. Diseño: Una muestra de 264 pacientes obesos fue analizada. Se realizó una bioimpedancia, evaluación nutricional y análisis bioquímico. Se genotiparon a los pacientes en función delpolimorfismos Tr64Arg del gen adrenoreceptor-beta 3. Resultados: Un total de 227 pacientes (77 varones/149 mujeres (85,6% presentaron el genotipo Trp64/Trp64 (grupo genotipo salvaje, con una media de edad de 41,12 ± 13,1 años y un total de 38 pacientes (16 varones/22 mujeres Trp64/Arg64 (14,4% (grupo genotipo mutante con una edad media de 40,5 ± 12,7 años. Se detectó una alta frecuencia alélica (Arg64

  4. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates

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    van der Westhuyzen, J.; Fernandes-Costa, F.; Metz, J.


    Nitrous oxide, which inactivates cobalamin when administered to fruit bats, results in severe neurological impairment leading to ataxia, paralysis and death. This occurs after about 6 weeks in animals depleted of cobalamin by dietary restriction, and after about 10 weeks in cobalamin replete bats. Supplementation of the diet with pteroylglutamic acid caused acceleration of the neurological impairment--the first unequivocal demonstration of aggravation of the neurological lesion in cobalamin deficiency by pteroylglutamic acid. The administration of formyltetrahydropteroylglutamic acid produced similar aggravation of the neurological lesion. Supplementation of the diet with methionine protected the bats from neurological impairment, but failed to prevent death. Methionine supplementation protected against the exacerbating effect of folate, preventing the development of neurological changes. These findings lend support to the hypothesis that the neurological lesion in cobalamin deficiency may be related to a deficiency in the methyl donor S-adenosylmethionine which follows diminished synthesis of methionine.

  5. Charges for criminal exposure to HIV and aggravated prostitution filed in the Nashville, Tennessee Prosecutorial Region 2000-2010. (United States)

    Galletly, Carol L; Lazzarini, Zita


    This paper examines comprehensive data on arrests for HIV-specific crimes within a single jurisdiction, the Nashville Tennessee prosecutorial region, over 11 years. There were 25 arrests for HIV exposure and 27 for aggravated prostitution. Eleven of the arrests for HIV exposure involved nonsexual behaviors; none alleged transmission. Sixteen of the arrests for HIV exposure involved sexual behavior; three alleged transmission. Aggravated prostitution cases (i.e. prostitution while knowing one has HIV) often involved solicitation of oral sex; none alleged transmission. Maximum sentences for HIV-specific crimes ranged from 5 to 8 years. We conclude that enforcement of US HIV-specific laws is underestimated. Fifty-two arrests over 11 years were recorded in one jurisdiction. Over half of the arrests involved behaviors posing minimal or no HIV transmission risk. Despite concerns about malicious, intentional HIV transmission, no cases alleged malice or intention.

  6. Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia. (United States)

    den Hoed, Marissa A H; Pluijm, Saskia M F; te Winkel, Mariël L; de Groot-Kruseman, Hester A; Fiocco, Martha; Hoogerbrugge, Peter; Leeuw, Jan A; Bruin, Marrie C A; van der Sluis, Inge M; Bresters, Dorien; Lequin, Maarten H; Roos, Jan C; Veerman, Anjo J P; Pieters, Rob; van den Heuvel-Eibrink, Marry M


    Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, Posteonecrosis: -1.73 versus without osteonecrosis: -0.57, Posteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, Posteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia.

  7. Vitamin D deficiency aggravates chronic kidney disease progression after ischemic acute kidney injury.

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    Janaína Garcia Gonçalves

    pathways and involvement of TGF-β1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.

  8. Chemerin aggravates DSS-induced colitis by suppressing M2 macrophage polarization. (United States)

    Lin, Yuli; Yang, Xuguang; Yue, Wenjie; Xu, Xiaofei; Li, Bingji; Zou, Linlin; He, Rui


    Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin (aa17-156) aggravated the severity of dextran sulfate sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-α and interferon (IFN-γ). Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1), Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.

  9. Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model (United States)

    Liang, Junjie; Li, Ning; Zhang, Yanli; Hou, Changyi; Yang, Xiaohan; Shimizu, Takahiro; Wang, Xiaoyu; Ikenaka, Kazuhiro; Fan, Kai; Ma, Jianmei


    Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future. PMID:28066178

  10. High Potassium Aggravates the Oxidative Stress Inducedy by Magnesium Deficiency in Rice Leaves

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    DING Yu-Chuan; CHANG Chun-Rong; LUO Wen; WU Yan-Shou; REN Xiao-Li; WANG Ping; XU Guo-Hua


    Magnesium (Mg) deficiency in plant affects photosynthesis and many other metabolic processes.Rice (Oryza sativa'Wuyunjing 7') plants were grown in hydroponics culture at three Mg and two potassium (K) levels under greenhouse conditions to examine the induction of oxidative stress and consequent antioxidant responses in rice leaves due to Mg deficiency.At low Mg (0.2 mmol L-1 Mg supply for two weeks after transplanting) and high K (6 mmol L-1) for 21days,the rice plants showed severe Mg deficiency and a significant decreases in the dry matter production. The Mg deficiency in leaves decreased chlorophyll concentrations,photosynthetic activity,and soluble protein,but significantly increased the concentrations of soluble sugars and malondialdehyde (MDA) and the activities of superoxide dismutase (SOD,EC,catalase (CAT,EC and peroxidase (POD,EC addition,Mg concentrations in the leaves and in the shoot biomass were negatively related to the activities of the three antioxidative enzymes and the concentration of MDA in leaves.There were very significant interactive effects between Mg and K supplied in the culture solution on shoot biomass yield,chlorophyll content,photosynthesis rate,the activities of SOD,CAT and POD,and MDA content in the leaves of rice.It is suggested that the high K level in the nutrient solution aggravated the effect of low Mg supply-induced Mg deficiency and created the oxidative damage in rice plants.

  11. Cigarette smoke exposure aggravates air space enlargement and alveolar cell apoptosis in Smad3 knockout mice. (United States)

    Farkas, Laszlo; Farkas, Daniela; Warburton, David; Gauldie, Jack; Shi, Wei; Stampfli, Martin R; Voelkel, Norbert F; Kolb, Martin


    The concept of genetic susceptibility factors predisposing cigarette smokers to develop emphysema stems from the clinical observation that only a fraction of smokers develop clinically significant chronic obstructive pulmonary disease. We investigated whether Smad3 knockout mice, which develop spontaneous air space enlargement after birth because of a defect in transforming growth factor-β (TGF-β) signaling, develop enhanced alveolar cell apoptosis and air space enlargement following cigarette smoke exposure. We investigated Smad3(-/-) and Smad3(+/+) mice at different adult ages and determined air space enlargement, alveolar cell proliferation, and apoptosis. Furthermore, laser-capture microdissection and real-time PCR were used to measure compartment-specific gene expression. We then compared the effects of cigarette smoke exposure on Smad3(-/-) and littermate controls. Smad3 knockout resulted in the development of air space enlargement in the adult mouse and was associated with decreased alveolar VEGF levels and activity and increased alveolar cell apoptosis. Cigarette smoke exposure aggravated air space enlargement and alveolar cell apoptosis. We also found increased Smad2 protein expression and phosphorylation, which was enhanced following cigarette smoke exposure, in Smad3-knockout animals. Double immunofluorescence analysis revealed that endothelial apoptosis started before epithelial apoptosis. Our data indicate that balanced TGF-β signaling is not only important for regulation of extracellular matrix turnover, but also for alveolar cell homeostasis. Impaired signaling via the Smad3 pathway results in alveolar cell apoptosis and alveolar destruction, likely via increased Smad2 and reduced VEGF expression and might represent a predisposition for accelerated development of emphysema due to cigarette smoke exposure.

  12. Administration of Mycobacterium leprae rHsp65 aggravates experimental autoimmune uveitis in mice.

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    Eliana B Marengo

    Full Text Available The 60 kDa heat shock protein family, Hsp60, constitutes an abundant and highly conserved class of molecules that are highly expressed in chronic-inflammatory and autoimmune processes. Experimental autoimmune uveitis [EAU] is a T cell mediated intraocular inflammatory disease that resembles human uveitis. Mycobacterial and homologous Hsp60 peptides induces uveitis in rats, however their participation in aggravating the disease is poorly known. We here evaluate the effects of the Mycobacterium leprae Hsp65 in the development/progression of EAU and the autoimmune response against the eye through the induction of the endogenous disequilibrium by enhancing the entropy of the immunobiological system with the addition of homologous Hsp. B10.RIII mice were immunized subcutaneously with interphotoreceptor retinoid-binding protein [IRBP], followed by intraperitoneally inoculation of M. leprae recombinant Hsp65 [rHsp65]. We evaluated the proliferative response, cytokine production and the percentage of CD4(+IL-17(+, CD4(+IFN-gamma(+ and CD4(+Foxp3(+ cells ex vivo, by flow cytometry. Disease severity was determined by eye histological examination and serum levels of anti-IRBP and anti-Hsp60/65 measured by ELISA. EAU scores increased in the Hsp65 group and were associated with an expansion of CD4(+IFN-gamma(+ and CD4(+IL-17(+ T cells, corroborating with higher levels of IFN-gamma. Our data indicate that rHsp65 is one of the managers with a significant impact over the immune response during autoimmunity, skewing it to a pathogenic state, promoting both Th1 and Th17 commitment. It seems comprehensible that the specificity and primary function of Hsp60 molecules can be considered as a potential pathogenic factor acting as a whistleblower announcing chronic-inflammatory diseases progression.

  13. Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.

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    Sung-Min Kim

    Full Text Available BACKGROUND: Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained can affect the loss of motor neurons or cognitive function in an in vivo model of ALS. OBJECTIVE: To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice. METHODS: Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation. RESULTS: Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation. CONCLUSIONS: Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in

  14. Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma. (United States)

    Yao, Hou Shan; Wang, Juan; Zhang, Xiao Ping; Wang, Liang Zhe; Wang, Yi; Li, Xin Xing; Jin, Kai Zhou; Hu, Zhi Qian; Wang, Wei Jun


    Hepatocyte nuclear factor 4-α (HNF4α), a nuclear receptor, is expressed at lower levels in colon carcinoma tissues than in adjacent normal tissues. However, the relation between HNF4α and colon cancer progression and the underlying molecular mechanisms remain unclear. Here, we investigated the role of HNF4α in the progression of colon carcinoma. We showed that HNF4α mRNA and protein were downregulated in colon carcinoma specimens. HNF4α expression was related to pT classification (P colon carcinoma patients. Patients with low or negative HNF4α expression had worse 3-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.005) than patients with high HNF4α expression. Low HNF4α expression was an independent prognostic factor for 3-year PFS (hazard ratio 2.94; 95% confidence interval 1.047-8.250; P = 0.041). Ectopic expression of HNF4α inhibited colon carcinoma cell (HT29, LoVo, and SW480) proliferation, migration, and invasion, induced G2/M phase arrest and promoted apoptosis. Ectopic expression of HNF4α upregulated E-cadherin and downregulated vimentin in vitro, and suppressed SW480 xenograft tumor growth and liver metastasis in vivo. Furthermore, HNF4α overexpression downregulated the expression of snail, slug and twist. HNF4α inhibited EMT through its effect on the Wnt/β-catenin signaling pathway, and HNF4α downregulation may be mediated by promoter methylation in cancer tissues. Our results suggest that downregulation of HNF4α plays a critical role in the aggravation of colon carcinoma possibly by promoting EMT via the Wnt/β-catenin signaling pathway and by affecting apoptosis and cell cycle progression.

  15. The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment

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    Miyauchi Akira


    thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.

  16. Respiratory Syncytial Virus Aggravates Renal Injury through Cytokines and Direct Renal Injury

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    Songhui Zhai


    Full Text Available The purpose of this study was to investigate the relationship between renal injury and reinfection that is caused by respiratory syncytial virus (RSV and to analyze the mechanism of renal injury. Rats were repeatedly infected with RSV on days 4, 8, 14, and 28, then sacrificed and examined on day 56 after the primary infection. Renal injury was examined by transmission electron microscopy and histopathology. The F protein of RSV was detected in the renal tissue by indirect immunofluorescence. Proteinuria and urinary glycosaminoglycans (GAGs, serum levels of albumin, urea nitrogen, and creatinine, secretion of cytokines, T lymphocyte population and subsets, and dendritic cell (DC activation state were examined. The results showed that renal injury was more serious in the reinfection group than in the primary infection group. At a higher infection dose, 6×106 PFU, the renal injury was more severe, accompanied by higher levels of proteinuria and urinary GAGs excretion, and lower levels of serum albumin. Podocyte foot effacement was more extensive, and hyperplasia of mesangial cells and proliferation of mesangial matrix were observed. The maturation state of DCs was specific, compared with the primary infection. There was also a decrease in the ratio of CD4+ to CD8+T lymphocytes, due to an increase in the percentage of CD8+T lymphocytes and a decrease in the percentage of CD4+T lymphocytes, and a dramatic increase in the levels of IL-6 and IL-17. In terms of the different reinfection times, the day 14 reinfection group yielded the most serious renal injury and the most significant change in immune function. RSV F protein was still expressed in the glomeruli 56 days after RSV infection. Altogether, these results reveal that RSV infection could aggravate renal injury, which might be due to direct renal injury caused by RSV and the inflammatory lesions caused by the anti-virus response induced by RSV.

  17. FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice

    Institute of Scientific and Technical Information of China (English)

    Takashi Nishimura; Akira Andoh; Atsushi Nishida; Makoto Shioya; Yuhsuke Koizumi; Tomoyuki Tsujikawa; Yoshihide Fujiyama


    AIM: To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.METHODS: BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4+ T cell and F4/80+ macrophage infiltration were also performed. Mucosal o/tokine expression was analyzed by RT-PCR.RESULTS: The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were found to be markedly reduced in FR167653-treated DSS mice.CONCLUSION: Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.

  18. Ocean acidification may aggravate social-ecological trade-offs in coastal fisheries.

    Directory of Open Access Journals (Sweden)

    Rudi Voss

    Full Text Available Ocean Acidification (OA will influence marine ecosystems by changing species abundance and composition. Major effects are described for calcifying organisms, which are significantly impacted by decreasing pH values. Direct effects on commercially important fish are less well studied. The early life stages of fish populations often lack internal regulatory mechanisms to withstand the effects of abnormal pH. Negative effects can be expected on growth, survival, and recruitment success. Here we study Norwegian coastal cod, one of the few stocks where such a negative effect was experimentally quantified, and develop a framework for coupling experimental data on OA effects to ecological-economic fisheries models. In this paper, we scale the observed physiological responses to the population level by using the experimentally determined mortality rates as part of the stock-recruitment relationship. We then use an ecological-economic optimization model, to explore the potential effect of rising CO2 concentration on ecological (stock size, economic (profits, consumer-related (harvest and social (employment indicators, with scenarios ranging from present day conditions up to extreme acidification. Under the assumptions of our model, yields and profits could largely be maintained under moderate OA by adapting future fishing mortality (and related effort to changes owing to altered pH. This adaptation comes at the costs of reduced stock size and employment, however. Explicitly visualizing these ecological, economic and social tradeoffs will help in defining realistic future objectives. Our results can be generalized to any stressor (or stressor combination, which is decreasing recruitment success. The main findings of an aggravation of trade-offs will remain valid. This seems to be of special relevance for coastal stocks with limited options for migration to avoid unfavorable future conditions and subsequently for coastal fisheries, which are often small

  19. Right Cervical Vagotomy Aggravates Viral Myocarditis in Mice Via the Cholinergic Anti-inflammatory Pathway (United States)

    Li-Sha, Ge; Xing-Xing, Chen; Lian-Pin, Wu; De-Pu, Zhou; Xiao-Wei, Li; Jia-Feng, Lin; Yue-Chun, Li


    The autonomic nervous system dysfunction with increased sympathetic activity and withdrawal of vagal activity may play an important role in the pathogenesis of viral myocarditis. The vagus nerve can modulate the immune response and control inflammation through a ‘cholinergic anti-inflammatory pathway’ dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Although the role of β-adrenergic stimulation on viral myocarditis has been investigated in our pervious studies, the direct effect of vagal tone in this setting has not been yet studied. Therefore, in the present study, we investigated the effects of cervical vagotomy in a murine model of viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of right cervical vagotomy and nAChR agonist nicotine on echocardiography, myocardial histopathology, viral RNA, and proinflammatory cytokine levels were studied. We found that right cervical vagotomy inhibited the cholinergic anti-inflammatory pathway, aggravated myocardial lesions, up-regulated the expression of TNF-α, IL-1β, and IL-6, and worsened the impaired left ventricular function in murine viral myocarditis, and these changes were reversed by co-treatment with nicotine by activating the cholinergic anti-inflammatory pathway. These results indicate that vagal nerve plays an important role in mediating the anti-inflammatory effect in viral myocarditis, and that cholinergic stimulation with nicotine also plays its peripheral anti-inflammatory role relying on α7nAChR, without requirement for the integrity of vagal nerve in the model. The findings suggest that vagus nerve stimulation mediated inhibition of the inflammatory processes likely provide important benefits in myocarditis treatment. PMID:28197102

  20. Aggravation of Allergic Airway Inflammation by Cigarette Smoke in Mice Is CD44-Dependent.

    Directory of Open Access Journals (Sweden)

    Smitha Kumar

    Full Text Available Although epidemiological studies reveal that cigarette smoke (CS facilitates the development and exacerbation of allergic asthma, these studies offer limited information on the mechanisms involved. The transmembrane glycoprotein CD44 is involved in cell adhesion and acts as a receptor for hyaluronic acid and osteopontin. We aimed to investigate the role of CD44 in a murine model of CS-facilitated allergic airway inflammation.Wild type (WT and CD44 knock-out (KO mice were exposed simultaneously to house dust mite (HDM extract and CS. Inflammatory cells, hyaluronic acid (HA and osteopontin (OPN levels were measured in bronchoalveolar lavage fluid (BALF. Proinflammatory mediators, goblet cell metaplasia and peribronchial eosinophilia were assessed in lung tissue. T-helper (Th 1, Th2 and Th17 cytokine production was evaluated in mediastinal lymph node cultures.In WT mice, combined HDM/CS exposure increased the number of inflammatory cells and the levels of HA and OPN in BALF and Th2 cytokine production in mediastinal lymph nodes compared to control groups exposed to phosphate buffered saline (PBS/CS, HDM/Air or PBS/Air. Furthermore, HDM/CS exposure significantly increased goblet cell metaplasia, peribronchial eosinophilia and inflammatory mediators in the lung. CD44 KO mice exposed to HDM/CS had significantly fewer inflammatory cells in BALF, an attenuated Th2 cytokine production, as well as decreased goblet cells and peribronchial eosinophils compared to WT mice. In contrast, the levels of inflammatory mediators were similar or higher than in WT mice.We demonstrate for the first time that the aggravation of pulmonary inflammation upon combined exposure to allergen and an environmental pollutant is CD44-dependent. Data from this murine model of concomitant exposure to CS and HDM might be of importance for smoking allergic asthmatics.

  1. Aggravation of fatigue by steroid therapy in terminally ill patients with cancer. (United States)

    Matsuo, Naoki; Yomiya, Kinomi


    Steroids are commonly used for fatigue relief in terminally ill cancer patients. However, steroid-induced adverse effects including depression, myopathy, and hyperglycemia may contribute to fatigue. We report our experiences with aggravation of fatigue with steroid use in three cases. Case 1 was a 65-year-old man with advanced gastric cancer. He was started on betamethasone (2 mg/d) for fatigue, but the fatigue worsened due to steroid-induced depression. Discontinuation of steroids and initiation of an antidepressant ameliorated the fatigue. Case 2 was a 68-year-old man with advanced lung cancer. He complained of fatigue. Betamethasone (1 mg/d) was started and alleviated the fatigue. However, when the betamethasone dose was increased to 2 mg/d, the fatigue, with muscle weakness and myalgia, worsened due to steroid-induced myopathy. We therefore switched from betamethasone (2 mg/d) to prednisolone (10 mg /d). The fatigue resolved and the patient returned to his previous condition. Case 3 was a 73-year-old man with recurrent bile duct cancer. He also had diabetes mellitus. He developed fatigue, anorexia and fever. We started betamethasone (1.5 mg/d) for these symptoms, but the fatigue and anorexia worsened due to steroid-induced hyperglycemia. Blood glucose rose to 532 mg/dL. Therefore, insulin therapy was started, and the dose of betamethasone was reduced to 0.5 mg/d. His glucose level decreased to less than 320 mg/dL and he recovered from the fatigue while achieving moderate oral intake. In conclusion, the possibility of steroid-induced secondary fatigue in terminally ill cancer patients should be taken into consideration.

  2. Ocean acidification may aggravate social-ecological trade-offs in coastal fisheries. (United States)

    Voss, Rudi; Quaas, Martin F; Schmidt, Jörn O; Kapaun, Ute


    Ocean Acidification (OA) will influence marine ecosystems by changing species abundance and composition. Major effects are described for calcifying organisms, which are significantly impacted by decreasing pH values. Direct effects on commercially important fish are less well studied. The early life stages of fish populations often lack internal regulatory mechanisms to withstand the effects of abnormal pH. Negative effects can be expected on growth, survival, and recruitment success. Here we study Norwegian coastal cod, one of the few stocks where such a negative effect was experimentally quantified, and develop a framework for coupling experimental data on OA effects to ecological-economic fisheries models. In this paper, we scale the observed physiological responses to the population level by using the experimentally determined mortality rates as part of the stock-recruitment relationship. We then use an ecological-economic optimization model, to explore the potential effect of rising CO2 concentration on ecological (stock size), economic (profits), consumer-related (harvest) and social (employment) indicators, with scenarios ranging from present day conditions up to extreme acidification. Under the assumptions of our model, yields and profits could largely be maintained under moderate OA by adapting future fishing mortality (and related effort) to changes owing to altered pH. This adaptation comes at the costs of reduced stock size and employment, however. Explicitly visualizing these ecological, economic and social tradeoffs will help in defining realistic future objectives. Our results can be generalized to any stressor (or stressor combination), which is decreasing recruitment success. The main findings of an aggravation of trade-offs will remain valid. This seems to be of special relevance for coastal stocks with limited options for migration to avoid unfavorable future conditions and subsequently for coastal fisheries, which are often small scale local

  3. Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice


    Marjo M P C Donners; Bai, Lili; Lutgens, Suzanne P. M.; Wijnands, Erwin; Johnson, Jason; Schurgers, Leon J.; Liu, Cong-Lin; Daemen, Mat; Cleutjens, Kitty B.J.M.; Shi, Guo-Ping; BIESSEN, Erik; Heeneman, Sylvia


    Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with w...

  4. Short-term air pollution exposure aggravates Parkinson’s disease in a population-based cohort (United States)

    Lee, Hyewon; Myung, Woojae; Kim, Doh Kwan; Kim, Satbyul Estella; Kim, Clara Tammy; Kim, Ho


    Increasing experimental evidence has suggested air pollution as new risk factor for neurological disease. Although long-term exposure is reportedly related to neurological disease, information on association with short-term exposure is scarce. We examined the association of short-term exposure to particles Health Insurance Service–National Sample Cohort, Korea during 2002–2013. PD aggravation cases were defined as emergency hospital admissions for primarily diagnosed PD and analyzed with a case-crossover analysis, designed for rare acute outcomes. Pollutants concentrations on case and control days were compared and effect modifications were explored. A unit increase in 8-day moving average of concentrations was significantly associated with PD aggravation. The association was consistent for PM2.5 (odds ratio [95% confidence interval]: 1.61 [1.14–2.29] per 10 μg/m3), NO2 (2.35 [1.39–3.97] per 10 ppb), SO2 (1.54 [1.11–2.14] per 1 ppb), and CO (1.46 [1.05–2.04] per 0.1 ppm). The associations were stronger in women, patients aged 65–74 years, and cold season, but not significant. In conclusion, short-term air pollution exposure increased risk of PD aggravation, and may cause neurological disease progression in humans. PMID:28300224

  5. Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. (United States)

    Müller, Daniel J; De Luca, Vincenzo; Sicard, Tricia; King, Nicole; Hwang, Rudi; Volavka, Jan; Czobor, Pal; Sheitman, Brian B; Lindenmayer, Jean-Pierre; Citrome, Leslie; McEvoy, Joseph P; Lieberman, Jeffrey A; Meltzer, Herbert Y; Kennedy, James L


    G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response. We hypothesized that this polymorphism may be associated with response to antipsychotics in a population of 145 chronic schizophrenic patients deriving from two study-samples and being mainly treated with clozapine for up to 6 months. Overall, the C/C genotype was significantly associated with relative clinical improvement as measured by Brief Psychiatric Rating Scale (BPRS) change scores after 6 and 12 weeks (ppoint to the role of intracellular mechanisms in antipsychotic response.

  6. RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation

    Directory of Open Access Journals (Sweden)

    Suri SS


    Full Text Available Sarabjeet Singh Suri1, Steven Mills1, Gurpreet Kaur Aulakh1, Felaniaina Rakotondradany2, Hicham Fenniri2, Baljit Singh11Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon; 2National Institute for Nanotechnology and Department of Chemistry, Edmonton, CanadaAbstract: Rosette nanotubes (RNT are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif. In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C and amino acid Lys (K-G∧C which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as Kx/RGDSKy-RNT, where x and y refer to the molar ratios of K-G∧C and RGDSK–G∧C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous Kx/RGDSKy-RNT on acute lipopolysaccharide (LPS-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 µg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1ß, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung.Keywords: RGD peptide, helical rosette

  7. Loss of p120 catenin aggravates alveolar edema of ventilation induced lung injury

    Institute of Scientific and Technical Information of China (English)

    DAI Chen-yang; DAI Guo-feng; SUN Yu; WANG Yue-lan


    Background p120 catenin (p120ctn) is an adheren junction protein that regulates barrier function,but its role has not been explored in alveolar edema induced by ventilation.We measured stretch-induced cell gap formation in MLE 12 cells due to the loss of p120.We hypothesized that alveolar permeability was increased by high lung inflation associated with alveolar epithelia cell tight junctions being destroyed,which resulted from the loss of p120.Methods Cultured MLE12 cells were subjected to being stretched or un-stretched (control) and some cells were pretreated with pp2 (c-src inhibitor).After the end of stretching for 0,1,2,and 4 hours,the cells were lysed,and p120 expression and c-src activation was determined by Western blotting analysis.In vivo,SD rats were taken to different tidal volumes (Vt 7 ml/kg or 40 ml/kg,PEEP=0,respiratory rate 30-40 betas/min) for 0,1,2,and 4 hour and some were pretreated with pp2,and alveolar edema was calculated.Rerults It was found that p120 expression was reduced and c-src activation increased in a time-dependent and strain-dependent manner due to cyclic-stretch of the alveolar epithelial cells.These changes could be reversed by inhibition of c-src.We obtained similar changes in rats when they were subjected to large tidal volumes and the alveolar edema increased more than in rats in the low Vt group.Pretreated the rats with inhibition of c-src had less pulmonary edema induced by the high tidal volume ventilation.Conclusions Cyclic stretch MLE 12 cells induced the loss of p120 and may be the same reason by high tidal volume ventilation in rats can aggravate alveolar edema.Maintenance of p120 expression may be a novel therapeutic strategy for the prevention and treatment of ventilation induced lung injury (VILI).

  8. A case of aggravation of hemolytic anemia, elevated liver enzymes and low platelet count syndrome after delivery

    Institute of Scientific and Technical Information of China (English)

    JIANG Yuan-hui; WANG Yong-qing; WANG Jing; YE Rong-hua


    Background Hemolytic anemia, elevated liver enzymes and low platelet count (HELLP) syndrome is a severe obstetric complication which usually resolves in most patients after delivery.Methods We report a rare case of aggravation of HELLP syndrome after delivery.Results The patient underwent the treatment for HELLP syndrome,.including glucocorticoid therapy. The symptoms of HELLP syndrome reappeared and became more severe than before the termination of pregnancy. The patient also had severe and persistent hypoproteinemia, hyponatremia and hypocalcemia.Conclusions HELLP syndrome is an acute and critical obstetric syndrome which can have heterogeneous presentations and variable prognosis. We should be fully aware of the diverse clinical characteristics of this condition.

  9. 严重暴力犯罪概念解析%Analyzing the Concept of Aggravated Violent Crime

    Institute of Scientific and Technical Information of China (English)



      Compared with a traditional violent crime, an aggravated violent crime has endangered public security, which is its essential characteristic. The article starts from confusing terms like“a violent crime”, “an aggravated violent crime”, “an unexpected public event” and “a terrorist attack event”, distinguishing each connotation and nature, and then proposes that the nature of an unexpected event should be defined with the combination of the behavioral means and the endangering public security. The fundamental difference between an aggravated violent crime and a common violent crime lies in the factor of with or without “willful and malicious destruction, and endangering public security”. Aggravated violent crimes, as one of the most serious in unexpected events, have to be dealt immediately with special means rather than relying on the sole way through criminal punishment.%  与传统暴力犯罪相比,严重暴力犯罪已经危害公共安全,这是其本质特征。文章从“暴力犯罪”、“严重暴力犯罪”、“突发公共事件”、“恐怖袭击事件”等易混淆的概念入手,从认识层面理清各自内涵属性,提出应从行为手段与危害公共安全二者的结合来界定突发事件的性质,认为是否内含“人为恶意破坏、危害公共安全”要素是严重暴力犯罪与一般暴力犯罪的根本差别。严重暴力犯罪案件作为突发事件中性质最为严重的一种,其发生、发展的控制不能寄刑罚手段一途,须动用特别手段紧急处置。

  10. Basis of aggravated hepatic lipid metabolism by chronic stress in high-fat diet-fed rat. (United States)

    Han, Ying; Lin, Min; Wang, Xiaobin; Guo, Keke; Wang, Shanshan; Sun, Mengfei; Wang, Jiao; Han, Xiaoyu; Fu, Ting; Hu, Yang; Fu, Jihua


    Our previous study has demonstrated that long-term stress, known as chronic stress (CS), can aggravate nonalcoholic fatty liver disease in high-fat diet (HFD)-fed rat. In this study, we tried to figure out which lipid metabolic pathways were impacted by CS in the HFD-fed rat. Male Sprague-Dawley rats (6 weeks of age, n = 8 per group) were fed with either standard diet or HFD with or without CS exposure for 8 weeks. Hepatic lipidosis, biochemical, hormonal, and lipid profile markers in serum and liver, and enzymes involved in de novo lipogenesis (DNL) of fatty acids (FAs) and cholesterol, β-oxidation, FAs uptake, triglycerides synthesis, and very low-density lipoprotein (VLDL) assembly in the liver were detected. CS exposure reduced hepatic lipidosis but further elevated hepatic VLDL content with aggravated dyslipidemia in the HFD-fed rats. There was a synergism between CS and HFD on VLDL production and dyslipidemia. PCR and western blot assays showed that CS exposure significantly promoted hepatic VLDL assembly in rats, especially in the HFD-fed rats, while it had little impact on DNL, β-oxidation, FAs uptake, and triglycerides synthesis in the HFD-fed rats. This phenomenon was in accordance with elevated serum glucocorticoid level. The critical influence of CS exposure on hepatic lipid metabolism in the HFD-fed rats is VLDL assembly which might be regulated by glucocorticoid.

  11. Oral exposure to low-dose bisphenol A aggravates testosterone-induced benign hyperplasia prostate in rats. (United States)

    Wu, Jian-Hui; Jiang, Xiu-Rong; Liu, Gui-Ming; Liu, Xiang-Yun; He, Gui-Lin; Sun, Zu-Yue


    The declining level of androgen during aging, associated with an inclining level of estrogen, has been hypothesized to be important in the development of benign prostatic hyperplasia (BPH). Within physiologic range, increasing estrogen levels can stimulate prostate to develop and permanently increase prostate size. As an estrogenic endocrine disruptor, bisphenol A (BPA) might be stimulatory to prostate development. We further hypothesized that low dose BPA could induce hyperplasia prostate to proliferate and aggravate the symptom of BPH in male SD rats. BPH was induced by testosterone and then treated with BPA (10, 30, or 90 μg/kg, i.g., daily), 17β-estradiol (E(2); 50.0 μg/kg, s.c., daily), or vehicle for 4 weeks. We found that weight and volume in rats treated with low dose BPA (10 μg/kg) was higher than that of model control, and BPA significantly increased the relative weight of prostate (p prostate lobes, BPA 10 μg/kg/day significantly increased relative weight of ventral prostate (VP), weight and relative weight of dorsolateral prostate (DLP) (p prostate-specific antigen level. E(2) treatment also showed an obvious effect on relative weight of VP and DLP, HEC, and hormone levels. We concluded that environment exposure to low dose of BPA may induce prostate to proliferate and aggravate testosterone-induced benign hyperplasia prostate in rats.

  12. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose. (United States)

    Arai, Tomoya; Koyama, Ryo; Yuasa, Makoto; Kitamura, Daisuke; Mizuta, Ryushin


    Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.

  13. Oral Candida as an aggravating factor of mucositis Induced by radiotherapy; Candida Oral como fator agravante da mucosite radioinduzida

    Energy Technology Data Exchange (ETDEWEB)

    Simoes, Cristiane Araujo; Castro, Jurema Freire Lisboa de; Cazal, Claudia [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de odontologia


    Antineoplastic treatment induces some undesirable consequences in head and neck cancer patients. Often, the emergence of major clinical manifestations, such as oral mucositis, results in temporary interruption of the treatment, decreasing the patients' quality of life, and increasing hospital costs. Radio-induced or chemo-induced oral mucositis is possibly aggravated by opportunist fungal infections, which turn the mucositis more resistant to the conventional treatments. Objective: this study aims to identify the presence of Candida sp. as a possible aggravating factor of oral mucositis in patients with head and neck cancer under antineoplastic treatment. Method: all patients with radio- or chemo-induced oral mucositis from the Cancer Hospital of Pernambuco, treated between October 2008 and April 2009, were selected for the study. The prevalence of Candida sp was measured through the cytological analysis of oral mucosa in patients with oral mucositis. The fungal presence was correlated with the mucositis severity. Results: the results showed a positive association between fungal colonization and more several lesions (degrees III and IV of mucositis). Conclusion: The outcomes shown may contribute to a solution for unconventional mucosites, which do not respond to the usual treatment. (author)

  14. Long-term management of sevelamer hydrochloride-induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients. (United States)

    Sonikian, Macroui; Metaxaki, Polyxeni; Iliopoulos, Anastasios; Marioli, Stamatia; Vlassopoulos, Dimosthenis


    Sevelamer hydrochloride use in hemodialysis patients is complicated by metabolic acidosis aggravation and hyperkalemia. Rare reports about a short-term correction of this complication have been published. The current authors investigated the long-term correction of metabolic acidosis and hyperkalemia in sevelamer hydrochloride-treated patients at doses adequate to achieve serum phosphate levels within K/DOQI recommendations. The authors followed 20 hemodialysis patients for 24 months in an open-label prospective study. The dialysate bicarbonate concentration was increased stepwise to a maximum 40 mEq/L and adjusted to reach patient serum bicarbonate levels of 22 mEq/L, according to K/DOQI recommendations. Laboratory results for serum bicarbonate, potassium, calcium, phosphate, albumin, alkaline phosphatase, iPTH, cholesterol (HDL-LDL), triglycerides, Kt/V, systolic-diastolic arterial pressure were recorded. Sevelamer hydrochloride-induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients were corrected, on the long-term, by an increase in dialysate bicarbonate concentration. Further improvement in bone biochemistry was noted with this adequate acidosis correction and parallel sevelamer hydrochloride administration, in sufficiently large doses to achieve K/DOQI phosphate recommendations.

  15. Introduction of silencing-inducing transgene against Fgf19 does not affect expression of Tbx5 and beta3-tubulin in the developing chicken retina. (United States)

    Okamoto, Mayumi; Tomonari, Sayuri; Naito, Yuki; Saigo, Kaoru; Noji, Sumihare; Ui-Tei, Kumiko; Ohuchi, Hideyo


    Fgf19 is known to be expressed in the developing chicken eye but its functions during retinal development have remained elusive. Since Fgf19 is expressed in the dorsal portion of the optic cup, it is intriguing to know whether FGF19 is required for expression of dorso-ventral morphogenetic genes in the eye. To clarify this, expression patterns of Tbx5 and Vax were examined in the developing eye after in ovo RNA interference targeted against Fgf19. Quantitative polymerase chain reaction (PCR) analysis showed that the short-hairpin RNAs (shRNAs) targeted against Fgf19 could reduce its expression in the eye to less than 50% of a relative amount of mRNA, compared with contralateral or untreated control eyes. However, no obvious alteration in expression domains of Tbx5 or Vax was observed. Misexpression of Tbx5 or Tbx5-RNAi did not alter the Fgf19 expression either. Furthermore, although Fgf19 is expressed in the central retina before neurogenesis occurs, beta3-tubulin, a marker for early retinal differentiation was still detected in the central retina after knockdown of Fgf19. Thus, knockdown of Fgf19 supports no obvious regulations between Fgf19 and Tbx5, or exhibits no phenotypes that perturb early retinal differentiation.

  16. Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. (United States)

    Wang, K; Xu, R; Snider, A J; Schrandt, J; Li, Y; Bialkowska, A B; Li, M; Zhou, J; Hannun, Y A; Obeid, L M; Yang, V W; Mao, C


    Increasing studies suggest that ceramides differing in acyl chain length and/or degree of unsaturation have distinct roles in mediating biological responses. However, still much remains unclear about regulation and role of distinct ceramide species in the immune response. Here, we demonstrate that alkaline ceramidase 3 (Acer3) mediates the immune response by regulating the levels of C18:1-ceramide in cells of the innate immune system and that Acer3 deficiency aggravates colitis in a murine model by augmenting the expression of pro-inflammatory cytokines in myeloid and colonic epithelial cells (CECs). According to the NCBI Gene Expression Omnibus (GEO) database, ACER3 is downregulated in immune cells in response to lipopolysaccharides (LPS), a potent inducer of the innate immune response. Consistent with these data, we demonstrated that LPS downregulated both Acer3 mRNA levels and its enzymatic activity while elevating C(18:1)-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C(18:1)-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C(18:1)-ceramide, but not C18:0-ceramide, potentiated LPS-induced expression of pro-inflammatory cytokines in immune cells. In the mouse model of dextran sulfate sodium-induced colitis, Acer3 deficiency augmented colitis-associated elevation of colonic C(18:1)-ceramide and pro-inflammatory cytokines. Acer3 deficiency aggravated diarrhea, rectal bleeding, weight loss and mortality. Pathological analyses revealed that Acer3 deficiency augmented colonic shortening, immune cell infiltration, colonic epithelial damage and systemic inflammation. Acer3 deficiency also aggravated colonic dysplasia in a mouse model of colitis-associated colorectal cancer. Taken together, these results suggest that Acer3 has an important anti-inflammatory role by suppressing cellular or tissue C(18

  17. Pseudomonas aeruginosa biofilm aggravates skin inflammatory response in BALB/c mice in a novel chronic wound model

    DEFF Research Database (Denmark)

    Trøstrup, Hannah; Thomsen, Kim; Christophersen, Lars J


    bacteria organized in clusters, resembling biofilms, and inflammation located adjacent to the PA. The chronic wound infection showed a higher number of PAO1 in the BALB/c mice at day 4 after infection as compared to C3H/HeN mice (p ... in the chronic wounds of BALB/c mice was observed at day 7 (p biofilm infection in mice. The results showed an aggravating impact of local inflammation induced by PA biofilms......Chronic wounds are presumed to persist in the inflammatory state, preventing healing. Emerging evidence indicates a clinical impact of bacterial biofilms in soft tissues, including Pseudomonas aeruginosa (PA) biofilms. To further investigate this, we developed a chronic PA biofilm wound infection...

  18. Human-specific SNP in obesity genes, adrenergic receptor beta2 (ADRB2, Beta3 (ADRB3, and PPAR γ2 (PPARG, during primate evolution.

    Directory of Open Access Journals (Sweden)

    Akiko Takenaka

    Full Text Available UNLABELLED: Adrenergic-receptor beta2 (ADRB2 and beta3 (ADRB3 are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM in many ethnic groups. Peroxisome proliferator-activated receptor γ (PPARG is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP. All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele. CONCLUSIONS: These results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods.

  19. Human-Specific SNP in Obesity Genes, Adrenergic Receptor Beta2 (ADRB2), Beta3 (ADRB3), and PPAR γ2 (PPARG), during Primate Evolution (United States)

    Takenaka, Akiko; Nakamura, Shin; Mitsunaga, Fusako; Inoue-Murayama, Miho; Udono, Toshifumi; Suryobroto, Bambang


    Adrenergic-receptor beta2 (ADRB2) and beta3 (ADRB3) are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM) in many ethnic groups. Peroxisome proliferator-activated receptor γ (PPARG) is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP). All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques) had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele. Conclusions These results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods. PMID:22937051

  20. Systematic determination of the peptide acceptor preferences for the human UDP-Gal:glycoprotein-alpha-GalNAc beta 3 galactosyltransferase (T-synthase). (United States)

    Perrine, Cynthia; Ju, Tongzhong; Cummings, Richard D; Gerken, Thomas A


    Mucin-type protein O-glycosylation is initiated by the addition of alpha-GalNAc to Ser/Thr residues of a polypeptide chain. The addition of beta-Gal to GalNAc by the UDP-Gal:glycoprotein-alpha-GalNAc beta 3 galactosyltransferase (T-synthase), forming the Core 1 structure (beta-Gal(1-3)-alpha-GalNAc-O-Ser/Thr), is a common and biologically significant subsequent step in O-glycan biosynthesis. What dictates the sites of Core 1 glycosylation is poorly understood; however, the peptide sequence and neighboring glycosylation effects have been implicated. To systematically address the role of the peptide sequence on the specificity of T-synthase, we used the oriented random glycopeptide: GAGAXXXX(T-O-GalNAc)XXXXAGAG (where X = G, A, P, V, I, F, Y, S, N, D, E, H, R, and K) as a substrate. The Core 1 glycosylated product was isolated on immobilized PNA (Arachis hypogaea) lectin and its composition determined by Edman amino acid sequencing for comparison with the initial substrate composition, from which transferase preferences were obtained. From these studies, elevated preferences for Gly at the +1 position with moderately high preferences for Phe and Tyr in the +3 position relative to the acceptor Thr-O-GalNAc were found. A number of smaller Pro enhancements were also observed. Basic residues, i.e., Lys, Arg, and His, in any position were disfavored, suggesting electrostatic interactions as an additional important component modulating transferase specificity. This work suggests that there are indeed subtle specific and nonspecific protein-targeting sequence motifs for this transferase.

  1. [Case of distal renal tubular acidosis complicated with renal diabetes insipidus, showing aggravation of symptoms with occurrence of diabetes mellitus]. (United States)

    Liu, Hexing; Tomoda, Fumihiro; Koike, Tsutomu; Ohara, Maiko; Nakagawa, Taizo; Kagitani, Satoshi; Inoue, Hiroshi


    We report herein a 27-year-old male case of inherited distal renal tubular acidosis complicated with renal diabetes insipidus, the symptoms of which were aggravated by the occurrence of diabetes mellitus. At 2 months after birth, he was diagnosed as having inherited distal renal tubular acidosis and thereafter supplementation of both potassium and alkali was started to treat his hypokalemia and metabolic acidosis. At the age of 4 years, calcification of the bilateral renal medulla was detected by computed tomography. Subsequently his urinary volume gradually increased and polyuria of approximately 4 L/day persisted. At the age of 27 years, he became fond of sugar-sweetened drinks and also often forgot to take the medicine. He was admitted to our hospital due to polyuria of more than 10 L day, muscle weakness and gait disturbance. Laboratory tests disclosed worsening of both hypokalemia and metabolic acidosis in addition to severe hyperglycemia. It seemed likely that occurrence of diabetes mellitus and cessation of medications can induce osmotic diuresis and aggravate hypokalemia and metabolic acidosis. Consequently, severe dehydration, hypokalemia-induced damage of his urinary concentration ability and enhancement of the renin angiotensin system occurred and thereby possibly worsened his hypokalemia and metabolic acidosis. As normalization of hyperglycemia and metabolic acidosis might have exacerbated hypokalemia further, dehydration and hypokalemia were treated first. Following intensive treatment, these abnormalities were improved, but polyuria persisted. Elevated plasma antidiuretic hormone (12.0 pg/mL) and deficit of renal responses to antidiuretic hormone suggested that the polyuria was attributable to the preexisting renal diabetes insipidus possibly caused by bilateral renal medulla calcification. Thiazide diuretic or nonsteroidal anti-inflammatory drugs were not effective for the treatment of diabetes insipidus in the present case.

  2. G-protein beta3 subunit gene variant is unlikely to have a significant influence on serum uric acid level in Japanese workers. (United States)

    Suwazono, Yasushi; Kobayashi, Etsuko; Uetani, Mirei; Miura, Katsuyuki; Morikawa, Yuko; Ishizaki, Masao; Kido, Teruhiko; Nakagawa, Hideaki; Nogawa, Koji


    The C825T variant of the G-protein beta3 subunit (GNB3) gene has attracted renewed attention as a candidate gene for obesity, hypertension and hyperuricemia. The main role of G-protein is to translate signals from the cell surface into a cellular response. The 825T allele is associated with a splice variant of GNB3 protein and enhanced G-protein activation. We examined the relationship between this variant and the risk of hyperuricemia in Japanese workers. The study subjects were 1,452 men and 1,169 women selected from 3,834 men and 2,591 women in 1997. On the basis of common clinical criteria, hyperuricemia I was defined as serum uric acid >or= 7.0 mg/dl in men and 6.0 mg/dl in women or taking antihyperuricemic medication. The hyperuricemia I group consisted of 186 men and 20 women and its control of 1,266 men and 1,149 women. Hyperuricemia II was defined as serum uric acid > 5.7 mg/dl (median) in men and 3.9 mg/dl (median) in women or taking antihyperuricemic medication. The hyperuricemic II group consisted of 684 men and 570 women and its control of 768 men and 599 women. To replicate previous significant results in young Caucasian men, we selected these criteria because the authors of the study in young Caucasian men adopted the median in their subjects as a cut-off. The statistical power was estimated as 99% based on the significant results in Caucasians. Genotype and allele distributions in men and women with hyperuricemia I and II were not significantly different from those in the corresponding control groups. Logistic regression analysis on hyperuricemia I and II, and multiple regression on serum uric acid level demonstrated no significant effect of the C825T genotype. Despite the sufficient statistical power, this study could not demonstrate the significant influence of C825T on hyperuricemia or serum uric acid. The targeting of this polymorphism is unlikely to be beneficial in the prevention of hyperuricemia in the general Japanese population.

  3. High-NaCl Diet Aggravates Cardiac Injury in Rats with Adenine-Induced Chronic Renal Failure and Increases Serum Troponin T Levels

    DEFF Research Database (Denmark)

    Kashioulis, Pavlos; Hammarsten, Ola; Marcussen, Niels


    correlation between the degree of LV fibrosis and serum cTnT levels in ACRF rats (r = 0.81, p produces LV injury and aggravates increases in serum cTnT levels, presumably by causing hypertension-induced small artery lesions leading...

  4. Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure

    Institute of Scientific and Technical Information of China (English)

    Chi-Jen Chu; Shou-Dong Lee; Ching-Chin Hsiao; Teh-Fang Wang; Cho-Yu Chan; Fa-Yauh Lee; Full-Young Chang; Yi-Chou Chen; Hui-Chun Huang; Sun-Sang Wang


    AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy.Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure.METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by were divided into two groups to receive intraperitoneal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α(TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay.RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S:438±102 vs841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-α (indomethacin vsN/S: 22±5 vs 10±1 pg/mL, P<0.05)and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S.CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant

  5. Distribution of cytoskeletal proteins, integrins, leukocyte adhesion molecules and extracellular matrix proteins in plastic-embedded human and rat kidneys

    NARCIS (Netherlands)

    van Goor, H; Coers, W; van der Horst, MLC; Suurmeijer, AJH


    OBJECTIVE: To study the distribution of cytoskeletal proteins (actin, alpha -actinin, vinculin, beta -tubulin, keratin, vimentin, desmin), adhesion molecules for cell-matrix interations (very later antigens [VLA1-6], beta1, beta2 [CD18], vitronectin receptor [alphav beta3], CD 11b), leukocyte adhesi

  6. Drug: D09929 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09929 Drug Maraciclatide (USAN/INN) C72H120N20O21S3 1696.8099 1698.0396 D09929.gif Diagnostic radio-pharmac...eutical integrin alphav/beta3 (VNR) imaging agent [HSA:3685 3690] [KO:K06487 K06493

  7. Drug: D09903 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available rmaceutical integrin alphav/beta3 (VNR) label [HSA:3685 3690] [KO:K06487 K06493]; i...D09903 Drug Fluciclatide F 18 (USAN/INN) C75H115FN18O27S3 1813.7351 1816.0134 D09903.gif Diagnostic radiopha

  8. IL-33 Aggravates DSS-Induced Acute Colitis in Mouse Colon Lamina Propria by Enhancing Th2 Cell Responses. (United States)

    Zhu, Junfeng; Yang, Fangli; Sang, Lixuan; Zhai, Jingbo; Zhang, Xiaoqing; Yue, Dan; Li, Shengjun; Li, Yan; Lu, Changlong; Sun, Xun


    Interleukin- (IL-) 33, a member of the IL-1 cytokine family, is an important modulator of the immune system associated with several immune-mediated diseases. IL-33 was expressed in high level on epithelial cells of intestinal tract. It suggested that IL-33 plays a potential role in inflammatory bowel diseases (IBD). We investigated the role of interleukin- (IL-) 33 in dextran sulphate sodium- (DSS-) induced acute colitis in mice using recombinant mouse IL-33 protein (rIL-33). We found that DSS-induced acute colitis was aggravated by rIL-33 treatment. rIL-33-treated DSS mice showed markedly reduced levels of interferon- (IFN-)γ and IL-17A in their colon lamina propria lymphocytes (LPL), but the levels of Th2 cytokines, such as IL-5 and IL-13, in these cells were significantly increased, compared to DSS mice treated with PBS. Our results suggested that IL-33 stimulated CD4(+)T cells and caused the cell to adopt a Th2-type response but at the same time suppressed Th17 and Th1 cell responses. Therefore, IL-33 may be involved in pathogenesis of DSS-induced acute colitis by promoting Th2 cell response in intestinal mucosa of mice. Modulation of IL-33/ST2 signaling by monoclonal antibody (mAb) could be a novel biological therapy in DSS-induced acute colitis.

  9. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium. (United States)

    Zhang, Qianpeng; Wu, Yanqiu; Wang, Jing; Wu, Guojun; Long, Wenmin; Xue, Zhengsheng; Wang, Linghua; Zhang, Xiaojun; Pang, Xiaoyan; Zhao, Yufeng; Zhao, Liping; Zhang, Chenhong


    Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn't induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates.

  10. Absence of Intestinal PPARγ Aggravates Acute Infectious Colitis in Mice through a Lipocalin-2–Dependent Pathway (United States)

    Kundu, Parag; Ling, Teo Wei; Korecka, Agata; Li, Yinghui; D'Arienzo, Rossana; Bunte, Ralph M.; Berger, Thorsten; Arulampalam, Velmurugesan; Chambon, Pierre; Mak, Tak Wah; Wahli, Walter; Pettersson, Sven


    To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion. PMID:24465207

  11. Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis. (United States)

    van Zwieten, Rob; van Oirschot, Brigitte A; Veldthuis, Martijn; Dobbe, Johannes G; Streekstra, Geert J; van Solinge, Wouter W; Schutgens, Roger E G; van Wijk, Richard


    In a family with mild dominant spherocytosis, affected members showed partial band 3 deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low pyruvate kinase activity. We investigated the contribution of partial PK deficiency to the phenotypic expression of mutant band 3 in this family. Pyruvate kinase deficiency and band 3 deficiency were characterized by DNA analysis. Results of red cell osmotic fragility testing, the results of cell deformability obtained by the Automated Rheoscope and Cell Analyzer and the results obtained by Osmotic Gradient Ektacytometry, which is a combination of these tests, were related to the red cell ATP content. Spherocytosis in this family was due to a novel heterozygous mutation in SLC4A1, the gene for band 3. Reduced PK activity of the index patient was attributed to a novel mutation in PKLR inherited from his mother, who was without clinical symptoms. Partial PK deficiency was associated with decreased red cell ATP content and markedly increased osmotic fragility. This suggests an aggravating effect of low ATP levels on the phenotypic expression of band 3 deficiency.

  12. A new update for radiocontrast-induced nephropathy aggravated with glycerol in rats: the protective potential of epigallocatechin-3-gallate. (United States)

    Palabiyik, Saziye Sezin; Dincer, Busra; Cadirci, Elif; Cinar, Irfan; Gundogdu, Cemal; Polat, Beyzagul; Yayla, Muhammed; Halici, Zekai


    Contrast media (CM) is known to have nephrotoxic adverse effects. Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin in green tea, and has strong antioxidant and anti-inflammatory properties. This study investigated whether EGCG can reduce contrast-induced nephrotoxicity (CIN), alone or with glycerol (GLY)-induced renal damage, and to understand its mechanisms of protection against toxicity, using models of GLY and CIN in rats. The rats were separated into eight groups (n = 6 in each), as follows: Healthy, GLY, CM, GLY + CM, CM + EGCG 50 mg/kg (po), GLY + CM + EGCG 50 mg/kg (po), CM + EGCG 100 mg/kg (po), and GLY + CM + EGCG 100 mg/kg (po). Both doses of EGCG protected against CM-induced renal dysfunction, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, EGCG treatment markedly improved CIN-induced oxidative stress, and resulted in a significant down-regulatory effect on tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB mRNA expression. Moreover, histopathological analysis showed that EGCG also attenuated CM-induced kidney damage. Considering the potential clinical use of CM and the numerous health benefits of EGCG, this study showed the protective role of multi-dose EGCG treatment on CIN and GLY-aggravated CIN through different mechanisms.

  13. Aggravation of brain infarction through an increase in acrolein production and a decrease in glutathione with aging. (United States)

    Uemura, Takeshi; Watanabe, Kenta; Ishibashi, Misaki; Saiki, Ryotaro; Kuni, Kyoshiro; Nishimura, Kazuhiro; Toida, Toshihiko; Kashiwagi, Keiko; Igarashi, Kazuei


    We previously reported that tissue damage during brain infarction was mainly caused by inactivation of proteins by acrolein. This time, it was tested why brain infarction increases in parallel with aging. A mouse model of photochemically induced thrombosis (PIT) was studied using 2, 6, and 12 month-old female C57BL/6 mice. The size of brain infarction in the mouse PIT model increased with aging. The volume of brain infarction in 12 month-old mice was approximately 2-fold larger than that in 2 month-old mice. The larger brain infarction in 12 month-old mice was due to an increase in acrolein based on an increase in the activity of spermine oxidase, together with a decrease in glutathione (GSH), a major acrolein-detoxifying compound in cells, based on the decrease in one of the subunits of glutathione biosynthesizing enzymes, γ-glutamylcysteine ligase modifier subunit, with aging. The results indicate that aggravation of brain infarction with aging was mainly due to the increase in acrolein production and the decrease in GSH in brain.

  14. Continuing Exposure to Low-Dose Nonylphenol Aggravates Adenine-Induced Chronic Renal Dysfunction and Role of Rosuvastatin Therapy

    Directory of Open Access Journals (Sweden)

    Yen Chia-Hung


    Full Text Available Abstract Background Nonylphenol (NP, an environmental organic compound, has been demonstrated to enhance reactive-oxygen species (ROS synthesis. Chronic exposure to low-dose adenine (AD has been reported to induce chronic kidney disease (CKD. Methods In this study, we tested the hypothesis that chronic exposure to NP will aggravate AD-induced CKD through increasing generations of inflammation, ROS, and apoptosis that could be attenuated by rosuvastatin. Fifty male Wistar rats were equally divided into group 1 (control, group 2 (AD in fodder at a concentration of 0.25%, group 3 (NP: 2 mg/kg/day, group 4 (combined AD & NP, and group 5 (AD-NP + rosuvastatin: 20 mg/kg/day. Treatment was continued for 24 weeks for all animals before being sacrificed. Results By the end of 24 weeks, serum blood urea nitrogen (BUN and creatinine levels were increased in group 4 than in groups 1–3, but significantly reduced in group 5 as compared with group 4 (all p  Conclusion NP worsened AD-induced CKD that could be reversed by rosuvastatin therapy.

  15. Food-advanced glycation end products aggravate the diabetic vascular complications via modulating the AGEs/RAGE pathway. (United States)

    Lv, Xing; Lv, Gao-Hong; Dai, Guo-Ying; Sun, Hong-Mei; Xu, Hui-Qin


    The aim of this study was to investigate the effects of high-advanced glycation end products (AGEs) diet on diabetic vascular complications. The Streptozocin (STZ)-induced diabetic mice were fed with high-AGEs diet. Diabetic characteristics, indicators of renal and cardiovascular functions, and pathohistology of pancreas, heart and renal were evaluated. AGEs/RAGE/ROS pathway parameters were determined. During the experiments, the diabetic mice exhibited typical characteristics including weight loss, polydipsia, polyphagia, polyuria, high-blood glucose, and low-serum insulin levels. However, high-AGEs diet effectively aggravated these diabetic characteristics. It also increased the 24-h urine protein levels, serum levels of urea nitrogen, creatinine, c-reactive protein (CRP), low density lipoprotein (LDL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the diabetic mice. High-AGEs diet deteriorated the histology of pancreas, heart, and kidneys, and caused structural alterations of endothelial cells, mesangial cells and podocytes in renal cortex. Eventually, high-AGEs diet contributed to the high-AGE levels in serum and kidneys, high-levels of reactive oxygen species (ROS) and low-levels of superoxide dismutase (SOD) in serum, heart, and kidneys. It also upregulated RAGE mRNA and protein expression in heart and kidneys. Our results showed that high-AGEs diet deteriorated vascular complications in the diabetic mice. The activation of AGEs/RAGE/ROS pathway may be involved in the pathogenesis of vascular complications in diabetes.

  16. Genetic predisposition to essential hypertension in a Mongolian population Detecting the C825T polymorphism of the G-protein beta 3 subunit gene

    Institute of Scientific and Technical Information of China (English)

    Chunyu Zhang; Shigang Zhao; Guangming Niu; Rile Hu; Zhiguang Wang; Mingfang Jiang; Rile Hu


    BACKGROUND: The prevalences of hypertension, cerebrovascular diseases, etc. are higher in Mongolian population because of the influence of various factors including genetics, geography, diet, etc. Therefore, it is helpful for prevention to develop researches on the genetics of various diseases including hypertension in Mongolian population.OBJECTIVE: To analyze the association between C825T polymorphisms of G-protein beta 3 subunit gene (GNB3), the important candidate gene of various disease of cardiovascular system, and Mongolian patients with essential hypertension.DESIGN: A comparative observation.SETTINGS: Department of Neurology, the First Affiliated Hospital of Inner Mongolia Medical College;Wulate Houqi Red Cross Society.PARTICIPANTS: Totally 267 Mongolian residents, whose blood relations of 3 generations were all Mongolians, were selected from Wulate Houqi, Inner Mongolia. The patients were screened based on the diagnostic standard of hypertension set by WHO in 1999, and the enrolled subjects were divided into two groups according to the level of blood pressure: ① Normal blood pressure group (n =124): 64 males and 60 females, systolic blood pressure (SBP) < 140 mm Hg (1 mm Hg=0.133 kPa), diastolic blood pressure (DBP) <90 mm Hg; ② Essential hypertension group (n =143): 71 males and 72 females, including 60 patients with simple high SBP (SBP ranged 145 to 195 mm Hg, whereas DBP < 90 mm Hg).METHODS: Peripheral venous blood (5 mL) was drawn from all the subjects, the genome DNA was extracted, and the polymorphisms of the GNB3 C825T genotype were detected with the Sequenom system.Polymerase chain reaction (PCR) experiment and SNP detection were performed in Beijing Huada gene laboratory. Then the univariate analysis of variance was applied in the sample comparison among groups, and the chi-square test was used to compare the genotypes and allele frequencies. The odd ratio (OR) and 95% confidence interval (CI)were calculated.MAIN OUTCOME MEASURES: The

  17. Over-starvation aggravates intestinal injury and promotes bacterial and endotoxin translocation under high-altitude hypoxic environment

    Institute of Scientific and Technical Information of China (English)

    Qi-Quan Zhou; Ding-Zhou Yang; Yong-Jun Luo; Su-Zhi Li; Fu-Yu Liu; Guan-Song Wang


    AIM: To study whether over-starvation aggravates intestinal mucosal injury and promotes bacterial and endotoxin translocation in a high-altitude hypoxic environment. METHODS: Sprague-Dawley rats were exposed to hypobaric hypoxia at a simulated altitude of 7000 m for 72 h. Lanthanum nitrate was used as a tracer to detect intestinal injury. Epithelial apoptosis was observed with terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Serum levels of diamino oxidase (DAO), malondialdehyde (MDA), glutamine (Gln), superoxide dismutase (SOD) and endotoxin were measured in intestinal mucosa. Bacterial translocation was detected in blood culture and intestinal homogenates. In addition, rats were given Gln intragastrically to observe its protective effect on intestinal injury. RESULTS: Apoptotic epithelial cells, exfoliated villi and inflammatory cells in intestine were increased with edema in the lamina propria accompanying effusion of red blood cells. Lanthanum particles were found in the intercellular space and intracellular compartment. Bacterial translocation to mesenteric lymph nodes (MLN) and spleen was evident. The serum endotoxin, DAO and MDA levels were significantly higher while the serum SOD, DAO and Gln levels were lower in intestine (P < 0.05). The bacterial translocation number was lower in the high altitude hypoxic group than in the high altitude starvation group (0.47 ± 0.83 vs 2.38 ± 1.45, P < 0.05). The bacterial translocation was found in each organ, especially in MLN and spleen but not in peripheral blood. The bacterial and endotoxin translocations were both markedly improved in rats after treatment with Gln. CONCLUSION: High-altitude hypoxia and starvation cause severe intestinal mucosal injury and increase bacterial and endotoxin translocation, which can be treated with Gln.

  18. Aggravation of north channels' shrinkage and south channels' development in the Yangtze Estuary under dam-induced runoff discharge flattening (United States)

    Zhu, Bo-yuan; Li, Yi-tian; Yue, Yao; Yang, Yun-ping


    Construction of dams on rivers has progressively affected the seasonal variability of runoff discharge, which has consequently produced remarkable impacts on the morphology of estuarine channels. This paper considers four-typical-order bifurcations of the Yangtze Estuary and adopts an ebb partition ratio (defined as the diversion ratio of ebb flow in a given branch divided by the total ebb tidal discharge immediately upstream of the river node where the bifurcation occurs) as a measure of water excavating force in the bifurcation channels. Results show that the seasonal variability of runoff discharge at Datong Hydrological Station (Datong) is flattened, being mainly driven by upstream runoff flattening observed at Yichang Hydrological Station (Yichang) and the tributary rivers. Yearly ebb partition ratios of the channels located to the north and south of the islands present decreasing and increasing trends respectively, and as also do the yearly north and south channel volume of the bifurcations. Yearly ebb partition ratio is proved to be an effective index to represent the water excavating force considering the stability of yearly ebb tidal discharge and its relationship with the channel erosion-deposition. River dams are the driving factors behind the runoff flattening at Datong because of their flattening effects on its main contributors (Yichang and tributary rivers). This flattening significantly helps reduce and enlarge the yearly ebb partition ratios of the north and south channels respectively, and then aggravates the shrinkage and development of the north and south channels separately. Yearly ebb partition ratio of the North Passage (NP) must be enlarged in order for the NP to maintain its function as a shipping channel.

  19. Erosive arthritis and hepatic granuloma formation induced by peptidoglycan polysaccharide in rats is aggravated by prasugrel treatment.

    Directory of Open Access Journals (Sweden)

    Analia E Garcia

    Full Text Available Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by peptidoglycan polysaccharide (PG-PS in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation.

  20. Iron as a possible aggravating factor for osteopathy in itai-itai disease, a disease associated with chronic cadmium intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Noda, M.; Yasuda, M.; Kitagawa, M. (Toyama Medical and Pharmaceutical Univ. (Japan))


    Itai-itai disease is thought to be the result of chronic cadmium (Cd) intoxication. We examined 23 autopsy cases of itai-itai disease and 18 cases of sudden death as controls. Urine and blood samples from 10 patients were collected before they died and revealed the presence of severe anemia and renal tubular injuries. Undecalcified sections of iliac bone were stained with Aluminon reagent, and ammonium salt of aurintricarboxylic acid, and Prussian blue reagent in all cases of itai-itai disease. These two reagents reacted at the same mineralization fronts. X-ray microanalysis revealed the presence of iron at mineralization fronts in itai-itai disease. Five patients showed evidence of hemosiderosis in the liver, spleen, and pancreas, probably as a result of post transfusion iron overload. Renal calculi and calcified aortic walls were also stained with Prussian blue reagent in several patients. Neither ferritin nor transferrin were visualized at mineralization fronts in itai-itai disease by immunohistochemical staining. These results suggest that iron is bound to calcium or to calcium phosphate by a physicochemical reaction. A marked osteomalacia was observed in 10 cases of itai-itai disease by histomorphometry. Regression analyses of data from cases of itai-itai disease suggested that an Aluminon-positive metal inhibited mineralization and that renal tubules were injured. Since bone Cd levels were increased in itai-itai disease, it is likely that renal tubules were injured by exposure to Cd. Therefore, stainable bone iron is another possible aggravating factor for osteopathy in itai-itai disease, and a synergistic effect between iron and Cd on mineralization is proposed.

  1. Extracellular heat-shock protein 70 aggravates cerulein-induced pancreatitis through toll-like receptor-4 in mice

    Institute of Scientific and Technical Information of China (English)

    SONG Jun-min; WANG Rong; LIU Hong-xiang; LI Yuan; ZENG Yu-jian; ZHOU Zong-guang; LIU Hai-yi; XU Bing; WANG Ling; ZHOU Bin


    Background In patients suffering from acute pancreatitis, the pathogenesis is not completely understood, and several recent studies in vitro suggested that heat shock proteins might play an important role in cell signaling. To investigate the possible role of extracellular heat shock protein 70 (Hsp70) in pancreatitis, toll-like receptor-4 (TLR4)-deficient and wild-type mice were administered with exogenous Hsp70 during the course of cerulein-induced pancreatitis (CIP).Methods Acute pancreatitis was induced by 5 intraperitoneal injections of cerulein at hourly intervals, and then treated with recombinant Hsp70 through the caudal vein 4 hours after the start of cerulein injections. Subsequently serum amylase and serum cytokines levels were detected. Histologic alteration of the pancreas was evaluated. Tumor necrosis factor alpha (TNF-a) concentrations and myeloperoxidase (MPO) activity in both pancreas and lungs were analyzed. The nuclear factor kappa B (NF-KB) activation in pancreatic tissue was measured using a sensitive RelA enzyme-linked immunosorbent assay.Results Treatment with recombinant Hsp70 to wild-type mice in CIP resulted in significant aggravation of inflammation in pancreas, elevated levels of serum cytokines, up-regulation of pulmonary MPO activity and increase of lung tissues TNF-α concentrations. In contrast, treatment with Hsp70 to TLR4-deficient mice had little effect on serum cytokines levels, pancreatic inflammation, pulmonary MPO activity and TNF-a concentrations.Conclusions The results suggest that extracellular HspTO might induce systemic inflammatory response syndrome (SIRS)-Iike response in vivo and TLR4 might be involved in the Hsp70-mediated activation of inflammatory reaction in the progression of CIP without infection.

  2. Inhibition of JNK aggravates the recovery of rat hearts after global ischemia: the role of mitochondrial JNK.

    Directory of Open Access Journals (Sweden)

    Sehwan Jang

    Full Text Available c-Jun N-terminal kinase (JNK, a stress-activated MAPK, is activated during cardiac ischemia-reperfusion (IR. The role of JNK inhibitors in cardioprotection against IR still remains controversial, in part, due to spill-over effects of non-specific inhibitors. In the present study, we sought to examine whether inhibition of JNK by SU3327, a specific JNK inhibitor that inhibits upstream JNK signaling rather than the kinase activity of JNK, improves cardiac function and reduces heart damage during IR. Hearts of male Sprague-Dawley rats perfused by Langendorff were subjected to 25 min of global ischemia followed by 30 min reperfusion in the presence or absence of SU3327. Cardiac function was monitored throughout the perfusion period. Myocardial damage was extrapolated from LDH activity in the coronary effluent. At the end of reperfusion, mitochondria were isolated and used to measure respiration rates and mitochondrial permeability transition pore opening. Protein analysis of mitochondria predictably revealed that SU3327 inhibited JNK phosphorylation. Although SU3327 significantly reduced cell damage during the first minutes of reperfusion, it did not improve cardiac function and, furthermore, reduced the mitochondrial respiratory control index. Interestingly, SU3327 activated the other stress-related MAPK, p38, and greatly increased its translocation to mitochondria. Mitochondrial P-JNK and P-p38 were co-immunoprecipitated with complex III of the electron transfer chain. Thus, JNK plays an essential role in cardiac signaling under both physiological and pathological conditions. Its inhibition by SU3327 during IR aggravates cardiac function. The detrimental effects of JNK inhibition are associated with reciprocal p38 activation and mitochondrial dysfunction.

  3. High-sodium intake aggravates myocardial injuriesinduced by aldosterone via oxidative stress inSprague-Dawley rats

    Institute of Scientific and Technical Information of China (English)

    Jing-yi LI; Shao-ling ZHANG; Meng REN; Yan-ling WEN; Li YAN; Hua CHENG


    To evaluate the effects of aldosterone with or without high sodium intake on blood pressure,myocardial structure and left ventricular function in rats,and to investigate the mechanisms underlying the effects.Methods:Eight-week-old male Sprague-Dawley rats were randomly divided into 3 groups:(1) control (CON) group fed a normal sodium diet,(2) aldosterone (ALD) group receiving aldosterone infusion and a normal sodium diet,and (3) high sodium plus aldosterone (HS-ALD) group receiving 1% NaCl diet in conjunction with aldosterone infusion.Aldosterone was administered through continuously subcutaneous infusion with osmotic minipump at the rate of 0.75 μg/h for 8 weeks.The myocardium structure was observed using transt-horacic echocardiography and transmission electron microscopy.The collagen deposition in left ventricle was evaluated with Masson'strichrome staining.The expression of IL-18,p22phox,and p47phox proteins was examined using Western blot analysis.Results:The systolic blood pressure in the ALD and HS-ALD groups was significantly higher than that in the CON group after 2-week treatment.But the blood pressure showed no significant difference between the HS-ALD and ALD groups.The left ventricular hyper-trophy,myocardial collagen deposition and oxidative stress were predominantly found in the HS-ALD and ALD group.Furthermore,the breakdown of myocardial structure and oxidative stress were more apparent in the HS-ALD group as compared with those in the ALDgroup.Conclusion:Long-term infusion of aldosterone results in hypertension and profibrotic cardiovascular responses in rats fed a normal sodium diet,which were mediated by oxidative stress.High-sodium intake could aggravate myocardial injuries induced by aldosterone.

  4. In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue. (United States)

    Barbe, P.; Millet, L.; Galitzky, J.; Lafontan, M.; Berlan, M.


    1. The involvement of beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow was investigated in abdominal subcutaneous adipose tissue of healthy young adults by use of an in situ microdialysis technique. 2. Dialysis probes were infused either with isoprenaline (non-selective beta-adrenoceptor agonist), CGP 12,177 (selective beta 3-adrenoceptor agonist having beta 1-/beta 2-antagonist properties), dobutamine (selective beta 1-adrenoceptor agonist) or terbutaline (selective beta 2-adrenoceptor agonist). The recovery of each probe used for perfusion was calculated by an in vivo calibration method. The local blood flow was estimated through the measurement of the escape of ethanol infused simultaneously with the drugs included in the probe. 3. Isoprenaline infusion at 0.01 microM had a weak effect while higher concentrations of isoprenaline (0.1 and 1 microM) caused a rapid, sustained and concentration-dependent increase of glycerol outflow; the maximum increase was 306 +/- 34% with 1 microM. Isoprenaline also increased the nutritive blood flow in adipose tissue; a significant effect appeared at 0.1 microM isoprenaline and was greater at 1 microM. 4. CGP 12,177 (10 and 100 microM) increased the glycerol concentration in the dialysate (128 +/- 8 and 149 +/- 12%, respectively) and nutritive blood flow. Terbutaline and dobutamine (100 microM) both provoked rapid and similar increases in glycerol outflow (252 +/- 18 and 249 +/- 18%, respectively). Both, terbutaline and dobutamine increased nutritive blood flow. 5. It is concluded that beta 1- and beta 2-adrenoceptor subtypes are both mainly involved in the mobilization of lipids and in the control of nutritive blood flow. beta 3-Adrenoceptors play a weaker role in the control of lipolysis and nutritive blood flow in human subcutaneous abdominal adipose tissue. PMID:8851509

  5. Synthesis, radiolabeling and baboon SPECT imaging of 2{beta}-carbomethoxy-3{beta}-(3'-[{sup 123}I]iodophenyl)tropane ([{sup 123}I]YP256) as a serotonin transporter radiotracer

    Energy Technology Data Exchange (ETDEWEB)

    Bois, Frederic; Baldwin, Ronald M.; Amici, Louis; Al-Tikriti, Mohammed S. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Kula, Nora; Baldessarini, Ross [Department of Psychiatry and Neuroscience Program, Harvard Medical School, Mailman Research Center McLean Division of Massachusetts General Hospital, Belmont, MA 02478 (United States); Innis, Robert B.; Staley, Julie K. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Tamagnan, Gilles D. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States)], E-mail:


    To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2{beta}-carbomethoxy-3{beta}-(3'-[{sup 123}I]iodophenyl) tropane (YP256, ). The radiolabeling was performed by iododestannylation using sodium [{sup 123}I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo.

  6. Libraries of RGD analogs, labeled through ReO{sup 3+} or TcO{sup 3+} coordination, targeting {alpha}V{beta}3 integrin: development of tracers for the early detection of tumor neo-angiogenesis; Chimiotheques de complexes du technetium et du rhenium ciblant l'integrine {alpha}V{beta}3: developpement de traceurs pour la detection precoce de la neoangiogenese tumorale

    Energy Technology Data Exchange (ETDEWEB)

    Aufort, M.


    Integrins form a family of hetero-dimeric integral glycoproteins which play a central role in cell-cell adhesion and cell-matrix interactions. In particular, they are over expressed during tumor neo-angiogenesis. About 10 of them recognize a structured RGD (Arg-Gly-Asp) sequence. Analogs of this sequence can be used for the early detection of tumors and metastases. We developed new tracers, labeled with {sup 99m}Tc, for the molecular imaging of {alpha}{sub V{beta}3} integrin. Until recently, there was no reliable ab initio structure prediction of complex molecules containing Re and Tc chelates. Therefore, we preferred a combinatorial approach to develop potential ligands of {alpha}{sub V{beta}3} integrin and we attempted to identify efficient tracers by in vivo screening. This method would account for biodistribution and pharmacokinetics properties in the early steps of the study. Tracers were obtained according two strategies: i) cyclization of linear RGD analogs; ii) combinatorial assembling of independent modules through metal core coordination by the well-known NS{sub 2}+S motif. After synthesis and labeling, the stability of the tracers was investigated in presence of glutathione and in murine plasma. In vitro screening on purified integrin showed that a cyclic rhenium coordinate binds specifically {alpha}{sub V{beta}3}. A tumor model (U87-MG tumor on nude mice) was validated in the laboratory and a method was developed to analyze in vivo experiments. Biodistribution data and percentage of activity found in tumors are encouraging for cyclic compounds though identification of efficient tracers is difficult due to their instability in the conditions of analyses. (author)

  7. Acute cold exposure-induced down-regulation of CIDEA, cell death-inducing DNA fragmentation factor-alpha-like effector A, in rat interscapular brown adipose tissue by sympathetically activated beta3-adrenoreceptors. (United States)

    Shimizu, Takahiro; Yokotani, Kunihiko


    The thermogenic activity of brown adipose tissue (BAT) largely depends on the mitochondrial uncoupling protein 1 (UCP1), which is up-regulated by environmental alterations such as cold. Recently, CIDEA (cell death-inducing DNA fragmentation factor-alpha-like effector A) has also been shown to be expressed at high levels in the mitochondria of BAT. Here we examined the effect of cold on the mRNA and protein levels of CIDEA in interscapular BAT of conscious rats with regard to the sympathetic nervous system. Cold exposure (4 degrees C for 3h) elevated the plasma norepinephrine level and increased norepinephrine turnover in BAT. Cold exposure resulted in down-regulation of the mRNA and protein levels of CIDEA in BAT, accompanied by up-regulation of mRNA and protein levels of UCP1. The cold exposure-induced changes of CIDEA and UCP1 were attenuated by intraperitoneal pretreatment with propranolol (a non-selective beta-adrenoreceptor antagonist) (2mg/animal) or SR59230A (a selective beta(3)-adrenoreceptor antagonist) (2mg/animal), respectively. These results suggest that acute cold exposure resulted in down-regulation of CIDEA in interscapular BAT by sympathetically activated beta(3)-adrenoreceptor-mediated mechanisms in rats.

  8. Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson's disease. (United States)

    Suzuki, Mari; Fujikake, Nobuhiro; Takeuchi, Toshihide; Kohyama-Koganeya, Ayako; Nakajima, Kazuki; Hirabayashi, Yoshio; Wada, Keiji; Nagai, Yoshitaka


    Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent multicenter genetic studies have revealed that mutations in the glucocerebrosidase 1 (GBA1) gene, which are responsible for Gaucher's disease, are strong risk factors for PD and DLB. However, the mechanistic link between the functional loss of glucocerebrosidase (GCase) and the toxicity of αSyn in vivo is not fully understood. In this study, we employed Drosophila models to examine the effect of GCase deficiency on the neurotoxicity of αSyn and its molecular mechanism. Behavioral and histological analyses showed that knockdown of the Drosophila homolog of GBA1 (dGBA1) exacerbates the locomotor dysfunction, loss of dopaminergic neurons and retinal degeneration of αSyn-expressing flies. This phenotypic aggravation was associated with the accumulation of proteinase K (PK)-resistant αSyn, rather than with changes in the total amount of αSyn, raising the possibility that glucosylceramide (GlcCer), a substrate of GCase, accelerates the misfolding of αSyn. Indeed, in vitro experiments revealed that GlcCer directly promotes the conversion of recombinant αSyn into the PK-resistant form, representing a toxic conformational change. Similar to dGBA1 knockdown, knockdown of the Drosophila homolog of β-galactosidase (β-Gal) also aggravated locomotor dysfunction of the αSyn flies, and its substrate GM1 ganglioside accelerated the formation of PK-resistant αSyn. Our findings suggest that the functional loss of GCase or β-Gal promotes the toxic conversion of αSyn via aberrant interactions between αSyn and their substrate glycolipids, leading to the aggravation of αSyn-mediated neurodegeneration.

  9. Enhanced formation of secondary air pollutants and aggravation of urban smog due to crop residue burning emissions in North India (United States)

    Sarkar, Chinmoy; Kumar, Vinod; Sinha, Vinayak


    Biomass burning causes intense perturbations to regional atmospheric chemistry and air quality and is a significant global source of reactive pollutants to the atmosphere (Andreae and Merlet, 2001). In November 2012, large areas in North India including New Delhi experienced several weeks of aggravated smog and poor air quality due to the impact of crop residue burning, which is a biannual post harvest activity that occurs during Oct-Nov and April-May every year in the agricultural belts of North western India. In-situ high temporal resolution (1 measurement every minute) measurements of a suite of volatile organic compounds measured using proton transfer reaction mass spectrometry (PTR-MS) such as acetonitrile (biomass burning tracer) and aromatic hydrocarbons were performed simultaneously with carbon monoxide, nitrogen oxides, ozone and aerosol mass concentrations (PM 2.5 and PM 10) at a suburban site (30.667°N, 76.729°E and 310 m asl), impacted by air masses that had passed over the burning fields less than 72 hours ago. By using data from the same season but before the post harvest crop residue burning activity had commenced, we were able to quantify enhancements in ambient levels of the measured species due to the crop residue burning activity. When air masses influenced by the fire emissions reached the measurement site, peak values of about 8 ppbV acetonitrile, 4 ppmV CO, 100 ppbV NOx , 30 ppbV toluene and 15 ppbV benzene were observed which represented a factor of 2-5 increase over their ambient levels in the non-fire influenced period. Emission ratios of aromatic hydrocarbons/CO also showed a marked increase. Non fire event (N.F. E.) influenced and fire event (F.E.) influenced air masses had the following emission ratio enhancements: benzene/CO (N.F.E = 3; F.E. = 5), toluene/CO (N.F.E = 4; F.E. = 8.7) and sum of C8 aromatics/CO (N.F.E = 4; F.E. = 7.3) and sum of C9 aromatics/CO (N.F.E = 2.6; F.E. = 3.4). The OH reactivity of air masses which has strong

  10. Expression of TGF-beta1, TGF-beta2, TGF-beta3 and the receptors TGF-betaRI and TGF-betaRII in placentomes of artificially inseminated and nuclear transfer derived bovine pregnancies. (United States)

    Ravelich, S R; Shelling, A N; Wells, D N; Peterson, A J; Lee, R S F; Ramachandran, A; Keelan, J A


    Bovine nuclear transfer pregnancies are characterized by a high incidence of placental abnormalities, notably, increased placentome size and deficiencies in trophoblast cell function and establishment of placental vasculature. Alterations in gene expression during placental growth and development may contribute to the appearance of large placentomes in pregnancies derived from nuclear transfer. The placenta synthesizes a number of cytokines and growth factors, including the transforming growth factor-betas (TGF-betas) that are involved in the establishment, maintenance and/or regulation of pregnancy. All forms of TGF-beta and their receptors are present at the fetal-maternal interface of the bovine placentome, where they are thought to play an important role in regulating growth, differentiation, and function of the placenta. Using real-time RT-PCR, we have examined the expression of TGF-beta1, TGF-beta2, TGF-beta3 and the receptors TGF-betaRI and TGF-betaRII in placentomes of artificially inseminated (AI) and nuclear transfer (NT)-derived bovine pregnancies at days 50, 100 and 150 of gestation. TGF-beta1, TGF-beta2 and TGF-beta3 mRNA expression increased by 2.0-2.8-fold, while TGF-betaRI and TGF-betaRII mRNA expression decreased by 1.7-2.0-fold in NT placentomes compared to AI controls at all gestational ages examined. These findings indicate that NT placentomes may be resistant to the growth suppressive effects of TGF-betas and could contribute to the placental proliferative abnormalities observed in NT-derived placentas. Alternatively, deficiencies in placentation may provide a mechanism whereby TGF-betas are dysregulated in NT pregnancies.

  11. Carboxylated multi-walled carbon nanotubes aggravated biochemical and subcellular damages in leaves of broad bean (Vicia faba L.) seedlings under combined stress of lead and cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chengrun, E-mail: [School of Life Science, Huainan Normal University, Huainan 232001 (China); Liu, Haitao; Chen, Jinyun [School of Life Science, Huainan Normal University, Huainan 232001 (China); Tian, Yuan [Department of Plant, Soil and Microbial Sciences, Michigan State University, East Lansing, MI 48824 (United States); Shi, Jian; Li, Dongdong; Guo, Chen; Ma, Qingping [School of Life Science, Huainan Normal University, Huainan 232001 (China)


    Highlights: • MWCNTs-COOH disturb mineral elements and cause oxidative damages in the leaves. • Cd and Pb combination result in reduction of mineral elements and enrichment of Na, involving in toxicity mechanisms. • MWCNTs-COOH facilitate Cd and Pb uptake, and aggravate biochemical and subcellular damages. - Abstract: Increasing industrialization of multi-walled carbon nanotubes (MWCNTs) would inevitably lead to their release into the environment and combination with heavy metals. However, studies concerning the combined effects of MWCNTs and heavy metals on agricultural crops are limited. Herein, effects and mechanisms of carboxylated MWCNTs (MWCNTs-COOH) (2.5, 5 and 10 mg/L) and their combination with 20 μM Pb and 5 μM Cd (shortened as Pb + Cd) on Vicia faba L. seedlings were investigated. The results showed that the MWCNTs-COOH disturbed the imbalance of nutrient elements, and caused oxidative stress and damages in the leaves. Additionally, the combination of MWCNTs-COOH with Pb + Cd resulted in enrichment of Pb and Cd, and deterioration of oxidative damages compared with the treatments of MWCNTs-COOH or Pb + Cd alone in the leaves. As the results, the concentrations of MWCNTs-COOH not only caused oxidative stress, but also exacerbated the biochemical and subcellular damages due to the treatment of Pb + Cd in the leaves. It also suggests that persistent release of MWCNTs-COOH into the environment may cause phytotoxicity and aggravate ecological risks due to combination of heavy metals.

  12. Effects of Kanlijian (坎离煎) on Exercise Tolerance, Quality of Life, and Frequency of Heart Failure Aggravation in Patients with Chronic Heart Failure

    Institute of Scientific and Technical Information of China (English)

    JIANG Mei-xian; RUAN Xiao-fen; XU Yan


    Objective: To observe the effects of conventional therapy combined with Kanlijian (坎离煎,KLJ) on exercise tolerance, quality of life and frequency of heart failure aggravation in patients with chronic heart failure(CHF). Methods: Sixty. CHF patients differentiated as sufferring from the syndrome of Xin-Shen Yang deficiency were included in the study and randomly assigned at the ratio of 2: 1 into the KLJ group (n=39) and the control group(n = 21). All the patients were treated with conventional therapy of Western medicine, but to those in the KLJ group, KLJ was medicated additionally one dose daily with 24 wks as one therapeutic course. The efficacy on TCM syndrome and changes of scores on TCM syndrome were observed after treatment. The indexes, including 6-minute walking distance (6MWD), quality of life (QOL, accessed by LHFQ scoring), NYHA grade, hemodynamic indexes and reducing/withdrawal rate of diuretic and digoxin before and after treatment were recorded and compared. Also the frequency of re-admission due to aggravation of heart failure in one year's time were observed. Results: ( 1 ) The efficacy on TCM syndrome, improvement on scores of TCM syndrome, therapeutic effects on 6MWD, QOL, and NYHA grade in the KLJ group were superior to those in the control group. (2) Hemodynamic indexes after treatment, left ventricular fractional shortening (LVFS) and E peak/A peak (E/A), between the two groups had no significant difference, while left ventricular ejection fraction (LVEF) was increased significantly in the KLJ group, but with no obvious change in the control group. (3) The reducing/withdrawal rate of diuretic and digoxin in the KLJ group was significantly higher than that in the control group. (4) The 1-year frequency of re-admission significantly decreased in the KLJ group. Conclusion: The adjuvant treatment of KLJ on the basis of Western conventional therapy can significantly improve CHF patients' exercise tolerance, quality of life and cardiac function

  13. Impaired removal of Vβ8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim). (United States)

    Leucht, K; Caj, M; Fried, M; Rogler, G; Hausmann, M


    We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim(-/-) animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type mice. The number of autoreactive T cell receptor (TCR) Vβ8(+) lymphocytes was significantly higher in Bim(-/-) mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim(-/-) mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation.

  14. Conditioned medium from mesenchymal stem cells induces cell death in organotypic cultures of rat hippocampus and aggravates lesion in a model of oxygen and glucose deprivation. (United States)

    Horn, Ana Paula; Frozza, Rudimar Luiz; Grudzinski, Patrícia Benke; Gerhardt, Daniéli; Hoppe, Juliana Bender; Bruno, Alessandra Nejar; Chagastelles, Pedro; Nardi, Nance Beyer; Lenz, Guido; Salbego, Christianne


    Cell therapy using bone marrow-derived mesenchymal stem cells (MSC) seems to be a new alternative for the treatment of neurological diseases, including stroke. In order to investigate the response of hippocampal tissue to factors secreted by MSC and if these factors are neuroprotective in a model of oxygen and glucose deprivation (OGD), we used organotypic hippocampal cultures exposed to conditioned medium from bone marrow-derived MSC. Our results suggest that the conditioned medium obtained from these cells aggravates lesion caused by OGD. In addition, the presence of the conditioned medium alone was toxic mainly to cells in the CA1, CA2 and CA3 areas of the hippocampal organotypic culture even in basal conditions. GABA stimulation and NMDA and AMPA receptors antagonists were able to reduce propidium iodide staining, suggesting that the cell death induced by the toxic factors secreted by MSC could involve these receptors.

  15. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice

    Directory of Open Access Journals (Sweden)

    Margarita Vida


    Full Text Available Interleukin-6 (IL-6 has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD in wild-type (WT and IL-6-deficient (IL-6−/− mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6. Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1 and signal transducer and activator of transcription-3 (STAT3, increased AMP kinase phosphorylation (p-AMPK, and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS and stearoyl-CoA desaturase 1 (SCD1. The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β, FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

  16. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice (United States)

    Gavito, Ana Luisa; Bautista, Dolores; Suarez, Juan; Badran, Samir; Arco, Rocío; Pavón, Francisco Javier; Serrano, Antonia; Rivera, Patricia; Decara, Juan; Cuesta, Antonio Luis; Rodríguez-de-Fonseca, Fernando


    High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats. PMID:27333268

  17. Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction.

    Directory of Open Access Journals (Sweden)

    Marta Gil-Ortega

    Full Text Available BACKGROUND: The hypothesis of this study is that long-term high-fat diets (HFD induce perivascular adipose tissue (PVAT dysfunction characterized by a redox imbalance, which might contribute to aggravate endothelial dysfunction in obesity. METHODS AND RESULTS: C57BL/6J mice were fed either control or HFD (45% kcal from fat for 32 weeks. Body weight, lumbar and mesenteric adipose tissue weights were significantly higher in HFD animals compared to controls. The anticontractile effect of PVAT in mesenteric arteries (MA was lost after 32 week HFD and mesenteric endothelial-dependent relaxation was significantly impaired in presence of PVAT in HFD mice (Emax = 71.0±5.1 vs Emax = 58.5±4.2, p<0.001. The inhibitory effect of L-NAME on Ach-induced relaxation was less intense in the HFD group compared with controls suggesting a reduction of endothelial NO availability. Expression of eNOS and NO bioavailability were reduced in MA and almost undetectable in mesenteric PVAT of the HFD group. Superoxide levels and NOX activity were higher in PVAT of HFD mice. Apocynin only reduced contractile responses to NA in HFD animals. Expression of ec-SOD and total SOD activity were significantly reduced in PVAT of HFD mice. No changes were observed in Mn-SOD, Cu/Zn-SOD or catalase. The ratio [GSSG]/([GSH]+[GSSG] was 2-fold higher in the mesenteric PVAT from HFD animals compared to controls. CONCLUSIONS: We suggest that the imbalance between pro-oxidant (NOX, superoxide anions, hydrogen peroxide and anti-oxidant (eNOS, NO, ecSOD, GSSG mechanisms in PVAT after long-term HFD might contribute to the aggravation of endothelial dysfunction.

  18. Expression of transforming growth factor beta (TGF beta) receptors and expression of TGF beta 1, TGF beta 2 and TGF beta 3 in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Damstrup, L; Rygaard, K; Spang-Thomsen, M;


    A panel of 21 small cell lung cancer cell (SCLC) lines were examined for the presence of Transforming growth factor beta receptors (TGF beta-r) and the expression of TGF beta mRNAs. By the radioreceptor assay we found high affinity receptors to be expressed in six cell lines. scatchard analysis...... of the binding data demonstrated that the cells bound between 4.5 and 27.5 fmol mg-1 protein with a KD ranging from 16 to 40 pM. TGF beta 1 binding to the receptors was confirmed by cross-linking TGF beta 1 to the TGF beta-r. Three classes of TGF beta-r were demonstrated, type I and type II receptors with M......(r) = 65,000 and 90,000 and the betaglycan (type III) with M(r) = 280,000. Northern blotting showed expression of TGF beta 1 mRNA in ten, TGF beta 2 mRNA in two and TGF beta 3 mRNA in seven cell lines. Our results provide, for the first time, evidence that a large proportion of a broad panel of SCLC cell...

  19. Progressive Seizure Aggravation in the Repeated 6-Hz Corneal Stimulation Model Is Accompanied by Marked Increase in Hippocampal p-ERK1/2 Immunoreactivity in Neurons (United States)

    Giordano, Carmela; Costa, Anna M.; Lucchi, Chiara; Leo, Giuseppina; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean; Torsello, Antonio; Biagini, Giuseppe


    the third session. The vast majority of p-ERK1/2 immunopositive cells were co-labeled with FosB/ΔFosB antibodies, suggesting the existence of a relationship between the investigated markers in a subpopulation of neurons activated by seizures. These findings suggest that p-ERK1/2 are useful markers to define the aggravation of seizures and the response to anticonvulsant treatments. In particular, p-ERK1/2 expression clearly identified the involvement of hippocampal regions during seizure aggravation in the 6-Hz model. PMID:28018175

  20. The mtDNA nt7778 G/T polymorphism augments formation of lymphocytic foci but does not aggravate cerulein-induced acute pancreatitis in mice.

    Directory of Open Access Journals (Sweden)

    Sarah Müller

    Full Text Available A polymorphism in the ATP synthase 8 (ATP8 gene of the murine mitochondrial genome, G-to-T transversion at position 7778, has been suggested to increase susceptibility to multiple autoimmune diseases, including autoimmune pancreatitis (AIP. The polymorphism also induces mitochondrial reactive oxygen species generation, secretory dysfunction and β-cell mass adaptation. Here, we have used two conplastic mouse strains, C57BL/6N-mtAKR/J (B6-mtAKR; nt7778 G; control and C57BL/6N-mtFVB/N (B6-mtFVB; nt7778 T, to address the question if the polymorphism also affects the course of cerulein-induced acute pancreatitis in mice. Therefore, two age groups of mice (3 and 12-month-old, respectively were subjected to up to 7 injections of the secretagogue cerulein (50 µg/kg body weight at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of α-amylase and activities of myeloperoxidase (MPO in lung tissue. A comparison of cerulein-induced pancreatic tissue damage and increases of α-amylase and MPO activities showed no differences between the age-matched groups of both strains. Interestingly, histological evaluation of pancreatic tissue of both untreated and cerulein-treated B6-mtAKR and B6-mtFVB mice also revealed the presence of infiltrates of immune cells surrounding ducts and vessels; a finding that is compatible with an early stage of AIP. After recovery from cerulein-induced pancreatitis (day 7 after the injections, 12-month-old B6-mtFVB mice but not B6-mtAKR mice displayed aggravated lymphocytic lesions. A comparison of 12-month-old mice with other age groups of both strains revealed that lymphocytic foci were largely absent in 3-month-old mice, while 24-month-old mice were more affected. Together, our data suggest that the mtDNA nt7778 G/T polymorphism does not aggravate cerulein-induced acute pancreatitis. Autoimmune-like lesions, however, may progress faster if

  1. Heterogeneity in hand veins responses to acetylcholine is not associated with polymorphisms in the G-protein beta3-subunit (C825T) and endothelial nitric oxide synthase (G894T) genes but with serum low density lipoprotein cholesterol. (United States)

    Grossmann, M; Dobrev, D; Siffert, W; Kirch, W


    Vascular responses to acetylcholine (ACh) are notoriously variable, the reason for this phenomenon is unknown. We tested the hypothesis that the variability in venous response to acetylcholine may be associated with two recently identified genetic polymorphisms for proteins involved in the signal transduction pathway, i.e. the G-protein beta3-subunit (GNB3) and endothelial nitric oxide synthase (eNOS). The dorsal hand vein technique was used in 37 healthy subjects. Hand veins were preconstricted with the alpha1-adrenoceptor agonist phenylephrine and the venodilator response to local ACh infusion was measured with and without comedication of acetylsalicylic acid or co-infusion of N(G)-monomethyl-L-arginine (L-NMMA). In addition, all subjects received routine laboratory tests and 26 of them were genotyped for the C825T polymorphism of the GNB3 gene and for the G894T polymorphism of the eNOS gene. A striking variability in venous response to ACh was found with dilation observed in the low ACh concentration range and reduced dilation or even constriction at high concentrations. ACh-induced venodilation was mediated by muscarinic receptors and abolished in the presence of both acetylsalicylic acid and L-NMMA suggesting dependence on endothelium. We did not find any association of the variability in ACh response with GNB3 or eNOS allele status. On the other hand, a significant positive correlation between ACh responsiveness and low density lipoprotein-cholesterol status was detected. Two recently discovered gene polymorphisms are not responsible for the profound heterogeneity in venodilator response to ACh. Surprisingly, this variability appears to relate to the lipid status of the subjects. The exact nature of this new finding requires further study.

  2. Antibiotic-induced imbalances in gut microbiota aggravates cholesterol accumulation and liver injuries in rats fed a high-cholesterol diet. (United States)

    Hu, Xu; Wang, Tao; Liang, Shan; Li, Wei; Wu, Xiaoli; Jin, Feng


    Increasing evidence suggests that maintenance of homeostasis between gut microbiota and host plays an important role in human health. Many diseases, such as those affecting the liver, have been linked to imbalances in gut microbial communities. However, it is not clear whether an imbalance in gut microbiota promotes the onset of liver injury or if the imbalance results from the pathological state. In the current study, antibiotics were used to disturb the gut microbiota of both rats fed a high-cholesterol diet and rats fed a normal diet (controls). The prevalence of Bacteroidetes and Firmicutes were reduced, and Proteobacteria was greatly increased in the guts of rats after antibiotic treatment. The antibiotic-induced perturbation of gut microbiota aggravated cholesterol accumulation and liver injury in rats fed a high-cholesterol diet. This may have been due to an increase in intestinal permeability and plasma lipopolysaccharide (LPS), which lead to an increase in LPS absorption and activation of TLR4 signaling, resulting in the synthesis of pro-inflammatory cytokines and chemokines in liver tissues. This study suggests that imbalances in gut microbiota may be a predisposing factor for the onset of metabolic diseases and liver injuries related to cholesterol and high-cholesterol diets. Modulation of gut microbiota could be a novel target for preventing cholesterol-related metabolic disorders.

  3. Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension. (United States)

    Uschner, Frank E; Ranabhat, Ganesh; Choi, Steve S; Granzow, Michaela; Klein, Sabine; Schierwagen, Robert; Raskopf, Esther; Gautsch, Sebastian; van der Ven, Peter F M; Fürst, Dieter O; Strassburg, Christian P; Sauerbruch, Tilman; Diehl, Anna Mae; Trebicka, Jonel


    Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.

  4. A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor. (United States)

    Wu, A; Molteni, R; Ying, Z; Gomez-Pinilla, F


    We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.

  5. 论聚众犯强制猥亵、侮辱妇女罪的加重犯%Aggravated Offense of Mass Compulsory Indecent Woman Crime

    Institute of Scientific and Technical Information of China (English)



    聚众犯罪是刑法分则特别规定的一种犯罪,与共同犯罪存在交叉关系,共同犯罪的制刑规则不能适用于聚众犯罪。聚众犯罪的特点和刑法体系内的协调性特征决定了聚众犯强制猥亵、侮辱妇女罪的加重犯限于首要分子,积极参加者和一般参加者不包含在内。%Mass crime is specifically stipulated by specific provisions of criminal law, which is interrelated with the joint crime, but the rule of joint crime cannot apply to the mass crime absolutely. On the basis of the difference characteristics of mass crime and coordination between the crime and the punishment, the aggravated offense just applies to the ringleaders of compulsory indecent woman crime.


    de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; de la Fuente, Beatriz; Romero, Enrique


    Introducción: la variante Trp64Arg del receptor Beta ha sido relacionada con un aumento del peso corporal y resistencia a la insulina. Objetivo: el objetivo de nuestro estudio fue investigar la influencia del polimorfismo (rs 4994) del gen del receptor adrenérgico-Beta-3 en la respuesta metabólica y la pérdida de peso en un estudio de intervención a medio plazo con una dieta con alto contenido en proteínas/baja en carbohidratos vs una dieta hipocalórica estándar (1.000 kcal / día). Material y métodos: se evaluó una muestra de 284 sujetos obesos con un diseño de ensayo aleatorio. Se realizó una evaluación nutricional al inicio y al final de un período de 9 meses en el que los sujetos recibieron una de las dos dietas (dieta HP: alta en proteínas/baja en carbohidratos vs dieta S: dieta estándar). Resultados: no hubo diferencias significativas entre los efectos positivos (sobre el peso, el índice de masa corporal, la circunferencia de la cintura, la masa grasa, la presión arterial sistólica y los niveles de leptina) en los dos genotipos con ambas dietas. Con ambas dietas y solo en el genotipo salvaje (dieta HP vs dieta S), colesterol total (-10,1 ± 3,9 mg / dl vs -10,1 ± 2,2 mg / dl; p> 0,05), colesterol LDL (-9,5 ± 2,1 mg / dl vs -8,5 ± 2,3 mg / dl; p> 0,05) y los triglicéridos (-19,1 ± 2,1 mg / dl vs -14,3 ± 2,1 mg / dl; p> 0,05) disminuyeron. La mejoría de estos parámetros fue similar en sujetos con dieta HP vs dieta HS. Con la dieta HP y solo en el genotipo salvaje, los niveles de insulina (-3,7 ± 1,9 UI / L; p.

  7. Bottlenecks aggravate rising construction costs

    Energy Technology Data Exchange (ETDEWEB)



    Rising demand for power in developing countries combined with concerns about carbon emissions from coal-fired power plants in developed countries have created a bonanza for carbon-light technologies, including nuclear, renewables and natural gas plants. This, in turn, has put upward pressure on the price of natural gas in key markets while resulting in shortages in critical components for building renewables and nuclear reactors. Globalization of the power industry means that pressures in one segment or one region translate into shortages and rising prices everywhere else.

  8. Integrin Alpha-v and HER2 in Breast Cancer Brain Metastasis (United States)


    increases the amount of HER2 in lysosomes where it is broken down. Finally, we have new preliminary results showing that metastatic-prone: αv-integrin...aim 1 of the grant. Manuscript is in preparation. b. Effect of αv integrin on cell invasion and migration in vitro. The αv integrin knockdown clones...physically complex in cells. Knockdown of αv-integrin altered HER2 localization from its normal membrane position to a predominantly lysosomal localization

  9. Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.

    Directory of Open Access Journals (Sweden)

    Geertje van der Horst

    Full Text Available Low survival rates of metastatic cancers emphasize the need for a drug that can prevent and/or treat metastatic cancer. αv integrins are involved in essential processes for tumor growth and metastasis and targeting of αv integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of αv integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an αv integrin antagonist as well as knockdown of αv integrin in the bladder carcinoma cell lines, resulted in reduced malignancy in vitro, as illustrated by decreased proliferative, migratory and clonogenic capacity. The CDH1/CDH2 ratio increased, indicating a shift towards a more epithelial phenotype. This shift appeared to be associated with downregulation of EMT-inducing transcription factors including SNAI2. The expression levels of the self-renewal genes NANOG and BMI1 decreased as well as the number of cells with high Aldehyde Dehydrogenase activity. In addition, self-renewal ability decreased as measured with the urosphere assay. In line with these observations, knockdown or treatment of αv integrins resulted in decreased metastatic growth in preclinical in vivo models as assessed by bioluminescence imaging. In conclusion, we show that αv integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of αv integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer.

  10. Constitution of pseudobinary hypoeutectic beta-NiAl + alpha-V alloys (United States)

    Cotton, J. D.; Kaufman, M. J.; Noebe, R. D.


    The formation of pseudobinary eutectics between NiAl (beta) and V (alpha) at high temperatures was investigated as a possible way of improving the ductility and toughness of the alloy. It is found that a pseudobinary eutectic, characterized by a large beta+alpha field, is formed in the Ni-Al-V ternary system below about 1370 C. The high-temperature solubility of V in beta is about 14 percent, decreasing markedly with decreasing temperature and increasing Al content above 50 at. pct Al. The pseudobinary hypoeutectic exibits crack resistance under indentation loading.

  11. Impairment of insulin-stimulated Akt/GLUT4 signaling is associated with cardiac contractile dysfunction and aggravates I/R injury in STZ-diabetic Rats

    Directory of Open Access Journals (Sweden)

    Deng Jen-Ying


    Full Text Available Abstract In this study, we established systemic in-vivo evidence from molecular to organism level to explain how diabetes can aggravate myocardial ischemia-reperfusion (I/R injury and revealed the role of insulin signaling (with specific focus on Akt/GLUT4 signaling molecules. The myocardial I/R injury was induced by the left main coronary artery occlusion for 1 hr and then 3 hr reperfusion in control, streptozotocin (STZ-induced insulinopenic diabetes, and insulin-treated diabetic rats. The diabetic rats showed a significant decrease in heart rate, and a prolonged isovolumic relaxation (tau which lead to decrease in cardiac output (CO without changing total peripheral resistance (TPR. The phosphorylated Akt and glucose transporter 4 (GLUT 4 protein levels were dramatically reduced in both I/R and non-I/R diabetic rat hearts. Insulin treatment in diabetes showed improvement of contractile function as well as partially increased Akt phosphorylation and GLUT 4 protein levels. In the animals subjected to I/R, the mortality rates were 25%, 65%, and 33% in the control, diabetic, and insulin-treated diabetic group respectively. The I/R-induced arrhythmias and myocardial infarction did not differ significantly between the control and the diabetic groups. Consistent with its anti-hyperglycemic effects, insulin significantly reduced I/R-induced arrhythmias but had no effect on I/R-induced infarctions. Diabetic rat with I/R exhibited the worse hemodynamic outcome, which included systolic and diastolic dysfunctions. Insulin treatment only partially improved diastolic functions and elevated P-Akt and GLUT 4 protein levels. Our results indicate that cardiac contractile dysfunction caused by a defect in insulin-stimulated Akt/GLUT4 may be a major reason for the high mortality rate in I/R injured diabetic rats.

  12. Are droughts occurrence and severity aggravating? A study on SPI drought class transitions using loglinear models and ANOVA-like inference

    Directory of Open Access Journals (Sweden)

    E. E. Moreira


    Full Text Available Long time series (95 to 135 yr of the Standardized Precipitation Index (SPI computed with the 12-month time scale relative to 10 locations across Portugal were studied with the aim of investigating if drought frequency and severity are changing through time. Considering four drought severity classes, time series of drought class transitions were computed and later divided into 4 or 5 sub-periods according to length of time series. Drought class transitions were calculated to form a 2-dimensional contingency table for each period. Two-dimensional loglinear models were fitted to these contingency tables and an ANOVA-like inference was then performed in order to investigate differences relative to drought class transitions among those sub-periods, which were considered as treatments of only one factor. The application of ANOVA-like inference to these data allowed to compare the four or five sub-periods in terms of probabilities of transition between drought classes, which were used to detect a possible trend in time evolution of droughts frequency and severity that could be related to climate change. Results for a number of locations show some similarity between the first, third and fifth period (or the second and the fourth if there were only 4 sub-periods regarding the persistency of severe/extreme and sometimes moderate droughts. In global terms, results do not support the assumption of a trend for progressive aggravation of droughts occurrence during the last century, but rather suggest the existence of long duration cycles.

  13. GDNF pre-treatment aggravates neuronal cell loss in oxygen-glucose deprived hippocampal slice cultures: a possible effect of glutamate transporter up-regulation. (United States)

    Bonde, C; Sarup, A; Schousboe, A; Gegelashvili, G; Noraberg, J; Zimmer, J


    Besides its neurotrophic and neuroprotective effects on dopaminergic neurons and spinal motoneurons, glial cell line-derived neurotrophic factor (GDNF) has potent neuroprotective effects in cerebral ischemia. The protective effect has so far been related to reduced activation of N-methyl-D-aspartate receptors (NMDAr). This study tested the effects of GDNF on glutamate transporter expression, with the hypothesis that modulation of glutamate transporter activity would affect the outcome of cerebral ischemia. Organotypic hippocampal slice cultures, derived from 1-week-old rats, were treated with 100 ng/ml GDNF for either 2 or 5 days, followed by Western blot analysis of NMDAr subunit 1 (NR1) and two glutamate transporter subtypes, GLAST and GLT-1. After 5-day exposure to GDNF, expression of GLAST and GLT-1 was up-regulated to 169 and 181% of control values, respectively, whereas NR1 was down-regulated to 64% of control. However, despite these changes that potentially would support neuronal resistance to excitotoxicity, the long-term treatment with GDNF was found to aggravate the neuronal damage induced by oxygen-glucose deprivation (OGD). The increased cell death, assessed by propidium iodide (PI) uptake, occurred not only among the most susceptible CA1 pyramidal cells, but also in CA3 and fascia dentata. Given that glutamate transporters are able to release glutamate by reversed action during energy failure, it is suggested that the observed increase in OGD-induced cell death in the GDNF-pretreated cultures was caused by the build-up of excitotoxic concentrations of extracellular glutamate released through the glutamate transporters, which were up-regulated by GDNF. Although the extent and consequences of glutamate release via reversal of GLAST and GLT-1 transporters seem to vary in different energy failure models, the present findings should be taken into account in clinical trials of GDNF.

  14. Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation (United States)

    Gan, Qiong-Zhi; Sun, Xin-Yuan; Bhadja, Poonam; Yao, Xiu-Qiong; Ouyang, Jian-Ming


    Background Renal epithelial cell injury facilitates crystal adhesion to cell surface and serves as a key step in renal stone formation. However, the effects of cell injury on the adhesion of nano-calcium oxalate crystals and the nano-crystal-induced reinjury risk of injured cells remain unclear. Methods African green monkey renal epithelial (Vero) cells were injured with H2O2 to establish a cell injury model. Cell viability, superoxide dismutase (SOD) activity, malonaldehyde (MDA) content, propidium iodide staining, hematoxylin–eosin staining, reactive oxygen species production, and mitochondrial membrane potential (Δψm) were determined to examine cell injury during adhesion. Changes in the surface structure of H2O2-injured cells were assessed through atomic force microscopy. The altered expression of hyaluronan during adhesion was examined through laser scanning confocal microscopy. The adhesion of nano-calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) crystals to Vero cells was observed through scanning electron microscopy. Nano-COM and COD binding was quantitatively determined through inductively coupled plasma emission spectrometry. Results The expression of hyaluronan on the cell surface was increased during wound healing because of Vero cell injury. The structure and function of the cell membrane were also altered by cell injury; thus, nano-crystal adhesion occurred. The ability of nano-COM to adhere to the injured Vero cells was higher than that of nano-COD crystals. The cell viability, SOD activity, and Δψm decreased when nano-crystals attached to the cell surface. By contrast, the MDA content, reactive oxygen species production, and cell death rate increased. Conclusion Cell injury contributes to crystal adhesion to Vero cell surface. The attached nano-COM and COD crystals can aggravate Vero cell injury. As a consequence, crystal adhesion and aggregation are enhanced. These findings provide further insights into kidney stone

  15. 二至天癸颗粒对克罗米芬诱导排卵小鼠子宫内膜整合素β3表达的影响%Effect of Erzhi Tiangui Granule on the expression of endometrial beta3-integrin in the mice of induced ovulation with clomifene citrate

    Institute of Scientific and Technical Information of China (English)

    连方; 李婷婷; 孙振高


    Objective: To explore the effect of Erzhi Tiangui Granules (ETG) on the expression of endometrial beta3-integrin in mice of induced ovulation with clomifene citrate (CC).Methods: Forty Kunming female mice with ovulation failure were randomized into TCM group (treated with CC and ETG) and CC group (treated with CC only), while other 20 healthy mice of the same age were as normal controls.Their implantation rate on the fourth day of pregnancy (PD4) and the morphological changes of endometrium were observed, and the expression of endometrial beta3-integrin was detected by immunohistochemistry.Results: More mice had their oestrous cycle recovered in TCM group than in CC group (P<0.05).The endometrial morphological changes on PD4 in TCM group were significantly more suitable for implantation(P<0.05).The immunostaining scores of beta3-integrin in luminal epithelium, glandular epithelium and stroma of endometrium were all higher in TCM group than in CC group (P<0.05).The number of implanted blastocysts, implantation rate, and the expression of beta3-integrin in glandular epithelium and stroma in TCM group were comparable to those in normal controls (P>0.05), while expression of beta3integrin in luminal epithelium was lower in TCM group than in normal controls (P<0.05).The expressions of beta3-integrin in luminal and glandular epithelium were both higher than that in stroma in all three groups (P<0.05).Conclusions: ETG can help to restore the oestrous cycle and improve the expression of endometrial beta3-integrin and implantation rate in the mouse with ovulation failure.%目的 探讨二至天癸颗粒对克罗米芬(CC)诱导排卵小鼠子宫内膜整合素β3表达的影响.方法 40只生育期排卵障碍模型小鼠分中药组及CC组两组,每组20只,中药组予二至天癸颗粒加CC,CC组单纯予CC,20只非模型鼠为空白组.观察三组胚泡着床率、子宫内膜形态学变化,并采用免疫组化方法测定子宫内膜整合素β3的表

  16. Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun-Jung, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Kim, Jun Won, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Yoo, Hyun, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Kwak, Woori, E-mail: [Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 151-747 (Korea, Republic of); Choi, Won Hoon, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Cho, Seoae, E-mail: [C& K Genomics, Seoul National University Mt.4-2, Main Bldg. #514, SNU Research Park, NakSeoungDae, Gwanakgu, Seoul 151-919 (Korea, Republic of); Choi, Yu Jeong, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Lee, Yoon-Jin, E-mail: [Division of Radiation Effects, Research Center for Radiotherapy, Korea Institute of Radiological & Medical Sciences, Seoul 139-760 (Korea, Republic of); Cho, Jaeho, E-mail: [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)


    We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm{sup 2} fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C–C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin. - Highlights: • Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33. • Vascular endothelial cells damaged by high-dose radiation secrete IL-33. • Blocking IL-33 suppressed migration of inflammatory cells and cytokine secretion. • IL

  17. Social Factors to Aggravate Disasters in Yunnan in Late Imperial China%清末民初云南灾荒加剧的社会因素

    Institute of Scientific and Technical Information of China (English)



    云南的自然环境极具灾害性。明清以降至清末民初,由于人口急速膨胀、农田过度开垦和山林矿藏的掠夺式开发,云南生态环境迅速恶化,进而加速加剧了各类自然灾害的发生;农业与家庭手工业相结合的自然经济又从根本上限制了社会抗灾减荒能力的生成与提高。封建剥削、战乱兵祸及列强的经济掠夺、迷信赌毒等造成社会环境的全面恶化,各族民众极度贫困,加重了灾后饥荒疾疫的蔓延与流行。中央与地方政府的荒政长久缺失,导致云南赈灾救荒活动严重乏力。总之,清末民初的云南已完全陷入人为破坏生态环境加剧自然灾害频发、逢灾必荒的结果加速了社会环境的恶化、社会环境恶化又加重了饥荒的蔓延这一恶性循环过程。%Yunnan is prone to natural disasters due to its environment. From the Ming and Qing dynasties to late imperial China, population explosion, over-farming, predatory exploitation of forests and minerals, and ecological damages aggravated all kinds of natural disasters in Yunnan on one hand, and on the other hand, natural economy of agriculture and household handicrafts weakened the power of society to prevent and reduce disasters. Feudal exploitation, government's taxes, wars, bandits, economic plunder of imperialists, superstition, gambling and drugs deteriorated social environment, and extreme poverty of ethnic people speeded.up the wide spread of famine and epidemic after disasters. Neither the central government nor the local governments made policies to deal with natural disasters. As a result, disaster relief in Yunnan was seriously weak. All in all, Yunnan in late imperial China was ecological damages leading to frequent natural disasters which totally stuck into a vicious circle of man-made then would deteriorate social environment, and which in turn would result in prolonged famines.

  18. Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation

    Directory of Open Access Journals (Sweden)

    Gan QZ


    , and cell death rate increased.Conclusion: Cell injury contributes to crystal adhesion to Vero cell surface. The attached nano-COM and COD crystals can aggravate Vero cell injury. As a consequence, crystal adhesion and aggregation are enhanced. These findings provide further insights into kidney stone formation. Keywords: nano-calcium oxalate crystals, cell injury, crystal adhesion, kidney stones

  19. The in-vivo use of superparamagnetic iron oxide nanoparticles to detect inflammation elicits a cytokine response but does not aggravate experimental arthritis.

    Directory of Open Access Journals (Sweden)

    Eline A Vermeij

    -term effects were evident for gene expression, histology or serum cytokine concentrations.Injection of SPION, either locally or systemically, gives an acute inflammatory response. In the long term, up to 14 days after the injection, while the SPION reside in the joint, no further activating effects of SPION were observed. Hence, we conclude that SPION do not aggravate arthritis and can therefore be used safely to detect joint inflammation by MR imaging.

  20. 探讨慢性肺源性心脏病急性加重期的临床护理对策%Clinical nursing countermeasure of chronic cor pulmonale with acute aggravating period

    Institute of Scientific and Technical Information of China (English)



    目的:应用全面护理模式对急性加重期慢性肺源性心脏病患者实施的护理效果进行研究。方法选择在我院就诊的急性加重期慢性肺源性心脏病患者82例,随机分为对照组和观察组,各41例。对照组采用常规护理模式;观察组采用全面护理模式。结果观察组患者对慢性肺源性心脏病急性加重期护理模式的满意度明显高于对照组;治疗时间明显短于对照组。结论应用全面护理模式对急性加重期慢性肺源性心脏病患者实施的护理效果非常明显。%Objective To apply the comprehensive nursing mode on condition of patients with acute aggravating period of chronic cor pulmonale implementation of nursing clinical effect were studied. Methods In the condition of our hospital in 82 patients with acute aggravating period of chronic cor pulmonale patients, randomly divided into control group and observation group, an average of 41 cases in each group. The conventional nursing care model to control the implementation of nursing;Observation group to implement the comprehensive nursing pattern on the nursing care. Results The observation group of patients of chronic cor pulmonale with acute aggravating period of the nursing mode satisfaction is signiifcantly higher than control group;Cor pulmonale clinical treatment time signiifcantly shorter than the control group.Conclusion Comprehensive nursing model was applied to the illness of patients with acute aggravating period of chronic cor pulmonale implementation of nursing clinical effect is very obvious.

  1. Aggravated unbundling in German energy industry (part 1). Basics: EU acceleration directive and economic monopoly theory; Verschaerftes Unbundling in der deutschen Energiewirtschaft (Teil 1). Grundlagen: EG-Beschleunigungsnovellen und volkswirtschaftliche Monopoltheorie

    Energy Technology Data Exchange (ETDEWEB)

    Wiedmann, K.P. [Hannover Univ. (Germany); Langerfeldt, M. [Lueneburg Univ. (Germany)


    The main innovations of the so-called acceleration directive are clearly aggravated regulations for divestiture of vertically integrated enterprises. This difficulty commonly known as unbundling is the topic of this two-part article. Part 1 reviews the process of European legislation. The unbundling regulations of the current and future laws are then presented systematically against the economic background. A microeconomic assessment of the regulations will follow in part 2. [German] Zu den wichtigsten Neuerungen der sog. Beschleunigungsrichtlinien zaehlen deutlich verschaerfte Entflechtungsregelungen fuer vertikal integrierte Versorger. Die gemeinhin mit dem Stichwort 'Unbundling' bezeichnete Problematik ist Gegenstand des vorliegenden zweiteiligen Beitrags. Der 1. Teil blickt kurz zurueck auf das Verfahren der europaeischen Rechtsetzung. Anschliessend werden die Unbundling-Vorschriften des bestehenden und des zukuenftigen Rechts systematisch im Spiegel ihres volkswirtschaftlichen Hintergrunds vorgestellt. Eine betriebswirtschaftliche Bewertung der Neuerungen folgt in Teil 2. (orig.)

  2. Research on Strategy of Foreign Trade Enterprises in Guangxi Based on the Aggravation of European Debt Crisis%欧债危机加剧下广西外贸企业对策探讨

    Institute of Scientific and Technical Information of China (English)



      The global economic, financial and trade situations deteriorate sharply with the European debt crisis erupting, spreading and upgrading. China's foreign trade is impacted tremendously and the development of foreign trade enterprises in Guangxi will inevitably be affected. In the paper, the aggravation of the European debt crisis is described. Its adverse effects on the development of foreign trade enterprises in Guangxi are analyzed through several aspects of the transmission mechanism in external demand, exchange rate fluctuations, exchange risk and trade frictions. And the development strategies coping with aggravation of the European debt crisis are proposed.%  欧债危机的爆发、蔓延和加剧,使全球经济、金融、贸易形势急剧恶化,我国外贸经济遭受巨大冲击,广西外贸企业的发展也不可避免地受到影响。文章就欧债危机加剧的态势,通过其外部需求、汇率变动、汇兑风险和贸易摩擦等几方面的传导机制,分析了欧债危机对广西对外贸易发展的不利影响,并相应地提出了外贸企业应对欧债危机日益加剧的策略。

  3. Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade. (United States)

    El-Gowelli, Hanan M; Saad, Evan I; Abdel-Galil, Abdel-Galil A; Ibrahim, Einas R


    In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients.

  4. 慢性耳鸣急性加重时的听阈改变及其对耳鸣预后的影响%Acute aggravation of chronic tinnitus: a study of the hearing characteristic and prognosis

    Institute of Scientific and Technical Information of China (English)

    曾祥丽; 王树芳; 黎志成; 岑锦添; 李源


    目的 探讨慢性耳鸣急性加重时患者的听阈改变及其对耳鸣预后的影响.方法 对32例在习服治疗过程中出现耳鸣急性加重的患者进行纯音听阈、声导抗、耳声发射、听性脑干反应、耳蜗电图及甘油试验等听力学检测,对新出现听阈提高者在习服治疗的同时,按照突发性聋方案治疗.对照组75例仅接受习服治疗.分析慢性耳鸣急性加重时的听阈改变,以及耳鸣加重组与对照组在习服治疗的第3、6、9、12个月时的耳鸣代偿情况.结果 慢性耳鸣急性加重时,出现3种类型的局部频率听阈提高:①既往为4~8 kHz高频下降型听力曲线,耳鸣加重时,相邻的中频区1~2个频率(含半倍频)听阈提高;②既往中频区单个频率听力损失,耳鸣加重时,紧邻的中频区新增单个频率听阈提高,听力曲线由锯齿型转变为凹槽型;③低频听力波动型,慢性耳鸣急性加重时,125~1000 Hz平均听阈较既往提高10~30 dB,而高频区听阈无改变.按照突发性聋方案治疗后,随着新出现听力损伤的恢复,25例随之实现耳鸣代偿.耳鸣加重组与对照组在习服治疗的第3、6、9个月,代偿率差异无统计学意义(X2值分别为0.005、0.005、2.587,P值均>0.05),12个月时,耳鸣加重组代偿率明显高于对照组,差异有统计学意义(X2=0.108,P<0.05).结论 慢性耳鸣急性加重时,出现了不同形式的局部频率听力损失,对新出现听力损失及时有效的治疗,在挽救听力的同时,加速了耳鸣的代偿.%Objective To ivestigate the hearing change when chronic tinnitus acute aggravated and the affect of prognosis due to hearing change. Methods The pure tone threshold and acoustic immittance were used for every case in the acute aggravation of chronic tinnitus(AACT)group, and for some of AACT group members the auditory brainstem response (ABR), distort-product otoacoustic emission (DPOAE), electrocochleogram (EcochG), glycerin test and

  5. A rare aggravation of severe mucositis post chemotherapy in a child with acute lymphoblastic leukemia [v1; ref status: indexed,

    Directory of Open Access Journals (Sweden)

    Adlette Inati


    Full Text Available Oral mucositis is a debilitating manifestation in children undergoing chemotherapy and radiotherapy. Children with mucositis should be properly managed in order to prevent further exacerbation and adverse complications. We hereby present the first report of a severe chemotherapy-induced mucositis, plausibly aggravated by improper dental hygiene leading to shedding of the ventral part of the tongue in a child with pre-B acute lymphoblastic leukemia (ALL. The patient steadily and gradually recovered her oral maneuvers and ability to speak several months later. Her tongue underwent hypertrophy as a compensatory mechanism. We recommend that critical and regular assessment of the oral mucosa and proper dental care and oral hygiene be emphasized in all pediatric patients receiving chemotherapy. Families of affected children need to be educated about the benefits and modes of optimal oral hygiene for their children and the need to seek immediate care for mouth pain and or lesions. Optimal treatment for mucositis needs to be instituted without delay in this high risk pediatric population. Such a preventive and therapeutic approach may prevent associated life threatening oral and systemic complications, promote rapid and complete mucosal healing, alleviate pain and improve quality of life in children with cancer.

  6. 高通量测序探讨胰腺炎加重肝损伤的研究%Through high-throughput sequencing technologies to explore the mechanism of pancreatitis aggravating liver damage

    Institute of Scientific and Technical Information of China (English)

    王谦; 白槟; 赵占伟; 余鹏飞; 郝一鸣; 邱兆岩; 郭敏; 冯全新; 刘朝旭


    目的 探讨急性胰腺炎(AP)加重肝脏损伤的机制.方法 将SD大鼠随机分为AP组和对照组(NC),采用牛磺胆酸钠逆行胰胆管注射的方法建立AP模型,造模后6h经下腔静脉采血,检测血清淀粉酶、脂肪酶水平、胰腺水含量,同时收集肝脏组织,用于提取RNA.通过转录组测序(RNA-seq)的方法分析AP加重肝损害的相关基因和通路改变.结果 AP组与NC组比,其血清淀粉酶[(8 964.65 ±401.23) U/L]和脂肪酶[(2350.00 ±201.90) U/L]含量明显上升(P<0.05);胰腺水含量AP组[(79.42±1.21)%]显著高于NC组[(70.14±1.02)%];RNA-seq结果显示两组间共有2 249个差异表达基因,其中564个表达上调,1 685个表达下调.京都基因与基因组百科全书(KEGG)通路富集结果由高到低为代谢通路、炎性因子通路、趋化因子通路、Toll样受体通路等.结论 AP可能通过炎性因子、Toll样受体(TLR)等通路介导了对肝脏的损伤.%Objective To explore the mechanism of acute pancrea titis (AP) aggravating liver damage.Methods SD rats were randomly divided into negative control (NC) and AP group.We use the method of sodium taurocholate retrograde pancreatic duct injection to establish the model of AP.After 6 h of anesthesia,the blood were collected from the inferior vena cava to detect the levels of serum amylase and lipase.The liver tissue was collected imnediately in order to extract total RNA.The genes and related pathways were analyzed by RNA-seq.Results Compared to NC group,the levels of serum amylase [(8 964.65 ±401.23) U/L] and lipase [(2 350.00 ± 201.90) U/L] were significantly higher in AP group (P <0.05);the pancreatic water content in AP group [(79.42 ± 1.21) %] were significantly higher than NC group [(70.14 ± 1.02) %];RNA-seq results showed that there were 2249 differently expressed genes between AP and NC group,among which 564 genes were up-regulated and 1685 genes were down-regulated.Kyoto gene and genome encyclopedia (KEGG

  7. Exposure to multi-walled carbon nanotubes results in aggravation of airway inflammation and remodeling and in increased production of epithelium-derived innate cytokines in a mouse model of asthma. (United States)

    Ronzani, Carole; Casset, Anne; Pons, Françoise


    With the development of nanotechnologies, the potential adverse effects of nanomaterials such as multi-walled carbon nanotubes (MWCNT) on the respiratory tract of asthmatics are questioned. Furthermore, investigations are necessary to understand how these effects might arise. In the present study, we hypothesized that epithelium-derived innate cytokines that are considered as important promoting factors in allergy may contribute to an aggravating effect of MWCNT on asthma. We investigated in the mouse the effect of MWCNT on systemic immune response and airway inflammation and remodeling induced by the most frequent allergen so far associated with asthma, house dust mite (HDM), and we examined the production of the innate cytokines thymic stromal lymphopoietin (TSLP), IL-25, IL-33, and GM-CSF. Mice exposed to HDM exhibited specific IgG1 in serum and inflammatory cell infiltration, and increased Th2 cytokine production, mucus hyperproduction, and collagen deposition in the airways when compared to naïve animals. Levels of total IgG1 and HDM-specific IgG1, influx of macrophages, eosinophils and neutrophils, production of collagen, TGF-β1, and mucus, as well as levels of IL-13, eotaxin, and TARC, were dose-dependently increased in mice exposed to HDM and MWCNT compared to HDM alone. These effects were associated with an increased production of TSLP, IL-25, IL-33, and GM-CSF in the airways. Our data demonstrate that MWCNT increase in a dose-dependent manner systemic immune response, as well as airway allergic inflammation and remodeling induced by HDM in the mouse. Our data suggest also a role for airway epithelium and innate cytokines in these effects.

  8. The correlation analysis between environmental factors, bone morphogenetic protein-4 and transforming growth factor beta-3 polymorphisms in nonsyndromic cleft lip with or without cleft palate%BMP4、TGF-β3基因多态性与环境暴露在非综合征性唇腭裂发生中的交互作用

    Institute of Scientific and Technical Information of China (English)

    林健燕; 栾荣生; 郭泽强; 林新勤; 汤洪洋; 陈苑萍


    目的 探讨环境暴露因素、骨形态生成蛋白4(BMP4)基因、转化生长因子β3(transforming growth factor beta-3,TGF-β3)基因之间的交互作用在非综合征性唇腭裂(nonsyndromic cleft lip and cleft palate,NSCLP)发生中的可能作用.方法 通过问卷调查获取环境暴露资料.用聚合酶链反应(PCR)-限制性片段长度多态性(restriction fragment length polymorphism,RFLP)技术对对照组(200例)和NSCLP组(200例)各基因位点的多态性进行检测.采用多因子降维法(multifactor djmensionality reduction,MDR)分析基因之间、基因与环境之间的交互作用关系,并对筛选的交互作用关系用Logistic回归进行验证.结果 BMP4 T538C、TGF-β3 C641A和TGF-β3G15572-三个单核苷酸多态性(single nucleotide polymorphism,SNP)位点间的交互作用与NSCLP的发生无关联.基因与环境交互作用分析发现,BMP4 T538C与母亲妊娠早期被动吸烟、母亲妊娠早期感染史对NSCLP的发生具有交互作用;TGF-β3G15572-与母亲妊娠早期被动吸烟、母亲妊娠早期感染史、父亲知晓妊娠前吸烟、父亲知晓妊娠前饮酒、母亲妊娠早期补充维生素对NSCLP的发生具有交互作用.经Logistic回归验证,结果一致.结论 NSCLP是基因与环境因素共同作用的结果,易感基因多态性影响着个体对环境因素的反应,研究它们之间的相互关系对阐明NSCLP的病因及发病机制具有重要意义.%Objective To investigate the effects of interactions among environmental factors, bone morphogenetic protein-4 ( BMP4 ) and transforming growth factor beta-3 ( TGF-β3 ) polymorphisms on nonsyndromic cleft lip and cleft palate (NSCLP) . MethodsThe data of environmental exposures were collected with questionnaires.Genotypes were determined with techniques of polymerase chain reactionrestriction fragment length polymorphism. Interactions between genes, environmental factors and NSCLP were analyzed using multifactor dimensionality

  9. Hyperbaric oxygen therapy aggravates liver reperfusion injury in rats Oxigenoterapia hiperbárica agrava lesão de reperfusão hepática em ratos

    Directory of Open Access Journals (Sweden)

    Cristiano Xavier Lima


    Full Text Available PURPOSE: To evaluate the effects of hyperbaric oxygen (HO therapy in the protection against liver ischemia/reperfusion injury. METHODS: Thirty-two male Wistar rats were divided into four groups of eight animals each: group A - laparotomy and liver manipulation, group B - liver ischemia and reperfusion, group C - HO pretreatment for 60 min followed by liver ischemia and reperfusion, and group D - pretreatment with ambient air at 2.5 absolute atmospheres for 60 min followed by liver ischemia and reperfusion. Plasma was assayed for aspartate aminotransferase (AST, alanine aminotransferase (ALT and lactate dehydrogenase (LDH. Intra-arterial blood pressure was monitored continuously. Myeloperoxidase activity in the liver and lung was assessed 30 min after reperfusion. RESULTS: Plasma AST, ALT and LDH increased after reperfusion in all animals. Plasma ALT values and myeloperoxidase activity in the liver parenchyma were higher in HO-pretreated animals than in groups A, B and D. HO had a negative hemodynamic effect during liver reperfusion. CONCLUSION: Liver preconditioning with hyperbaric oxygen therapy aggravated liver ischemia/reperfusion injury in rats as demonstrated by plasma ALT and liver myeloperoxidase activity.OBJETIVO: Avaliar os efeitos da oxigenoterapia hiperbárica (OH como método preventivo da lesão de isquemia e reperfusão (LIR do fígado. MÉTODOS: Trinta e dois ratos machos Wistar foram distribuídos em quatro grupos de oito animais cada: A - laparotomia e manipulação hepática, B - isquemia e reperfusão hepática, C - pré-tratamento com OH por 60 minutos seguido de isquemia e reperfusão hepática e D - pré-tratamento com ar ambiente a 2,5 atmosferas absolutas por 60 minuto e isquemia e reperfusão hepática. Dosagens seriadas de AST, ALT e DHL foram realizadas. A pressão intra arterial foi monitorizada continuamente. O grau de infiltração leucocitária no fígado e pulmões foi inferido pela dosagem de mieloperoxidade

  10. 氧化应激 DNA 损伤在重症肺炎中的作用研究%Key factor of pneumonia′s occurrence and aggravation:oxidative stress-DNA damage

    Institute of Scientific and Technical Information of China (English)

    杨小琼; 李国平; 王孝芸; 戴曦; 王媛媛; 陈媛媛; 谢桃; 伍娟


    was significantly negative correlation with ROS average fluorescent intensity(r =-0.847,P <0.01)、ROS average optical density(r =-0.952,P <0.01) respectively.Conclusions ①There existes oxidative stress in airway tissue and peripheral blood of pneumonia patients;oxidation/anti-oxidation imbalance;oxidative stress takes part in cells DNA damage.②Oxidative stress-DNA damage may be one of the important reasons of pneumonia′s occurrence and aggravation.%目的:研究肺炎患者机体中氧化应激程度、抗氧化能力及其细胞 DNA 损伤情况的相应改变,探讨氧化应激-DNA 损伤在肺炎中可能发生的作用。方法收集2011年6月至2012年3月泸州医学院附属医院呼吸内科住院部肺炎患者67例(肺炎组35例,重症肺炎组32例),招募32名健康志愿者作为正常对照组。对其中3名志愿者及3例肺炎组患者分别行经纤维支气管镜气道组织钳取活检观察气道组织氧化应激及炎症细胞浸润情况,对剩余64例患者及32名志愿者分别行无菌静脉取血2 ml,分离外周血单个核细胞(peripheral blood mononuclear cell,PBMC)测定各组细胞氧化应激程度,DNA 损伤情况,留取血清测定各组抗氧化水平。结果①肺炎组支气管气道组织炎症细胞浸润明显多于正常对照组;②肺炎组支气管气道组织 ROS 红色荧光强度明显强于正常对照组;③肺炎组、重症肺炎组细胞 ROS 平均荧光强度均高于正常对照组,分别为3.308±0.240、6.628±0.349、1.505±0.352(P <0.01);肺炎组、重症肺炎组细胞 ROS 平均光密度值均高于正常对照组,分别为0.913±0.065、1.260±0.023、0.390±0.031(P <0.01);④肺炎组、重症肺炎组细胞平均拖尾长度均高于正常对照组,分别为6.783±5.015、30.363±7.436、0.095±0.123(P <0.05);⑤肺炎组、重症肺炎组血清 SOD 平均光密度值均低于正常对照组,分别为0.225±0.030、0.159±0.033、0.456±0.024(P <0.01)。人外周血单个核细

  11. Th17细胞在慢性乙型肝炎及其重症化中的变化%The changes of Th17 cells in the pathogenesis and aggravation of chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    杨波; 赵彩彦; 王亚东; 车宏浩; 阎文昭; 赵萌


    Objective To explore the changes of Th17 cells in the pathogenesis and aggravation of chronic hepatitis B (CHB).Methods Thirty-two CHB patients,44 hepatitis B virus (HBV)related acute-on-chronic liver [ailure (ACLF) patients and 20 healthy controls (HC) were involved in our research. The frequencies of circulating Th17 cells were detected by flow cyrometry. The interleukin 17 (IL-17) mRNA expressions in the peripheral blood mononuclear cells (PBMC) were detected by quantitative real-time polymerase chain reaction (PCR).Immunohistochemical staining was performed to determine the expressions of IL-17+ cells in the liver tissues.The serum IL-17 concentrations were detected by enzyme-linked immunosorhent assay (ELISA),and the dynamic changes in ACLF patients with different prognosis were also observed.Normal distribution data were used by analysis of variance and non-normal distribution data were used by Kruskal-Wallis H test or Mann-Whitney U test.Results In CHB,ACLF and healthy control groups,Th17 cells frequencies in PBMC were (1.47 ± 0.60) %,(3.20 ± 1.08) % and (0.86 ± 0.43) %,respectively ; IL-17 mRNA were 4.32±11.77,18.32±8.21 and 1.00,respectively; IL-17+ cells in the liver tissues were (10.6±4.8),(21.1±6.6) and (0.5±0.2)/high power field; the level of IL-17 in serum were (15.88±6.51),(35.03±11.54) and (10.04±4.06) ng/L,respectively (all P<0.05).Moreover,the frequencies of circulating Th17 cells and the levels of serum IL-17 in medium-stage and end-stage ACLF patients were higher than that in early-stage ACLF patients (both P < 0.01). In ACLF patients,the circulating Th17 cells frequencies were positively correlated with international normalized ratio (INR,r=0.44,P<0.01) and model of end-stage liver disease (MELD) score (r=0.44,P<0.01).And the frequencies of circulating Th17 cells were positively associated with the serum alanine transaminase (ALT) levels in CHB patients (r=0.51,P<0.01).Moreover,the survival ACLF patients had an

  12. Interaction of alphaVbeta3 and alphaVbeta6 integrins with human parechovirus 1. (United States)

    Seitsonen, Jani; Susi, Petri; Heikkilä, Outi; Sinkovits, Robert S; Laurinmäki, Pasi; Hyypiä, Timo; Butcher, Sarah J


    Human parechovirus (HPEV) infections are very common in early childhood and can be severe in neonates. It has been shown that integrins are important for cellular infectivity of HPEV1 through experiments using peptide blocking assays and function-blocking antibodies to alpha(V) integrins. The interaction of HPEV1 with alpha(V) integrins is presumably mediated by a C-terminal RGD motif in the capsid protein VP1. We characterized the binding of integrins alpha(V)beta(3) and alpha(V)beta(6) to HPEV1 by biochemical and structural studies. We showed that although HPEV1 bound efficiently to immobilized integrins, alpha(V)beta(6) bound more efficiently than alpha(V)beta(3) to immobilized HPEV1. Moreover, soluble alpha(V)beta(6), but not alpha(V)beta(3), blocked HPEV1 cellular infectivity, indicating that it is a high-affinity receptor for HPEV1. We also showed that HPEV1 binding to integrins in vitro could be partially blocked by RGD peptides. Using electron cryo-microscopy and image reconstruction, we showed that HPEV1 has the typical T=1 (pseudo T=3) organization of a picornavirus. Complexes of HPEV1 and integrins indicated that both integrin footprints reside between the 5-fold and 3-fold symmetry axes. This result does not match the RGD position predicted from the coxsackievirus A9 X-ray structure but is consistent with the predicted location of this motif in the shorter C terminus found in HPEV1. This first structural characterization of a parechovirus indicates that the differences in receptor binding are due to the amino acid differences in the integrins rather than to significantly different viral footprints.

  13. Clinical Study on Whether Cold-aggravated Joint Pain Is the Key Indicator to Cold Bi in the Syndrome Differentiation of Rheumatoid Arthritis%关节遇冷痛增是否类风湿关节炎中医证候寒痹关键指标的临床研究

    Institute of Scientific and Technical Information of China (English)

    张子扬; 娄玉钤


    Objective:To investigate whether cold-aggravated joint pain is the key indicator to cold bi in the syndrome differentiation of rheumatoid arthritis.Methods:Four hundred cases with Rheumatoid Arthritis from the HFRA Database of the Henan Rheumatism Hospital were divided into a cold-aggravated group and a control group.SPSS 19.0 was used to analyze the difference and relationship on the aspects of joint and extra articular manifestations of the 2 groups.Results:In the clustering analysis result 3 of the cold-aggravated group,heat manifestations such as heat pain,dry mouth,dry throat,bitter taste of mouth and dry nose appeared. This analysis was not carried out for the control group since it was not suitable.After the X2 test for 82 joints and extra articular manifestations,cold manifestations such as aggravation due to coldness,cold pain,aversion to cold,cold limbs and hot drink preference appeared more frequently in the cold-aggravated group than the control group,the difference between them being signiifcant(P< 0.05).In the cold-aggravated group,294 cases had heat manifestations:151 cases(51.36%)with dry mouth,122 cases(36.75%)with dreaminess,103 cases(35.03%) with bitter taste of mouth,87 cases(29.59%) with yellow urine,78 cases(26.53%)with burning sensation of five centres,77 cases (26.19%)with dry throat,57(19.39%)cases with heat pain,33 cases(11.22%)with hot drink preference,and 32 cases with sore throat(10.88%).In the control group,115 cases had cold manifestations:61 cases(53.04%) with aversion to coldness,38 cases(33.04%)with aversion to coldness and cold limbs,23 Cases(20%)with hot drink preference,21 cases(18.26%)with cold limbs,and 15 cases(4.35%)with cold diarrhea.Conclusion:The increase of pain due to coldness cannot be seen as a key indicator for arthritis rheumatoid.%目的:探讨关节遇冷痛增是否是类风湿关节炎中医证候寒痹的关键指标。方法:将河南风湿病医院RA数据库(HFRA数据库)中收录的409例RA患者

  14. Alpha-v Integrin Targeted PET Imaging of Breast Cancer Angiogenesis and Low-Dose Metronomic Anti-Angiogenic Chemotherapy Efficacy (United States)


    reversed-phase high-performance liquid chro- matography (RP-HPLC) on a Dionex 680 chromatography system with a UVD 170U absorbance detector. After...Burt HM, Von Hoff D, Dexter D, Mangold G, Degen D, et al. An investigation of the antitumor activity and biodistribution of polymeric micellar ...addi- tion of N,N-diisopropylethylamine. The labeled peptide was puri- fied by reversed-phase high-performance liquid chromatography on a

  15. Alpha-V Integrin Targeted PET Imagining of Breast Cancer Angiogenesis and Lose-Dose Metronomic Anti-Angiogenic Chemotherapy Efficacy (United States)


    Arthritis Rheum . 50, 2459--65. 593 527 combination of many factors, including, but not limited, (10) Mahmood U., and Weissleder, R. (2003) Near...ymethyl cellulose (CMC) (Aldrich, Milwaukee, WI) in cent-injected close per gram (%ID/g) was determined for water mixture within a stainless steel mold ...The mold each sample. For each mouse, radioactivity of the tissue was placed in the dry ice and isopropyl alcohol bath for samples was calibrated

  16. Closed headpiece of integrin [alpah]IIb[beta]3 and its complex with an [alpha]IIb[beta]3-specific antagonist that does not induce opening

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jieqing; Zhu, Jianghai; Negri, Ana; Provasi, Davide; Filizola, Marta; Coller, Barry S.; Springer, Timothy A. (Sinai); (Rockefeller); (CH-Boston)


    The platelet integrin {alpha}{sub IIb}{beta}{sub 3} is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the {alpha}{sub IIb}{beta}{sub 3} headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the {alpha}{sub IIb}{beta}{sub 3} headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the {alpha}{sub IIb} subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, {alpha}{sub IIb} Y190 and {alpha}{sub aIIb} D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce {alpha}{sub IIb}{beta}{sub 3} to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.

  17. Exclusion of the phosphatidylinositol-specific phospholipase C beta 3 (PLC beta 3) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene

    NARCIS (Netherlands)

    de Wit, M J; Landsvater, R M; Sinke, R J; Geurts van Kessel, A; Lips, C J; Höppener, J W


    Multiple endocrine neoplasia type 1 (MEN 1) is inherited as an autosomal dominant disorder, characterized by hyperplasia and neoplasia in several endocrine organs. The MEN 1 gene, which is most probably a tumor suppressor gene, has been localized to a 900-kb region on chromosome 11q13. The human pho

  18. 高压喷射氧雾化吸入沐舒坦对慢性阻塞性肺疾病急性加重期痰液性状的影响%The Effects of Ambroxol Mucosolvan Inhalated by High-pressure Jet Oxygen Atomization to Sputum Properties in Patients with Chronic Obstructive Pulmonary Disease During Acute Aggravating Period

    Institute of Scientific and Technical Information of China (English)

    杨玉平; 周向东


    Objective To observe the effects of Ambroxol mucosolvan inhalated by High-pressure jet oxygen atomization to the physical and chemical properties of sputum in patients with chronic obstructive pulmonary disease during acute aggravating period. Method 72 cases of COPD patients with acute aggravating period to give an easy high-pressure jet oxygen atomization inhalation,bathing separately col ected before detect atomization,1 hours after atomization sputum volume,wet/dry weight and viscosity. Results After oxygen atomization,oxygen atomization before amount of sputum,sputum viscosity,sputum dry/wet weight had significant dif erence (p<0.05), and inflammatory biomarkers of neutrophil (PMN) combined with elastic enzyme membrane(HLE) has no obvious change. Conclusion High-pressure jet oxygen atomization inhalation of Ambroxol mucosolvan with dilute sputum and increased sputum volume effect,so as to ease of airway obstruction caused by high mucus secretion,relieve the patient's clinical symptoms,but the inhibition effect of the inflammatory response in the airways of has yet to be further research.%目的:观察高压喷射氧雾化吸入沐舒坦对慢性阻塞性肺疾病(COPD)急性加重期患者痰液理化性质的作用。方法72例COPD急性加重期患者给予沐舒坦高压喷射氧雾化吸入,分别收集检测雾化前、雾化后1h痰液量、干/湿重及黏度。结果氧雾化前与雾化后的痰液量、痰液黏度、痰液干/湿重均有明显差异(P<0.05)。而炎症指标中性粒细胞(PMN)膜结合弹力酶(HLE)无明显改变。结论高压喷射氧雾化吸入沐舒坦有稀释痰液、增加排痰量的作用。从而缓解黏液高分泌所致的气道阻塞、减轻患者的临床症状,但抑制气道炎症反应的作用尚无明确证据。

  19. Does Population Ageing Aggravate Income Inequality? Evidence from China 1996 -2009%人口老龄化是否加剧收入不平等?——基于中国(1996~2009)的实证研究

    Institute of Scientific and Technical Information of China (English)

    董志强; 魏下海; 汤灿晴


    Since inequality differs cross population groups, changing population age structure may have an effect on overall income inequality. This paper develops an analytical (statistical) model to describe conditions under which population ageing could aggravate income inequality, and show theoretically and empirically that the conditions are true in China. Thus, it is hypothesized that population ageing aggravates inequality in China. With Gini coefficient as measurement of income inequality, and employing provincial level panel data over 1996 -2009, this paper confirms that population ageing (i. e. an increasing aged dependency ratio and a decreasing child dependency ratio) is a positive and significant factor contributing to income inequality. This suggests that inequality studies need to incorporate population ageing, as it conveys different policy implications as compared to other factors.%不同年龄群体内部的收入程度通常存在差异,因而人口年龄结构变迁会影响整个经济的收入不平等程度。文章建立了一个(统计性)分析框架,刻画出老龄化导致收入不平等加剧的条件,并从经济理论和经验证据上说明该条件在中国成立,从而提出假说:中国的老龄化加剧了经济中的收入不平等。运用1996—2009年省级面板数据,以基尼系数衡量收入不平等,从经验上证实老龄化(老年抚养比上升和少儿抚养比下降)对我国收入不平等有显著的正向影响。这一结论表明,研究收入不平等问题时,应注意老龄化这一长期被研究者们忽视的因素,因为它蕴含着与其他因素大不相同的政策含义。

  20. Residential characteristics aggravating infestation by Culex quinquefasciatus in a region of Northeastern Brazil Características agravantes por infestación residencial de Culex quinquefasciatus, en una región del Noreste de Brasil Características agravantes por infestação residencial de Culex quinquefasciatus, em Olinda, PE

    Directory of Open Access Journals (Sweden)

    Juliana Cavalcanti Correia


    Full Text Available OBJECTIVE: Analyse how basic sanitation conditions, water supply and housing conditions affect the concentration of Culex quinquefasciatus METHODS: Populations of C. quinquefasciatus in 61 houses in the municipality of Olinda, PE, were monitored between October 2009 and October 2010. Observations were carried out in homes without the presence of preferred breeding sites in order to identify characteristics that may be aggravating factors for the development of the mosquito. Five aggravating factors were analysed: vegetation cover surrounding the home, number of residents/home, water storage, sewage drainage and water drainage. These characteristics were analysed in terms of presence or absence and as indicators of the degree of infestation, which was estimated through monitoring the concentration of eggs (oviposition traps - BR-OVT and adults (CDC light traps. RESULTS: Sewage drainage to a rudimentary septic tank or to the open air was the most frequent aggravating factor in the homes (91.8%, although the presence of vegetation was the only characteristic that significantly influenced the increase in the number of egg rafts (p = 0.02. The BR-OVT achieved positive results in 95.1% of the evaluations, with the presence of at least one egg raft per month. A total of 2,366 adults were caught, with a mosquito/room/night ratio of 32.9. No significant difference was found in the number of mosquitoes caught in the homes. CONCLUSIONS: Although the sanitation and water supply influence the population density of C. quinquefasciatus, residence features that are not usually considered in control measures can be aggravating factors in sustaining the mosquito population.OBJETIVO: Analizar como las condiciones de saneamiento básico, abastecimiento de agua y habitaciones afectan la densidad de Culex quinquefasciatus MÉTODOS: se monitoreó la población de C. quinquefasciatus en 61 residencias del municipio de Olinda, PE, Brasil, de octubre de 2009 a octubre de

  1. RGD-conjugated mesoporous silica-encapsulated gold nanorods enhance the sensitization of triple-negative breast cancer to megavoltage radiation therapy

    Directory of Open Access Journals (Sweden)

    Zhao N


    Full Text Available Ning Zhao,1,2,* Zhangru Yang,2,3,* Bingxin Li,2 Jin Meng,2 Zeliang Shi,2 Ping Li,4 Shen Fu4 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Radiation Oncology, 6th People’s Hospital of Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Multifunctional nanoprobes have great potential as effective radiosensitizers and drug carriers. RGD-modified gold nanorods could increase the uptake of nanoparticles via receptor-mediated endocytosis in integrin alphaV beta3-overexpressing breast cancer cells, which could enhance the effects of radiation on tumor cells, leading to further radiosensitization. The purpose of our study was to demonstrate that RGD-conjugated mesoporous silica-encapsulated gold nanorods significantly enhanced the sensitization of triple-negative breast cancer to megavoltage energy. The results indicated that RGD-conjugated mesoporous silica-encapsulated gold nanorod multifunctional nanoprobes could achieve radiosensitization in vitro and in vivo, which suggests the potential translation of this nanotechnology to clinical applications in tumor-targeting and selective therapy. Keywords: gold nanorods, triple-negative breast cancer, Arg-Gly-Asp peptides, integrin alphaV beta3, megavoltage radiation therapy

  2. Aggregation without the Aggravation? Nonparametric Analysis of the Representative Consumer

    NARCIS (Netherlands)

    Cherchye, L.J.H.; Crawford, I.; de Rock, B.; Vermeulen, F.M.P.


    Abstract: In the tradition of Afriat (1967), Diewert (1973) and Varian (1982), we provide a revealed preference characterisation of the representative consumer. Our results are simple and complement those of Gorman (1953, 1961), Samuelson (1956) and others. They can also be applied to data very read

  3. Inflammation aggravates disease severity in Marfan syndrome patients.

    Directory of Open Access Journals (Sweden)

    Teodora Radonic

    Full Text Available BACKGROUND: Marfan syndrome (MFS is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far. METHODOLOGY/PRINCIPAL FINDINGS: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml, when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6, 95% CI: 70-159 pg/ml. Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR = 0%, ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC = 1.8; 1.4; 1.5, FDR = 0% and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%. Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02 and increased number of CD8+ T-cells (p = 0.003 in the adventitia of the MFS patients. CONCLUSION/SIGNIFICANCE: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

  4. Arteriovenous fistulas aggravate the hemodynamic effect of vein bypass stenoses

    DEFF Research Database (Denmark)

    Nielsen, T G; Djurhuus, C; Pedersen, Erik Morre;


    PURPOSE: The purpose of this study was to assess the impact of arteriovenous fistulas combined with varying degrees of stenosis on distal bypass hemodynamics and Doppler spectral parameters. METHODS: In an in vitro flow model bypass stenoses causing 30%, 55%, and 70% diameter reduction were induced...... 10 cm upstream of a fistula with low outflow resistance. Flow and intraluminal pressure were measured proximal to the stenosis and downstream of the fistula. The waveform parameters peak systolic velocity, end-diastolic velocity, pulsatility index, and pulse rise time were determined from midstream...... Doppler spectra obtained 10 cm downstream of the fistula. All measurements were carried out with open and clamped fistula. RESULTS: At 30% diameter reducing stenosis opening of the fistula induced a 12% systolic pressure drop across the stenosis but had no adverse effect on the Doppler waveform parameters...

  5. TLR2 deficiency aggravates lung injury caused by mechanical ventilation

    NARCIS (Netherlands)

    Kuipers, Maria Theresa; Jongsma, Geartsje; Hegeman, Maria A; Tuip-de Boer, Anita M; Wolthuis, Esther K; Choi, Goda; Bresser, Paul; van der Poll, Tom; Schultz, Marcus J; Wieland, Catharina W


    Innate immunity pathways are found to play an important role in ventilator-induced lung injury. We analyzed pulmonary expression of Toll-like receptor 2 (TLR2) in humans and mice and determined the role of TLR2 in the pathogenesis of ventilator-induced lung injury in mice. Toll-like receptor 2 gene

  6. PP005. Vitamin D depletion aggravates hypertension in transgenic rats

    DEFF Research Database (Denmark)

    Bjørkholt Andersen, Louise; Herse, Florian; Christesen, Henrik Thybo


    overexpressing the human renin and angiotensinogen genes, group 1 (n=18) received vitamin D depleted chow; group 2 (n=15) standard chow and intraperitoneal paricalcitol at 800ng/kg thrice weekly; and group 3 (n=15) standard chow and vehicle injections. Blood pressure (tail cuff) and 24-h albuminuria were...... determined once weekly. After three weeks, animals were sacrificed. Heart tissue was examined for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by RT-PCR. RESULTS: The vitamin D depleted group had higher blood pressure at week 1 (mean difference 23.4mmHg, 95% CI 9.1-37.7) and tended...... to have higher blood pressure in weeks 2 and 3 (mean difference 14.3mmHg 95% CI -0.02-28.7 and 15.2mmHg 95% CI -1.5-33). The depletion group had higher heart-to-body weight ratio, and a trend towards higher ANP and BNP levels. The group receiving paricalcitol did not perform better. No differences were...

  7. Migraine: etiology, risk, triggering, aggravating factors and clinical manifestations

    Directory of Open Access Journals (Sweden)

    Natalia Lindemann Carezzato


    Full Text Available This study aimed to identify the etiology and clinical manifestations of migraine. An integrative literature review was performed guided by the question: What is the evidence available in the literature about the etiology, signs and symptoms of migraine? The article search was conducted in the electronic databases PubMed and LILACS, considering publications in the period from 2006 to 2010. The selected articles were categorized and evaluated according to the level of evidence. One found 1,677 articles and 26 were selected for full reading. Most studies (84.6% consisted of a non-experimental design and were classified as evidence level IV. Although the clinical manifestations found in this study confirm the data available in the literature, it is noticed that migraine does not have well-established causes

  8. Chronic kidney disease aggravates arteriovenous fistula damage in rats. (United States)

    Langer, Stephan; Kokozidou, Maria; Heiss, Christian; Kranz, Jennifer; Kessler, Tina; Paulus, Niklas; Krüger, Thilo; Jacobs, Michael J; Lente, Christina; Koeppel, Thomas A


    Neointimal hyperplasia (NIH) and impaired dilatation are important contributors to arteriovenous fistula (AVF) failure. It is unclear whether chronic kidney disease (CKD) itself causes adverse remodeling in arterialized veins. Here we determined if CKD specifically triggers adverse effects on vascular remodeling and assessed whether these changes affect the function of AVFs. For this purpose, we used rats on a normal diet or on an adenine-rich diet to induce CKD and created a fistula between the right femoral artery and vein. Fistula maturation was followed noninvasively by high-resolution ultrasound (US), and groups of rats were killed on 42 and 84 days after surgery for histological and immunohistochemical analyses of the AVFs and contralateral femoral vessels. In vivo US and ex vivo morphometric analyses confirmed a significant increase in NIH in the AVFs of both groups with CKD compared to those receiving a normal diet. Furthermore, we found using histological evaluation of the fistula veins in the rats with CKD that the media shrank and their calcification increased significantly. Afferent artery dilatation was significantly impaired in CKD and the downstream fistula vein had delayed dilation after surgery. These changes were accompanied by significantly increased peak systolic velocity at the site of the anastomosis, implying stenosis. Thus, CKD triggers adverse effects on vascular remodeling in AVFs, all of which contribute to anatomical and/or functional stenosis.

  9. Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

    NARCIS (Netherlands)

    Radonic, Teodora; de Witte, Piet; Groenink, Maarten; de Waard, Vivian; Lutter, Rene; van Eijk, Marco; Jansen, Marnix; Timmermans, Janneke; Kempers, Marlies; Scholte, Arthur J.; Hilhorst-Hofstee, Yvonne; van den Berg, Maarten P.; van Tintelen, J. Peter; Pals, Gerard; Baars, Marieke J. H.; Mulder, Barbara J. M.; Zwinderman, Aeilko H.


    Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-beta signaling. However, the contribution of tissue inflammation is not ad

  10. Public Administration Efficiency and the Aggravation of Public Health Issues

    Directory of Open Access Journals (Sweden)

    Vladimir Aleksandrovich Ilyin


    Full Text Available December 3, 2015, the President of Russia Vladimir Putin delivered his annual Address to the Federal Assembly. Having analyzed the Address, experts pointed out the President’s worries and concerns about the efficiency of execution of development priorities he had set out. Vladimir Putin repeatedly urged the Government to implement effective measures on specific issues in the shortest time possible. However, it has not been done so far; therefore, we think that the President’s concern is reasonable. Recent research carried out by ISEDT RAS reveals certain alarming trends in the social health of the regional society

  11. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Patrizia Pessina


    Full Text Available Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD, skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  12. Lack of Galanin 3 Receptor Aggravates Murine Autoimmune Arthritis. (United States)

    Botz, Bálint; Kemény, Ágnes; Brunner, Susanne M; Locker, Felix; Csepregi, Janka; Mócsai, Attila; Pintér, Erika; McDougall, Jason J; Kofler, Barbara; Helyes, Zsuzsanna


    Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells. However, since there are minimal in vivo data on the role of GAL3 in joint diseases, we analyzed its involvement in different inflammatory mechanisms of the K/BxN serum transfer-model of autoimmune arthritis employing GAL 3 gene-deficient mice. After arthritis induction, GAL3 knockouts demonstrated increased clinical disease severity and earlier hindlimb edema than wild types. Vascular hyperpermeability determined by in vivo fluorescence imaging was also elevated compared to the wild-type controls. However, neutrophil accumulation detected by in vivo luminescence imaging or arthritic mechanical hyperalgesia was not altered by the lack of the GAL3 receptor. Our findings suggest that GAL3 has anti-inflammatory properties in joints by inhibiting vascular hyperpermeability and consequent edema formation.

  13. Seawater Immersion Aggravates Burn Injury Causing Severe Blood Coagulation Dysfunction



    This study aimed to investigate the endothelial function in a canine model of burn injury combined with seawater immersion. The model of burn injury was established. The dogs were randomly divided into four groups including dogs with burn injury (B group), or burn injury combined with seawater immersion (BI group), or only immersion in seawater (I group), or control animals with no injury or immersion (C group). The circulating endothelial cell (CEC) count and coagulation-fibrinolysis paramet...

  14. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy. (United States)

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura


    Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  15. Some necessary criminalist methods for the investigation of aggravated murders

    Directory of Open Access Journals (Sweden)

    Valon Brahimi


    Full Text Available Crime is a negative, complex and dynamic occurrence that fits to the social changes. So in order to fight the crime and prevent it in society, it is very important to know some social disciplines which clearly help to understand the aim of this phenomenon. To reach this aim we must use different techniques which are based on the proceedings pair. The investigations are based on the scene, witnesses, police, criminalist experts, medicine, processes and the treatment of cases in the most correct form through a structure of investigation.

  16. NaCl胁迫加重强光胁迫下超大甜椒叶片的光系统Ⅱ和光系统Ⅰ的光抑制%NaCl stress aggravates photoinhibition of photosystem Ⅱ and photosystem Ⅰ in Capsicum annuum leaves under high irradiance stress

    Institute of Scientific and Technical Information of China (English)

    宋旭丽; 胡春梅; 孟静静; 侯喜林; 何启伟; 李新国


    快速叶绿素荧光动力学可以在无损情况下探知叶片光合机构的损伤程度,快速叶绿素荧光测定和分析技术(JIP-test)将测量值转化为多种具有生物学意义的参数,因而被广泛应用于植物光合机构对环境的响应机制研究.该文研究了超大甜椒(Capsicum annuum)幼苗在强光及不同NaCl浓度胁迫下的荧光响应情况.与单纯强光胁迫相比,NaCl胁迫引起了叶绿素荧光诱导曲线的明显改变,光系统Ⅱ(PSⅡ)光抑制加重,同时PSⅡ反应中心和受体侧受到明显影响,而且高NaCl浓度胁迫下PSⅡ供体侧受伤害明显,同时PSⅠ反应中心活性(P700+)在盐胁迫下明显降低.这些结果表明,NaCl胁迫会增强强光对超大甜椒光系统的光抑制,并且浓度越高抑制越明显,但对PSⅠ的抑制作用低于PSⅡ.高NaCl浓度胁迫易对PSⅡ供体侧造成破坏,且PSⅠ光抑制严重.%Aims Our aim was to study effects of salt stress and high irradiance on photoinhibition of photosystem Ⅱ (PSⅡ)and Ⅰ (PSⅠ) in leaves of sweet pepper (Capsicum annuum).Methods We used the chlorophyll a fluorescence technique and the JIP-test to study the responses of sweet pepper leaves to salt stress with different NaCl concentrations and under high irradiance (1 000 μmol.m-2·s-l).Important findings The chlorophyll a fluorescence induction curves changed greatly as induced by NaCI stress under high irradiance, and photoinhibition of PSⅡ was aggravated with apparent effects on PSⅡ reaction centers and the acceptor side. Also, the donor side of PSⅡ was damaged by high NaCl concentration under high irradiance. Additionally, the activity of PSⅠ reaction centers (P700+) was inhibited by NaCl stress under high irradiance.Therefore, NaCl stress could aggravate photoinhibition of sweet pepper photosystem under high irradiance, and photoinhibition was greater with higher NaCl concentration. However, PSI photoinhibition was less than PSⅡ photoinhibition

  17. Clinical Observation of Chronic Obstructive Pulmonary Disease at Acute Aggravation Stage Treated with Yiqi Huoxue Formula%益气活血方治疗急性加重期慢性阻塞性肺疾病临床观察

    Institute of Scientific and Technical Information of China (English)



    目的 观察益气活血方治疗急性加重期慢性阻塞性肺疾病(COPD)的临床疗效.方法 首先将符合诊断标准的患者分为男、女两组,每组60例,按照入组时间先后顺序,男、女两组中单号入治疗组,双号入对照组.对照组60例,采用吸氧联合西药治疗;治疗组60例,在对照组治疗基础上加用益气活血方治疗.两组均以治疗2周为1个疗程,比较两组治疗前后第一秒用力呼气容积占预计值百分比(FEV1%),并评价中医症状积分,判定疗效.结果 治疗后治疗组中医症状积分为(6.3± 5.3)分,对照组中医症状积分为(9.8±7.2)分,两组比较,差异有统计学意义(P<0.05);治疗组有效27例,对照组有效15例,两组比较,差异有统计学意义(P<0.01).结论 益气活血方治疗急性加重期慢性阻塞性肺疾病,针对病因病机,结合患者多为老年人的特点,遣方用药,取得了良好的临床疗效.%Objective To observe the clinical efficacy of yiqi huoxue formula on chronic obslruclive pulmonary disease ( COPD) at acute aggravation stage. Methods The palienls who were complied with the diagnostic criteria were divided into a male group and a female group, 60 cases in each one. In accordance with the inclusive sequence, of the cases in male group and female group, those with single number in the sequence were classified into a trial group and those with double number were into a control group. 60 cases in control group were treated with oxygen combined with western medicine therapy. 60 cases in trial group were treated with yiqi huoxue formula supplemented on the basis of the treatment as control group. The cases in either group were treated for 2 weeks as 1 session. The forced expiration volume in one second/predicted value (FEV1%)was compared before and after treatment between two groups. The symptom score of traditional Chinese medicine ( TCM ) and the efficacy were assessed. Results After treatment, the symptom score of TCM was(6

  18. Rotavirus enterotoxin NSP4 binds to the extracellular matrix proteins laminin-beta3 and fibronectin.

    NARCIS (Netherlands)

    J.A. Boshuizen; J.W. Rossen (John); C.K. Sitaram; F.F.P. Kimenai; Y. Simons-Oosterhuis (Ytje); C. Laffeber; H.A. Büller (Hans); A.W.C. Einerhand (Sandra)


    textabstractRotavirus is the most important cause of viral gastroenteritis and dehydrating diarrhea in young children. Rotavirus nonstructural protein 4 (NSP4) is an enterotoxin that was identified as an important agent in symptomatic rotavirus infection. To identify cellular prote

  19. Rotavirus enterotoxin NSP4 binds to the extracellular matrix proteins laminin-beta3 and fibronectin

    NARCIS (Netherlands)

    Boshuizen, J A; Rossen, J W A; Sitaram, C K; Kimenai, F F P; Simons-Oosterhuis, Y; Laffeber, C; Büller, H A; Einerhand, A W C


    Rotavirus is the most important cause of viral gastroenteritis and dehydrating diarrhea in young children. Rotavirus nonstructural protein 4 (NSP4) is an enterotoxin that was identified as an important agent in symptomatic rotavirus infection. To identify cellular proteins that interact with NSP4, a

  20. A macroporous bioreactor super activated by the recombinant human transforming growth factor-beta 3

    Directory of Open Access Journals (Sweden)

    Ugo eRipamonti


    Full Text Available Macroporous single-phase hydroxyapatite (HA and biphasic HA/β-tricalcium phosphate with 33% post-sinter hydroxyapatite (HA/β-TCP were combined with 25 or 125 µg recombinant human transforming growth factor-β3 (hTGF-β3 to engineer a super activated bioreactor implanted in orthotopic calvarial and heterotopic rectus abdominis muscle sites and harvested on day 30 and 90. Coral-derived calcium carbonate fully converted (100% and partially converted to 5% and 13% hydroxyapatite/calcium carbonate (HA/CC preloaded with 125 and 250 µg hTGF-β3, and 1:5 and 5:1 binary applications of hTGF-β3: hOP-1 by weight, were implanted in the rectus abdominis and harvested on day 20 and 30, respectively, to monitor spatial/temporal morphogenesis by high doses of hTGF-β3. Bone formation was assessed on decalcified paraffin-embedded sections by measuring the fractional volume of newly-formed bone. On day 30 and 90, single phase HA implants showed greater amounts of bone when compared to biphasic specimens; 5 % and 13 % HA/CC pre-loaded with 125 and 250 µg hTGF-β3 showed substantial induction of bone formation; 250 µg hTGF-β3 induced as yet unreported massive induction of bone formation as early as 20 days prominently outside the profile of the macroporous constructs. The induction of bone formation is controlled by the implanted ratio of the recombinant morphogens, i.e. the 1:5 hTGF-β3:hOP-1 ratio by weight was greater than the inverse ratio. The unprecedented tissue induction by single doses of 250 µg hTGF-β3 resulting in rapid bone morphogenesis of vast mineralized ossicles with multiple trabeculations surfaced by contiguous secreting osteoblasts is the novel molecular and morphological frontier for the induction of bone formation in clinical contexts.

  1. Sizeable beta-strength in 31Ar (beta 3p) decay

    DEFF Research Database (Denmark)

    T. Koldste, G.; Blank, B.; J. G. Borge, M.


    We present for the first time precise spectroscopic information on the recently discovered decay mode beta-delayed 3p-emission. The detection of the 3p events gives an increased sensitivity to the high energy part of the Gamow-Teller strength distribution from the decay of 31Ar revealing that as ...

  2. Perspectives on mirabegron in the treatment of overactive bladder syndrome: A new beta-3 adrenoceptor agonist

    Directory of Open Access Journals (Sweden)

    Chia-Hao Kuei


    Full Text Available Mirabegron, the first β3-adrenoceptor agonist introduced for use in clinical practice, differs from antimuscarinic agents in terms of mechanism of action. This review discusses various perspectives on mirabegron in terms of efficacy, mechanism of action, pharmacokinetics, safety, and tolerability for overactive bladder syndrome in studies conducted thus far. Mirabegron administered at daily doses of 25 mg, 50 mg, and 100 mg demonstrated significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition as early as the first assessment, and these were maintained throughout the treatment course. Mirabegron seemed well tolerated. The most common adverse events observed with mirabegron in clinical trials were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to that with placebo, between 3- and 5-fold lower than with 4 mg tolterodine extended release. Considering that dry mouth is the most bothersome adverse event associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients. The benefit of mirabegron (at doses of 50 mg and 100 mg was also evident in elderly patients and in both treatment-naive patients and those who previously discontinued antimuscarinic therapy. Mirabegron can also be used in combination with antimuscarinics or in addition to alpha blockers. Mirabegron may quickly become a standard treatment of overactive bladder syndrome.

  3. Transforming growth factor Beta 3 is required for excisional wound repair in vivo.

    Directory of Open Access Journals (Sweden)

    Mark Le

    Full Text Available Wound healing is a complex process that relies on proper levels of cytokines and growth factors to successfully repair the tissue. Of particular interest are the members of the transforming growth factor family. There are three TGF-ß isoforms-TGF- ß 1, 2, and 3, each isoform showing a unique expression pattern, suggesting that they each play a distinct function during development and repair. Previous studies reported an exclusive role for TGF-ß 3 in orofacial development and a potent anti-scarring effect. However, the role of TGF- ß 3 in excisional wound healing and keratinocyte migration remains poorly understood. We tested the effect of TGF-ß 3 levels on excisional cutaneous wounds in the adult mouse by directly injecting recombinant TGF-ß 3 or neutralizing antibody against TGF-ß 3 (NAB in the wounds. Our results demonstrate that TGF-ß 3 does not promote epithelialization. However, TGF-ß 3 is necessary for wound closure as wounds injected with neutralizing antibody against TGF-ß 3 showed increased epidermal volume and proliferation in conjunction with a delay in keratinocyte migration. Wild type keratinocytes treated with NAB and Tgfb3-deficient keratinocytes closed an in vitro scratch wound with no delay, suggesting that our in vivo observations likely result from a paracrine effect.

  4. Dystroglycans and laminin 'BETA' 3 features on the prostate of mdx mice


    Leslie Cristina Pinto


    Resumo: A distroglicana (DG) é uma importante proteína estrutural a qual está envolvida no desenvolvimento celular epitelial, formação de membrana basal e manutenção da integridade de diferentes tecidos. Estudos indicaram que a alteração na expressão da DG é um evento freqüente nas malignecências humanas e sugerem que esta molécula tem um papel importante no desenvolvimento de tumor. No câncer de próstata, verificou-se expressiva redução das distroglicanas, especialmente da _-DG, acarre...

  5. 黄褐斑病因、加重因素及对生活质量影响的横断面研究%Etiology and aggravating factors of melasma and its influence on quality of life: a cross-sectional study

    Institute of Scientific and Technical Information of China (English)

    王辉; 郭丽芳; 葛一平; 吴余乐; 吴秋菊; 张孟丽; 王千秋; 林彤


    Objective To investigate the etiology,aggravating factors of melasma and its influence on quality of life in patients.Methods Demographic,behavioral and clinical data were collected from 166 female patients with melasma through a questionnaire survey.Melasma area severity index (MASI),dermatology life quality index (DLQI) and melasma quality of life scale (MELA-SQOL) were calculated.Multiple linear regression analysis was carried out to identify factors influencing melasma severity and quality of life in patients.Results Of the 166 patients,55 (33.13%) had a history of pregnancy within 1 year before the occurrence of melasma,and 8 (4.82%) had a history of sun exposure within 1 month before it.The MASI,DLQI and MELA-SQOL scores were 5.99 ± 4.01,4.34 ± 4.41 and 30.54 ± 17.91 in these patients respectively.Multiple linear regression analysis showed that the MELA-SQOL score significantly decreased with age (β =-0.220,t =2.874,P< 0.05),but increased with deepening of skin color (β =0.217,t =2.827,P< 0.05).Moreover,the MASI score significantly increased with age among premenopausal patients with melasma (β =0.244,t =3.387,P =0.001),and higher in patients with Fitzpatrick skin type Ⅳ than in those with Fitzpatrick skin type Ⅲ (β =0.322,t =4.615,P < 0.001).Conclusions The occurrence of melasma is associated with fluctuation of hormone levels and sun exposure.The darker the lesion color and the younger the age,the greater the impact on the quality of life in patients with melasma.Melasma is more severe in patients with Fitzpatrick skin type Ⅳ than in those with Fitzpatrick skin type Ⅲ,and seems to exacerbate with age among premenopausal patients.%目的 研究黄褐斑患者的病因、加重因素及对生活质量的影响.方法 通过问卷形式收集166例女性黄褐斑患者的人口学资料、行为学资料、临床资料,并计算黄褐斑面积及严重程度评分(MASI)、皮肤病生活质量评分(DLQI)、黄褐斑生活质量评

  6. The electroconvulsive shock can aggravate the cognitive impairment of the depression model rats though up-regulate the hyperphosphorylation of protein tau%电休克通过上调tau蛋白过度磷酸化程度加重抑郁模型大鼠认知障碍

    Institute of Scientific and Technical Information of China (English)

    陈安; 刘鸿章; 刘超


    indicate that the electroconvulsive shock reduce the impairment of learning-memory in depressed rats by aggravating the hyperphosphorylation of tau protein and up-regulating the content of glutamate.%目的 观察不同电量和不同时程电休克(ECT)对嗅球切除抑郁模型大鼠海马ECT后认知能力的变化.方法 建立大鼠嗅球切除抑郁模型,采用随机单位组3×3析因设计:将每只大鼠视为1个单位,对每个单位施加2个处理因素,即电流(25、50、75 mA)和时程(3次、6次、9次ECT)的所有组合(共9组,n=6).电休克结束24 h内行Morris水迷宫、高效液相色谱法测谷氨酸(Glu)在海马组织中含量,Western blot法测磷酸化tau蛋白(p-AT8Ser202)、糖原合成酶激酶-3β(GSK-3β1H8)表达.结果 随ECT电流加大,延长逃避潜伏期并缩短空间探索时间,随ECT时程延长,延长逃避潜伏期缩短空间探索时间,75 mA且行9次ECT组逃避潜伏期最长[(100.51±6.64)s]、空间探索时间最短[(10.02±1.20)s].随ECT电流加大,Glu浓度增加,随ECT时程延长,Glu浓度增加,75 mA且行9次ECT组Glu浓度最高[(184.39±20.86)μmol/gprot].随ECT电流加大,目标蛋白表达增加,随ECT时程延长,目标蛋白表达增加,75 mA且行9次ECT组目标蛋白表达最高(p-AT8Ser202:1771.50 ±278.26;GSK-3β1H8:1747.13±162.23).结论 ECT导致海马Glu浓度升高,加剧海马tau蛋白的磷酸化程度,诱发认知障碍.

  7. Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide (United States)

    Dijkgraaf, Ingrid; Terry, Samantha; McBride, William J.; Goldenberg, David M.; Laverman, Peter; Franssen, Gerben M.; Oyen, Wim J. G.; Boerman, Otto C.


    Integrin αvβ3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αvβ3, but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of 18F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with 18F in a simple one-pot process with a radiolabeling yield of 20%; the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with 18F at a specific activity of 1.8 MBq/nmol and a radiochemical purity of 100% could be achieved. Log P value of 18F-labeled NODAGA-E-[c(RGDfK)]2 was −4.26 ± 0.02. In biodistribution studies, 18F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 %ID/g in the blood at 2 h p.i., mainly via the kidneys and showed good in vivo stability. Tumor uptake of 18F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID/g, 2 h p.i.) was significantly lower than that of reference compounds 68Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID/g; P <0.001) and 111In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID/g; P < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with 18F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID/g). The αvβ3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with 18F-labeled NODAGA-E-[c(RGDfK)]2. In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with 18F using a direct aqueous, one-pot method and it accumulated specifically in αvβ3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET. PMID:23606427

  8. PC02 Beta3-adrenoceptor agonist-induced relaxation of human placental arteries is reduced in pregnancy-induced hypertension

    Institute of Scientific and Technical Information of China (English)



    AIM: Preeclampsia is one of the leading causes of neonatal and maternal morbidity and mortality. The purpose of this study is to investigate the functionality of β2- and 133-adrenoreceptors(β-ARs) in human placental arteries and to assess the influence of pregnancy-induced hypertension on β-ARs responsiveness.METHODS: We performed in vitro functional and biochemical studies as well as RT-PCR experiments. RESULTS: SR59119

  9. Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout. (United States)

    Fatima, Tahzeeb; Altaf, Sara; Phipps-Green, Amanda; Topless, Ruth; Flynn, Tanya J; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R


    The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.

  10. Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling.

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    Full Text Available Nebivolol, third-generation β-blocker, may activate β3-adrenergic receptor (AR, which has been emerged as a novel and potential therapeutic targets for cardiovascular diseases. However, it is not known whether nebivolol administration plays a cardioprotective effect against myocardial infarction (MI injury. Therefore, the present study was designed to clarify the effects of nebivolol on MI injury and to elucidate the underlying mechanism. MI model was constructed by left anterior descending (LAD artery ligation. Nebivolol, β3-AR antagonist (SR59230A, Nitro-L-arginine methylester (L-NAME or vehicle was administered for 4 weeks after MI operation. Cardiac function was monitored by echocardiography. Moreover, the fibrosis and the apoptosis of myocardium were assessed by Masson's trichrome stain and TUNEL assay respectively 4 weeks after MI. Nebivolol administration reduced scar area by 68% compared with MI group (p<0.05. Meanwhile, nebivolol also decreased the myocardial apoptosis and improved the heart function after MI (p<0.05 vs. MI. These effects were associated with increased β3-AR expression. Moreover, nebivolol treatment significantly increased the phosphorylation of endothelial NOS (eNOS and the expression of neuronal NOS (nNOS. Conversely, the cardiac protective effects of nebivolol were abolished by SR and L-NAME. These results indicate that nebivolol protects against MI injury. Furthermore, the cardioprotective effects of nebivolol may be mediated by β3-AR-eNOS/nNOS pathway.

  11. $\\beta$3$p$-spectroscopy and proton-$\\gamma$ width determination in the decay of $^{31}$Ar

    CERN Multimedia

    We propose to perform a detailed study of the $\\beta$-decay of the dripline nucleus $^{31}$Ar. This will allow a detailed study of the $\\beta$-delayed 3$p$-decay as well as provide important information on the resonances of $^{30}$S and $^{29}$P, in particular the ratio between the $p$- and $\\gamma$- partial widths relevant for astrophysics.

  12. Staphylococcus epidermidis serine--aspartate repeat protein G (SdrG) binds to osteoblast integrin alpha V beta 3. (United States)

    Claro, T; Kavanagh, N; Foster, T J; O'Brien, F J; Kerrigan, S W


    Staphylococcus epidermidis is the leading etiologic agent of orthopaedic implant infection. Contamination of the implanted device during insertion allows bacteria gain entry into the sterile bone environment leading to condition known as osteomyelitis. Osteomyelitis is characterised by weakened bones associated with progressive bone loss. The mechanism through which S. epidermidis interacts with bone cells to cause osteomyelitis is poorly understood. We demonstrate here that S. epidermidis can bind to osteoblasts in the absence of matrix proteins. S. epidermidis strains lacking the cell wall protein SdrG had a significantly reduced ability to bind to osteoblasts. Consistent with this, expression of SdrG in Lactococcus lactis resulted in significantly increased binding to the osteoblasts. Protein analysis identified that SdrG contains a potential integrin recognition motif. αVβ3 is a major integrin expressed on osteoblasts and typically recognises RGD motifs in its ligands. Our results demonstrate that S. epidermidis binds to recombinant purified αVβ3, and that a mutant lacking SdrG failed to bind. Blocking αVβ3 on osteoblasts significantly reduced binding to S. epidermidis. These studies are the first to identify a mechanism through which S. epidermidis binds to osteoblasts and potentially offers a mechanism through which implant infection caused by S. epidermidis leads to osteomyelitis.

  13. MVL-PLA2, a snake venom phospholipase A2, inhibits angiogenesis through an increase in microtubule dynamics and disorganization of focal adhesions.

    Directory of Open Access Journals (Sweden)

    Amine Bazaa

    Full Text Available Integrins are essential protagonists of the complex multi-step process of angiogenesis that has now become a major target for the development of anticancer therapies. We recently reported and characterized that MVL-PLA2, a novel phospholipase A2 from Macrovipera lebetina venom, exhibited anti-integrin activity. In this study, we show that MVL-PLA2 also displays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular-endothelial cells (HMEC-1 in a dose-dependent manner without being cytotoxic. Using Matrigel and chick chorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesis both in vitro and in vivo. We have also found that the actin cytoskeleton and the distribution of alphav beta3 integrin, a critical regulator of angiogenesis and a major component of focal adhesions, were disturbed after MVL-PLA2 treatment. In order to further investigate the mechanism of action of this protein on endothelial cells, we analyzed the dynamic instability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubule dynamicity in HMEC-1 cells by 40%. We propose that the enhancement of microtubule dynamics may explain the alterations in the formation of focal adhesions, leading to inhibition of cell adhesion and migration.

  14. A dominant negative mutant of rab5 inhibits infection of cells by foot-and-mouth disease virus; implications for virus entry

    DEFF Research Database (Denmark)

    Johns, Helen; Berryman, Stephen; Monaghan, Paul;


    is also dependent on clathrin-mediate endocytosis and an acidic pH within endosomes. Also, the effect on FMDV infection of dominant-negative (DN) mutants of cellular rab proteins that regulate endosomal traffic was examined. Expression of DN rab5 reduced the number of FMDV-infected cells by 80%, while......Foot-and-mouth disease virus (FMDV) can use a number of different integrins (alphavβ1, alphavβ3, alphavβ6, and alphavβ8) as receptors to initiate infection. Infection mediated by alphavβ6 is known to occur by clathrin-mediated endocytosis and is dependent on the acidic pH within endosomes...

  15. Of Malthus and Methuselah: does longevity treatment aggravate global catastrophic risks? (United States)

    Jebari, Karim


    Global catastrophic risk is a term that refers to the risk of the occurrence of an event that kills at least millions of people across several continents. While it has been argued by a number of scholars that one major potential risk comes from technology, the obscure nature of future technologies makes it difficult to utilize traditional probabilistic risk for the meaningful study of these risks. This article describes an alternative approach and applies it to a research program that has attracted a considerable amount of resources recently: namely longevity research. The aim of this research is to delay or reverse the ageing process. This article argues that this research program is much more risky or less beneficial than its proponents argue. In particular, they tend to underestimate the concerns associated with the potentially drastic population growth that longevity treatment could cause. The ethical benefit often ascribed to longevity treatment is that such treatment would add more subjective life-years that are worth living. However, in light of contemporary environmental problems, such an increase of the human population might be reckless. Drastically reducing fertility to reduce risks associated with environmental stress would make the benefits of such technology much less compelling.

  16. Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms


    Yan, Haijing; Zhang, Xiangnan; Hu, Weiwei; Ma, Jing; Hou, Weiwei; Zhang, Xingzhou; Wang, Xiaofen; Gao, Jieqiong; Yao SHEN; Lv, Jianxin; Ohtsu, Hiroshi; Han, Feng; Wang, Guanghui; Chen, Zhong


    The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinfor...

  17. Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia

    NARCIS (Netherlands)

    den Hoed, Marissa A. H.; Pluijm, Saskia M. F.; te Winkel, Mariel L.; de Groot-Kruseman, Hester A.; Fiocco, Martha; Hoogerbrugge, Peter; Leeuw, Jan; Bruin, Marrie C. A.; van der Sluis, Inge M.; Bresters, Dorien; Lequin, Maarten H.; Roos, Jan C.; Veerman, Anjo J. P.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.


    Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence e

  18. Stanol esters attenuate the aggravating effect of dietary cholesterol on atherosclerosis in homozygous Watanabe rabbits

    DEFF Research Database (Denmark)

    Schrøder, Malene; Husche, Constanze; Pilegaard, Kirsten


    Plant stanols are marketed as natural means to lower blood cholesterol in humans; hence the effect on combined familial hyperlipidemia is not known. The objective was to investigate the effect of stanol esters on blood lipids and aortic atherosclerosis in homozygous WHHL rabbits challenged...... with dietary cholesterol. A total of 36 rabbits, 6 weeks of age, with initial plasma cholesterol of 22.5 mmol/L were assigned to two treatment groups fed a standard rabbit chow with 1 g/kg cholesterol or this diet added 34 g/kg stanol ester, respectively, for 16 weeks. Plasma cholesterol was measured initially...... and at termination, also in lipoproteins. Aortic atherosclerosis was evaluated as cholesterol content and area covered by plaque. Plasma cholesterol was not significantly different between the groups at termination (35.7 mmol/L vs. 35.5 mmol/L). A significant increase in LDL was seen (13.1 mmol/L vs. 16.5 mmol...

  19. Response to Comment on "Tissue Factor-Dependent Chemokine Production Aggravates Experimental Colitis"

    NARCIS (Netherlands)

    Queiroz, K.C.; Spek, C.A.


    In our recent work we utilized genetically modified mice to investigate the role of tissue factor (TF) in experimental colitis. We present evidence suggesting TF plays a detrimental role in this disease via signal transduction dependent KC production in colon epithelial cells, which provokes granulo

  20. Is Behavioral Regulation in Children With ADHD Aggravated by Comorbid Anxiety Disorder?

    DEFF Research Database (Denmark)

    Sørensen, Lin; Plessen, Kerstin J; Nicholas, Jude


    Background: The present study investigated the impact of coexisting anxiety disorder in children with ADHD on their ability to regulate behavior. Method: Parent reports on the Behavior Rating Inventory of Executive Function (BRIEF) in a comorbid group of children with ADHD and anxiety (n = 11) were...... compared to BRIEF reports in a group of children with a "pure" ADHD (n = 23), a "pure" anxiety (n = 24) and a group without any diagnosis (n = 104) in a 2 (ADHD vs. no ADHD) x 2 (anxiety vs. no anxiety) design. Results: The children with ADHD and anxiety disorder scored significantly higher on the Inhibit...... scale than children within the other three groups. Main effects of diagnosis appeared in ADHD children on the Inhibit, Emotional Control, and Working Memory scales, and on the Shift and Emotional Control scales in anxious children. Conclusion: The results indicate that a behavioral dysregulation in ADHD...

  1. Dietary phosphorus overload aggravates the phenotype of the dystrophin-deficient mdx mouse. (United States)

    Wada, Eiji; Yoshida, Mizuko; Kojima, Yoriko; Nonaka, Ikuya; Ohashi, Kazuya; Nagata, Yosuke; Shiozuka, Masataka; Date, Munehiro; Higashi, Tetsuo; Nishino, Ichizo; Matsuda, Ryoichi


    Duchenne muscular dystrophy is a lethal X-linked disease with no effective treatment. Progressive muscle degeneration, increased macrophage infiltration, and ectopic calcification are characteristic features of the mdx mouse, a murine model of Duchenne muscular dystrophy. Because dietary phosphorus/phosphate consumption is increasing and adverse effects of phosphate overloading have been reported in several disease conditions, we examined the effects of dietary phosphorus intake in mdx mice phenotypes. On weaning, control and mdx mice were fed diets containing 0.7, 1.0, or 2.0 g phosphorus per 100 g until they were 90 days old. Dystrophic phenotypes were evaluated in cryosections of quadriceps and tibialis anterior muscles, and maximal forces and voluntary activity were measured. Ectopic calcification was analyzed by electron microscopy to determine the cells initially responsible for calcium deposition in skeletal muscle. Dietary phosphorus overload dramatically exacerbated the dystrophic phenotypes of mdx mice by increasing inflammation associated with infiltration of M1 macrophages. In contrast, minimal muscle necrosis and inflammation were observed in exercised mdx mice fed a low-phosphorus diet, suggesting potential beneficial therapeutic effects of lowering dietary phosphorus intake on disease progression. To our knowledge, this is the first report showing that dietary phosphorus intake directly affects muscle pathological characteristics of mdx mice. Dietary phosphorus overloading promoted dystrophic disease progression in mdx mice, whereas restricting dietary phosphorus intake improved muscle pathological characteristics and function.

  2. Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS-induced pneumonia in rats

    NARCIS (Netherlands)

    Smeding, Lonneke; Kuiper, Jan Willem; Plotz, Frans B.; Kneyber, Martin C. J.; Groeneveld, A. B. Johan


    Background: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo

  3. Ovariectomy aggravated sodium induced hypertension associated with altered platelet intracellular Ca2+ in Dahl rats. (United States)

    Otsuka, K; Ohno, Y; Sasaki, T; Yamakawa, H; Hayashida, T; Suzawa, T; Suzuki, H; Saruta, T


    Our purpose was to determine the effect of ovariectomy on intracellular Ca2+ mobilization and platelet aggregation in sodium induced hypertension. At the age of 12 weeks ovariectomy or sham operation was performed in female Dahl-Iwai salt sensitive rats on a 0.3% NaCl diet. Four weeks later we assessed the effects of ovariectomy and an 8% NaCl diet on agonist induced intracellular Ca2+ mobilization in fura-2 loaded platelets and platelet aggregation. Ovariectomy enhanced the increase of systolic blood pressure and heart to body weight ratio on an 8% NaCl diet. However, thrombin evoked intracellular Ca2+ was not correlated with systolic blood pressure (r = -0.338, P = .17), and was lowered by sodium loading and ovariectomy (360+/-23 to 285+/-9, 296+/-10 nmol/L, P calcium fraction in the absence of external Ca2+ that reflected internal Ca2+ discharge capacity was reduced in ovariectomized rats compared with sham operated rats on an 8% NaCl diet (648+/-15 v 768+/-35 nmol/L, P hypertensive rats. We concluded that ovariectomy enhanced sodium induced hypertension associated with the decreased internal Ca2+ discharge capacity and increased platelet aggregation in Dahl-Iwai salt-sensitive rats.


    Directory of Open Access Journals (Sweden)

    N. N. Yurchenko


    Full Text Available The article is devoted to problems of administrative and political governance in Russia in the context of social unrest. The analysis of the situation prevailing in contemporary Russian society and the factors contributing to increased social tensions. It is noted that in the current environment, the organization of the system of administrative and political governance is a key factor in the reduction of tension in the social ecology. In the process of administrative and political management of social conflict is important to consider the stage of its formation and development. The parameters of variability, the variability of political behavior in complex space is a multi-ethnic society are fixed on the basis of monitoring ethno-social interactions, as well as methods of event analysis and cognitive mapping. For sustainable development of the Russian state, there is a need for timely anticipation and prevention of dangerous trends in the growth of social tension that, in turn, indicates the need for continuous improvement of all activities of public authorities, including supervision and management. These circumstances require leadership fundamentally new approaches to the administrative and political management, based on advanced, forward-looking information, allowing you to move from reactive management to proactive government and regional regulation, in a timely manner recognizing potential threats.

  5. Multiple Discriminations – between a Contravention Per Se and an Aggravating Circumstances

    Directory of Open Access Journals (Sweden)

    Cristian Jura


    Full Text Available There are some references on multiple discrimination like in the Recital 14 of the Racial Equality Directive, 2000/43/EC: „In implementing the principle of equal treatment irrespective of racial or ethnic origin, the Community should, in accordance with Article 3(2 of the EC Treaty, aim to eliminate inequalities, and to promote equality between men and women, especially since women are often the victims of multiple discrimination”. Even in this case there is no legal definition of multiple discriminations.In 2008, so after 8 years, in the Explanatory Memorandum of the Proposal for a Council Directive on implementing the principle of equal treatment between persons irrespective of religion or belief, disability, age or sexual orientation there is a reference regarding multiple discrimination in the sense that „Attention was also drawn to the need to tackle multiple discrimination, for example by defining it as discrimination and by providing effective remedies. These issues go beyond the scope of this Directive but nothing prevents Member States taking action in these areas.”

  6. Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

    NARCIS (Netherlands)

    Scharpfenecker, Marion; Floot, Ben; Russell, Nicola S.; Coppes, Rob P.; Stewart, Fiona A.


    Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent

  7. Autophagy activation aggravates neuronal injury in the hippocampus of vascular dementia rats

    Institute of Scientific and Technical Information of China (English)

    Bin Liu; Jing Tang; Jinxia Zhang; Shiying Li; Min Yuan; Ruimin Wang


    It remains unclear whether autophagy affects hippocampal neuronal injury in vascular dementia. In the present study, we investigated the effects of autophagy blockade on hippocampal neuro-nal injury in a rat model of vascular dementia. In model rats, hippocampal CA1 neurons were severely damaged, and expression of the autophagy-related proteins beclin-1, cathepsin B and microtubule-associated protein 1 light chain 3 was elevated compared with that in sham-oper-ated animals. These responses were suppressed in animals that received a single intraperitoneal injection of wortmannin, an autophagy inhibitor, prior to model establishment. The present results conifrm that autophagy and autophagy-related proteins are involved in the pathological changes of vascular dementia, and that inhibition of autophagy has neuroprotective effects.

  8. Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease

    DEFF Research Database (Denmark)

    Nobili, Elena; Salvado, M Dolores; Folkersen, Lasse Westergaard;


    Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and ...

  9. Rethinking Acquisition Reform: Cost-Growth Solutions May Aggravate More Important Problems (United States)


    specifically at cost- estimating accuracy, Melese and his colleagues employ transaction cost economics (TCE) theory to the problem of cost growth. While...Dillard, J. (2007). Apply insights from transaction cost economics to improve cost estimates for public sector purchases: The case of U.S. Military...Fenced Capital Accounts (DAPA 2006) Rational Cost Model Reforms Budget to Higher Probability (DAPA 2006) Transaction Cost Economics (Melese, et

  10. The Iranian problem against the backdrop of the russia-u. S. relations aggravation


    Gegelashvili, Nana


    The article gives an analysis on the Iranian problem from Russian and American perspectives with an emphasis on possible areas of cooperation and confrontation as well as their stance on the Iranian problem as a whole. The author points out the two states have an important legacy of preventing proliferation of which they should be proud. It is a legacy that should be revived and focused on the core proliferation threats in Iran and elsewhere before the nuclear confrontation of the Cold War is...

  11. Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice (United States)

    Chen, Jinmiao; Hong, Tao; Ding, Suling; Deng, Long; Abudupataer, Mieradilijiang; Zhang, Weiwei; Tong, Minghong; Jia, Jianguo; Gong, Hui; Zou, Yunzeng; Wang, Timothy C.; Ge, Junbo; Yang, Xiangdong


    Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC−/−) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC−/− mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6−/−) mice had a phenotype similar to that of HDC−/− mice post-MI; however, in contrast to HDC−/− mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6−/− mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway. PMID:28272448

  12. TLR4-dependent internalization of CX3CR1 aggravates sepsis-induced immunoparalysis. (United States)

    Ge, Xin-Yu; Fang, Shang-Ping; Zhou, Miao; Luo, Jing; Wei, Juan; Wen, Xue-Ping; Yan, Xiao-Di; Zou, Zui


    Sepsis, the most severe manifestation of infection, poses a major challenge to health-care systems around the world. Limited ability to clean and remove the pathogen renders difficulty in septic patients to recover from the phase of immunoparalysis. The present study found the vital role of CX3CR1 internalization on sepsis-induced immunoparalysis. A mouse model with cecal ligation and puncture (CLP) and cell model with lipopolysaccharides (LPS) were employed to explore the relationship between CX3CR1 internalization and septic immunoparalysis. Immunoparalysis model in mice was established 4 days after CLP with significantly decreased proinflammatory cytokines. Flow cytometry analysis found a decreased surface expression of CX3CR1 during immunoparalysis, which was associated with reduced mRNA level and increased internalization of CX3CR1. G-protein coupled receptor kinase 2 (GRK2) and β-arrestin2 were significantly increased during septic immunoparalysis and involved in the internalization of CX3CR1. TLR4(-/-) or TLR4 inhibitor-treated macrophages exhibited an inhibited expression of GRK2 and β-arrestin2, along with reduced internalization of CX3CR1. Moreover, the knockdown of GRK2 and β-arrestin2 inhibited the internalization of CX3CR1 and led to a higher response on the second hit, which was associated with an increased activation of NF-κB. The critical association between internalization of CX3CR1 and immunosuppression in sepsis may provide a novel reference for clinical therapeutics.

  13. Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer. (United States)

    Sun, Ting Ting; Wang, Yan; Cheng, Hong; Xiao, Hu Zhang; Xiang, Juan Juan; Zhang, Jie Ting; Yu, Siu Bun Sydney; Martin, Tracey Amanda; Ye, Lin; Tsang, Lai Ling; Jiang, Wen Guo; Xiaohua, Jiang; Chan, Hsiao Chang


    How mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains an open question. Here we report the interaction between CFTR and an adherens junction molecule, AF-6/afadin, and its involvement in the development of colon cancer. We have found that CFTR and AF-6/afadin are co-localized at the cell-cell contacts and physically interact with each other in colon cancer cell lines. Knockdown of CFTR results in reduced epithelial tightness and enhanced malignancies, with increased degradation and reduced stability of AF-6/afadin protein. The enhanced invasive phenotype of CFTR-knockdown cells can be completely reversed by either AF-6/afadin over-expression or ERK inhibitor, indicating the involvement of AF-6/MAPK pathway. More interestingly, the expression levels of CFTR and AF-6/afadin are significantly downregulated in human colon cancer tissues and lower expression of CFTR and/or AF-6/afadin is correlated with poor prognosis of colon cancer patients. The present study has revealed a previously unrecognized interaction between CFTR and AF-6/afadin that is involved in the pathogenesis of colon cancer and indicated the potential of the two as novel markers of metastasis and prognostic predictors for human colon cancer.

  14. Inhibiting platelets aggregation could aggravate the acute infection caused by Staphylococcus aureus. (United States)

    Zhang, Xin; Liu, Yu; Gao, Yaping; Dong, Jie; Mu, Chunhua; Lu, Qiang; Shao, Ningsheng; Yang, Guang


    Several fibrinogen binding proteins (Fibs) play important roles in the pathogenesis of Staphylococcus aureus (S. aureus). Most Fibs can promote the aggregation of platelets during infection, but the extracellular fibrinogen-binding protein (Efb) is an exception. It is reported that Efb can specifically bind fibrinogen and inhibit the aggregation of platelet with its N terminal. However, the biological significance of platelet aggregation inhibition in the infection caused by S. aureus is unclear until now. Here, we demonstrated that the persistence and aggregation of platelets were important for killing S. aureus in whole blood. It was found that the N terminal of Efb (EfbN) and platelets inhibitors could increase the survival of S. aureus in whole blood. The study in vivo also showed that EfbN and platelets inhibitors could reduce the killing of S. aureus and increase the lethality rate of S. aureus in the acute infection mouse model.

  15. Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke


    Inácio, Ana R; Ruscher, Karsten; Leng, Lin; Bucala, Richard; Deierborg, Tomas


    Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo)....

  16. Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling

    DEFF Research Database (Denmark)

    Caesar, Robert; Tremaroli, Valentina; Kovatcheva-Datchary, Petia


    Dietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased...... Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif(-/-) and Myd88(-/-) mice are protected against lard......-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation...


    NARCIS (Netherlands)



    Airway damage resulting in bronchiolitis obliterans occurs frequently in patients after heart-lung and lung transplantation. Generally, chronic rejection is assumed to be the most important cause of bronchiolitis obliterans. However, viral infections might also be potential causes of airway damage a

  18. Passive behavior of the government. Budget problems are aggravating in the regions

    Directory of Open Access Journals (Sweden)

    Anna Ivanovna Povarova


    Full Text Available Despite a number of reforms, the current multi-level budgetary system does not fully correspond to the development strategy of the country and its regions. Still the Russian Government has not taken effective measures to address the main structural contradiction of the budgetary system, based on the non-adequate distribution of revenue and expenditure responsibilities, manifested in the sharp decline in the revenue base of territorial budgets during the 2009 global financial crisis. However, the crisis effects have not been analyzed and the conclusions have not been made. The Ministry of Finance of the Russian Federation tried to solve the problem of territorial budgets imbalance not by enhancing existing mechanisms of revenue distribution at the regional level, but by granting large-scale loans to be repaid after 2012. Despite it, due to the sharp rise in the social burden, the deficit and the debt load enlarged and resulted in the budget crisis in the regions. The experts of the Higher School of Economics state that 20 RF subjects, having the level of public debt above 80%, had been actually in default by the end of 2014. Instead of finding ways out of the fiscal crisis, the Russian authorities gradually lose overall control over the processes of regional development. The mechanisms of federal target programs work poorly and the RF subjects have to finance program activities. In fact, the management of territorial development is reduced to the transfer of financial resources from the federal budget to the regions and the Ministry of Finance of the Russian Federation regulating interbudgetary relations has, in fact, become the only real institute of regional policy. But the interbudgetary policy of the Ministry of Finance does not gain visible economic returns: in 2006–2014 the amount of repayable financial assistance to the regional budgets increased from 0.6 to 1.5 trillion rubles, and the number of selfsufficient territories decreased from 20 to 11. The worsening of socio-economic problems is accompanied by a difficult international environment, adverse effects of external sanctions against Russia and falling oil prices. Already in 2014 the losses from the sanctions amounted to 40 billion U.S. dollars, from the decline in oil prices 100 billion U.S. dollars . However, the federal budget for 2015 was approved without taking into account these factors. It demonstrates the inability of the Russian Government to accurately assess the situation and forecast events even in the short term. Due to forced significant amendments to the federal budget in April 2015, its deficit was increased seven-fold, from 0.4 to 2.7 trillion rubles. Surely, this imbalance of the country’s budget will seriously complicate the implementation of local budgets. In the new version of the federal budget transfers to regions cut by 72 billion rubles, or by 10.5%. The anti-crisis plan of the Russian Federation Government aimed at cutting budget spending provides not grant financial support to the regions, but allocation of budgetary loans in the amount of 160 billion rubles, which will be returned to the Federal Treasury. These funds will be enough to repay only 15% of the accumulated commercial debt of regional budgets. Such a short-sighted budgetary policy of the central authorities deprives the regions of any hope of solving the problem of rising public debt. The crisis, greatly affecting the regions with metallurgical specialization, has highlighted the limits of countercyclical potential of fiscal policy. The lack of budget risk management involves deep drop in tax revenues, a major revenue source of regional budgets. Another negative consequence is that the Vologda Oblast, the Lipetsk Oblast, the Chelyabinsk Oblast and the Kemerovo Oblast have lost the status of donor regions. The article presents the results of the research in the problems of budgetary provision of the Vologda Oblast, the Lipetsk Oblast and the Chelyabinsk Oblast, carried out by ISEDT RAS. The leading domestic corporations of ferrous metallurgy are located in these areas. The work evaluates the state of regional budgets, debt policy and interaction with the federal budget as of year-end 2014. The main accent is made on the analysis of relations between metallurgical corporations and territorial budgets. Despite the fact that the metallurgy-oriented regions are characterized by significant structural features, the estimates vary greatly in the territorial context. However, we can make a general conclusion that in these regions one can observe the growing problems connected with the receipt of tax payments from the key revenue generating industry since 2009. It entails a number of other negative factors of the regional budget systems functioning. Due to highly inefficient economic policies pursued by the central government in respect of the largest taxpayers, the regional authorities have completely lost the ability to regulate their economic activities

  19. A hypomagnetic field aggravates bone loss induced by hindlimb unloading in rat femurs.

    Directory of Open Access Journals (Sweden)

    Bin Jia

    Full Text Available A hypomagnetic field is an extremely weak magnetic field--it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption.

  20. A hypomagnetic field aggravates bone loss induced by hindlimb unloading in rat femurs. (United States)

    Jia, Bin; Xie, Li; Zheng, Qi; Yang, Peng-fei; Zhang, Wei-ju; Ding, Chong; Qian, Ai-rong; Shang, Peng


    A hypomagnetic field is an extremely weak magnetic field--it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption.

  1. Aggravation of psoriasis by infections: a constitutional trait or a variable expression?

    NARCIS (Netherlands)

    Blok, S.; Vissers, W.H.P.M.; Duijnhoven, M. van; Kerkhof, P.C.M. van de


    Focal infections are a well known triggering factor in patients with psoriasis. A question which remains to be answered is whether relapsing of psoriasis after infections is a constitutional trait of a restricted population or whether it is a feature of all patients in some phase of their disease. A

  2. P2Y2 receptor deficiency aggravates chronic kidney disease progression

    Directory of Open Access Journals (Sweden)

    Sebastian Alexander Potthoff


    Full Text Available Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP. Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT and P2Y2 receptor knockout (KO mice.During the observational period of 56 ± 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9±7.7 vs. 84.3±8.7µl/min at day 56. The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177±2 vs. 156±7 mmHg and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-β1, PAI-1 and proinflammatory target genes (MCP1 were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease.

  3. Cedar Pollen Aggravates Atopic Dermatitis in Childhood Monozygotic Twin Patients with Allergic Rhino Conjunctivitis


    Yukako Murakami; Saki Matsui; Akiko Kijima; Shun Kitaba; Hiroyuki Murota; Ichiro Katayama


    We report a case of 7-year-old monozygotic twin patients with atopic dermatitis. The HLA haplotypes were HLA A2, A11, B27, B61, DR1, and DR4. Both serum IgE levels and cedar pollen radioallergosorbent test (RAST) scores were high in the twins (elder/younger sister: IgE: 5170/3980 IU/ml and Japansese cedar pollen: >100/64.0) in contrast to low mite and food RAST scores (Dermatophagoides Pterygonium; 0.59/0.4 and egg white 9.24/4.6). The patients showed positive immediate (20 min in both sister...

  4. Acetylcholinesterase (AChE inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver

    Directory of Open Access Journals (Sweden)

    Shin-Ichi Yokota


    Full Text Available Although fasting induces hepatic triglyceride (TG accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1 and liver-fatty acid binding-protein (L-FABP. Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.

  5. Is Behavioral Regulation in Children With ADHD Aggravated by Comorbid Anxiety Disorder?

    DEFF Research Database (Denmark)

    Sørensen, Lin; Plessen, Kerstin J; Nicholas, Jude;


    Background: The present study investigated the impact of coexisting anxiety disorder in children with ADHD on their ability to regulate behavior. Method: Parent reports on the Behavior Rating Inventory of Executive Function (BRIEF) in a comorbid group of children with ADHD and anxiety (n = 11) were...... scale than children within the other three groups. Main effects of diagnosis appeared in ADHD children on the Inhibit, Emotional Control, and Working Memory scales, and on the Shift and Emotional Control scales in anxious children. Conclusion: The results indicate that a behavioral dysregulation in ADHD...

  6. Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection. (United States)

    Dhungana, Hiramani; Malm, Tarja; Denes, Adam; Valonen, Piia; Wojciechowski, Sara; Magga, Johanna; Savchenko, Ekaterina; Humphreys, Neil; Grencis, Richard; Rothwell, Nancy; Koistinaho, Jari


    Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17α and tumor necrosis factor-α levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.

  7. Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

    Energy Technology Data Exchange (ETDEWEB)

    Scharpfenecker, Marion, E-mail: [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands); Floot, Ben [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands); Russell, Nicola S. [Division of Radiotherapy, The Netherlands Cancer Institute, Amsterdam (Netherlands); Coppes, Rob P. [Departments of Radiation Oncology and Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Stewart, Fiona A. [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands)


    Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Methods and Materials: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, and 40 weeks after irradiation. Results: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Conclusions: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.

  8. Viola Playing May Be a Strong Aggravating Factor for Temporomandibular Disorder


    Mahmut Alpayci


    Temporomandibular disorder (TMD) is the general term used to describe the symptoms originated from temporomandibular joint region. The most common symptom of the disorder is pain during mandibular movement. Etiology of TMD is multifactorial. Several factors such as trauma, occlusal discrepancies, stress, parafunctions, hypermobility, and heredity can make one more vulnerable to this disorder. It has been reported that viola playing might be a predisposing factor for TMD. In this article, we p...


    Directory of Open Access Journals (Sweden)

    N. Grazhevska


    Full Text Available The article deals with the role and importance of corporate social responsibility as an important mechanism for overcoming the crisis of the welfare state and to mitigate the social problems caused by the world globalization processes. The experience of post-socialist countries, the Baltic States and Ukraine in this field is analyzed and barriers to effective implementation of CSR in the national economy are identified. The priority of the state policy to promote socially responsible business behavior in Ukraine is proved.

  10. Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis

    NARCIS (Netherlands)

    Summers, Shaun A.; van der Veen, Betty S.; O'Sullivan, Kim M.; Gan, Poh-Yi; Ooi, Joshua D.; Heeringa, Peter; Satchell, Simon C.; Mathieson, Peter W.; Saleem, Moin A.; Visvanathan, Kumar; Holdsworth, Stephen R.; Kitching, A. Richard


    Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of

  11. Absence of Fas-L aggravates renal injury in acute Trypanosoma cruzi infection

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    Gabriel Melo de Oliveira


    Full Text Available Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.

  12. TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice

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    Kai-Uwe Jarr


    Full Text Available Background. TNF-like weak inducer of apoptosis (TWEAK has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. Results. TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14 -/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14 +/+. Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. Conclusions. TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.

  13. Capital Sentencing: The Effect of Adding Aggravators to Death Penalty Statutes in Pennsylvania

    Directory of Open Access Journals (Sweden)

    Sandra Schultz Newman


    Full Text Available The birthplace of the American republic—the Commonwealth of Pennsylvania—has historically been at the forefront of the capital punishment legislation in the United States. It was the first colony in the Union to abolish the death penalty for all crimes with the exception of murder. It was the first to set forth a statutory distinction between different degrees of criminal homicide, confining imposition of capital punishment to the most chilling form of this crime—“willful, deliberate, and premeditated killing.” With this storied history in mind, we have undertaken the task of examining the current state of the death penalty in the Commonwealth. Hence, in Part II of this Article, we set forth a detailed history of the capital sentencing scheme in Pennsylvania. Part III undertakes a statistical study of the imposition of the death penalty in the Commonwealth from 1978 until 1997. In Part IV, we conclude by summing up our general observations.

  14. Increase in hippocampal water diffusion and volume during experimental pneumococcal meningitis is aggravated by bacteremia

    DEFF Research Database (Denmark)

    Holler, Jon G; Brandt, Christian T; Leib, Stephen L;


    pneumococci. The study comprised of four experimental groups. I. Uninfected controls (n = 8); II. Meningitis (n = 11); III. Meningitis with early onset bacteremia by additional i.v. injection of live pneumococci (n = 10); IV. Meningitis with attenuated bacteremia by treatment with serotype-specific anti...

  15. Aggravated test of Intermediate temperature solid oxide fuel cells fed with tar-contaminated syngas (United States)

    Pumiglia, Davide; Vaccaro, Simone; Masi, Andrea; McPhail, Stephen J.; Falconieri, Mauro; Gagliardi, Serena; Della Seta, Livia; Carlini, Maurizio


    In the present work, the effects of a tar-containing simulated syngas on an IT-SOFC (Intermediate Temperature Solid Oxide Fuel Cell) are evaluated. Performance and degradation rate of a planar anode-supported cell, operating under a simulated syngas obtained from steam-enriched air gasification of biomass, have been studied. The simulated syngas was contaminated using toluene as a model tar. Polarization curves and electrochemical impedance spectroscopy have been carried out under different toluene concentrations. A cell was then operated under a constant current density on a long run. EIS measurements were made during the operation to analyze the degradation, and the voltage evolution of the cell was compared to that obtained from another identical cell operated in clean syngas for 1000 h under similar conditions. A deep post-mortem characterization was performed by means of XRD measurements, Raman spectroscopy and SEM/EDS analysis. Results show that the presence of tar dramatically reduces the electrochemical performances of the cell, affecting both activation and mass transport processes. Post-mortem analysis shows the formation of carbon deposits, oxidation of Ni to NiO, segregation of ZrO2 from the YSZ phase, particle coarsening and enhanced fragility of the anode structure, in good agreement with what suggested from the electrochemical results.

  16. MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias. (United States)

    Xue, Y; Yamada, C; Aye, N N; Hashimoto, K


    We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (Platent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.

  17. MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias


    Xue, Yixue; Yamada, Chikaomi; Nu Aye, Nu; Hashimoto, Keitaro


    We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 μg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurr...

  18. A Mycobacterium leprae Hsp65 mutant as a candidate for mitigating lupus aggravation in mice.

    Directory of Open Access Journals (Sweden)

    Eliana B Marengo

    Full Text Available Hsp60 is an abundant and highly conserved family of intracellular molecules. Increased levels of this family of proteins have been observed in the extracellular compartment in chronic inflammation. Administration of M. leprae Hsp65 [WT] in [NZBxNZW]F(1 mice accelerates the Systemic Lupus Erythematosus [SLE] progression whereas the point mutated K(409A Hsp65 protein delays the disease. Here, the biological effects of M. leprae Hsp65 Leader pep and K(409A pep synthetic peptides, which cover residues 352-371, are presented. Peptides had immunomodulatory effects similar to that observed with their respective proteins on survival and the combined administration of K(409A+Leader pep or K(409A pep+WT showed that the mutant forms were able to inhibit the deleterious effect of WT on mortality, indicating the neutralizing potential of the mutant molecules in SLE progression. Molecular modeling showed that replacing Lysine by Alanine affects the electrostatic potential of the 352-371 region. The number of interactions observed for WT is much higher than for Hsp65 K(409A and mouse Hsp60. The immunomodulatory effects of the point-mutated protein and peptide occurred regardless of the catalytic activity. These findings may be related to the lack of effect on survival when F(1 mice were inoculated with Hsp60 or K(409A pep. Our findings indicate the use of point-mutated Hsp65 molecules, such as the K(409A protein and its corresponding peptide, that may minimize or delay the onset of SLE, representing a new approach to the treatment of autoimmune diseases.

  19. Is Behavioral Regulation in Children with ADHD Aggravated by Comorbid Anxiety Disorder? (United States)

    Sorensen, Lin; Plessen, Kerstin J.; Nicholas, Jude; Lundervold, Astri J.


    Background: The present study investigated the impact of coexisting anxiety disorder in children with ADHD on their ability to regulate behavior. Method: Parent reports on the Behavior Rating Inventory of Executive Function (BRIEF) in a comorbid group of children with ADHD and anxiety (n = 11) were compared to BRIEF reports in a group of children…

  20. Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice

    DEFF Research Database (Denmark)

    Liu, Cong-Lin; Wang, Yi; Liao, Mengyang


    OBJECTIVE: Asthma and abdominal aortic aneurysms (AAA) both involve inflammation. Patients with asthma have an increased risk of developing AAA or experiencing aortic rupture. This study tests the development of one disease on the progression of the other. APPROACH AND RESULTS: Ovalbumin...... sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth...

  1. Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease.

    Directory of Open Access Journals (Sweden)

    Elena Nobili

    Full Text Available BACKGROUND: Cysteinyl-leukotrienes (cys-LT are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe(-/- mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2 in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia. METHODS AND PRINCIPAL FINDINGS: Myocardial biopsies from Apoe(-/- mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C(4 synthase (LTC(4S and CysLT1 expression in the myocardium of Apoe(-/- mice. Acute bouts of hypoxia further induced LTC(4S expression, increased LTC(4S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe(-/- mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC(4S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling. CONCLUSION: Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.

  2. Aggravation of Hypertriglyceridemia and Acute Pancreatitis in a Bipolar Patient Treated with Quetiapine


    Liou, Li-Syue; Hung, Yi-Jen; Hsieh, Chang-Hsun; Hsiao, Fone-Ching


    Pancreatitis is a very rare adverse effect of quetiapine treatment, with only 5 cases of quetiapine-associated pancreatitis reported in the English literature to date. Herein, we report one patient who developed severe hypertriglyceridemia (>1000 mg/dL) after quetiapine administration, resulting in acute pancreatitis. An analysis of the underlying pathogenic mechanisms and a review of relevant literature are also presented. Clinicians should be aware of the potentially life-threatening metabo...

  3. Action mechanism of corticosteroids to aggravate Guillain-Barré syndrome



    Corticosteroids have been proved to be ineffective for Guillain-Barré syndrome, but the mechanism remains unknown. In a rabbit model of axonal Guillain-Barré syndrome, treatment with corticosteroids significantly reduced macrophage infiltration in the spinal ventral roots and the survival rate as well as clinical improvement. On 30th day after onset, there was significantly higher frequency of axonal degeneration in the corticosteroids-treated rabbits than saline-treated rabbits. Corticostero...

  4. Maturity aggravates sepsis-associated skeletal muscle catabolism in growing pigs (United States)

    Synthesis and accretion of muscle protein is elevated in neonates and decreases with development. During sepsis, muscle protein synthesis is reduced, but the effect of development on the metabolic response to sepsis in skeletal muscle is not well understood. Fasted 7- and 26-d-old pigs were infused ...

  5. Aggravation by vanadium of magnesium deficiency in STZ-induced diabetic rats. (United States)

    Bermúdez-Peña, M C; López-Chaves, C; Llopis, J; Guerrero-Romero, F; Montes-Bayón, M; Sanz-Medel, A; Sánchez-González, C


    This study examined changes in the metabolism of magnesium (Mg), and related serum parameters, following treatment with vanadium (V) in streptozotocin-diabetic rats. Over a period of five weeks, four groups were examined: control, diabetic, diabetic-treated with 1 mg V/day or 3 mg V/day. The V was supplied in drinking water as bis(maltolato)oxovanadium(IV). The Mg levels were measured in food, faeces, urine, serum, muscle, kidney, liver, spleen, heart and femur. Albumin, uric acid, urea, total-cholesterol, LDL-cholesterol, triglycerides, aspartate-aminotransferase and alkaline-phosphatase were determined in serum. In the diabetic group, Mg retained and Mg content in serum and femur decreased, while levels of uric acid, urea, total-cholesterol, LDL-cholesterol, triglycerides and alkaline-phosphatase and aspartate-aminotransferase activity increased compared with control rats. In the diabetic group treated with 1 mg V/day, Mg retained, serum levels of Mg, urea and triglycerides, and alkaline-phosphatase activity remained unchanged, while levels of uric acid, total-cholesterol and LDL-cholesterol increased and the Mg content in femur and aspartate-aminotransferase activity decreased compared with the diabetic untreated group. In the diabetic rats treated with 3 mg V/day, food intake and glycaemia were normal. In this group, Mg content in serum, kidney and femur, levels of urea and aspartate-aminotransferase and alkaline-phosphatase activity decreased, whereas LDL-cholesterol increased, uric acid and total-cholesterol levels remained unchanged in comparison with untreated diabetic rats. In conclusion, although treatment with 3 mg V/day normalised the glycaemia, the hypomagnesaemia and tissue depletion of Mg seen in the diabetic rats, caused by the treatment with V, could have partially contributed to the fact that V did not normalise other serum parameters altered by the diabetes.

  6. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease (United States)

    Leung, Christopher; Herath, Chandana B; Jia, Zhiyuan; Andrikopoulos, Sof; Brown, Bronwyn E; Davies, Michael J; Rivera, Leni R; Furness, John B; Forbes, Josephine M; Angus, Peter W


    AIM To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/- animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD. PMID:27672297

  7. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury (United States)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae


    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  8. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M;


    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed...... effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested...... overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic...

  9. Male sex aggravates the phenotype in mouse models of hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    Maass, AH; Maier, SKG


    The authors have created transgenic mouse models of hypertrophic cardiomyopathy with mutations in either cardiac troponin T or myosin heavy chain. Mice mutant in myosin heavy chain develop significant cardiac hypertrophy at young adult age. Female mice keep that hypertrophic state, whereas male mice

  10. Acute exposure to silica nanoparticles aggravate airway inflammation: different effects according to surface characteristics


    Park, Hye Jung; Sohn, Jung-Ho; Kim, Yoon-Ju; Park, Yoon Hee; Han, Heejae; Park, Kyung Hee; Lee, Kangtaek; Choi, Hoon; Um, Kiju; Choi,In-Hong; Park, Jung-Won; Lee, Jae-Hyun


    Silica nanoparticles (SNPs) are widely used in many scientific and industrial fields despite the lack of proper evaluation of their potential toxicity. This study examined the effects of acute exposure to SNPs, either alone or in conjunction with ovalbumin (OVA), by studying the respiratory systems in exposed mouse models. Three types of SNPs were used: spherical SNPs (S-SNPs), mesoporous SNPs (M-SNPs), and PEGylated SNPs (P-SNPs). In the acute SNP exposure model performed, 6-week-old BALB/c ...

  11. Gene-gun DNA vaccination aggravates respiratory syncytial virus-induced pneumonitis

    DEFF Research Database (Denmark)

    Bartholdy, Christina; Olszewska, Wieslawa; Stryhn, Anette


    elicited with recombinant vaccinia virus expressing the complete RSV M2 protein, but stronger than those induced by a similar DNA construct without the beta2m gene. DNA vaccination led to enhanced pulmonary disease after RSV challenge, with increased weight loss and cell recruitment to the lung. Depletion......A CD8+ T-cell memory response to respiratory syncytial virus (RSV) was generated by using a DNA vaccine construct encoding the dominant Kd-restricted epitope from the viral transcription anti-terminator protein M2 (M2(82-90)), linked covalently to human beta2-microglobulin (beta2m). Cutaneous gene......+ T-cell responses were not induced. Thus, in addition to specific CD8+ T cell-mediated immunopathology, gene-gun DNA vaccination causes non-specific enhancement of RSV disease without affecting virus clearance....

  12. Dyssynergic defecation may aggravate constipation : results of mostly pediatric cases with congenital anorectal malformation

    NARCIS (Netherlands)

    van Meegdenburg, Maxime M.; Heineman, Erik; Broens, Paul M. A.


    BACKGROUND: Most patients with congenital anorectal malformation suffer from mild chronic constipation. To date, it is unclear why a subgroup of patients develops a persistent form of constipation. Because dyssynergic defecation is a common cause of constipation in the general population, we hypothe

  13. Shift work aggravates metabolic syndrome development among early-middle-aged males with elevated ALT

    Institute of Scientific and Technical Information of China (English)

    Yu-Cheng Lin; Tun-Jen Hsiao; Pau-Chung Chen


    AIM: To examine whether shift work accelerates metabolic syndrome (MetS) development among early middle- aged males with elevated alanine aminotransferase (e-ALT).METHODS: A retrospective, observational followup study on MetS development at a 5-year interval was conducted using health examination data. Nine hundred and ninety six male employees not fulfilling MetS criteria at screening were enrolled. Age, MetScomponents,liver enzymes, serological markers for viral hepatitis, abdominal ultrasound, insulin resistance status, lifestyles, and workplace factors were analyzed.RESULTS: The prevalence of elevated serum ALT (> 40 U/L, e-ALT) at baseline was 19.1%. There were 381 (38.3%) workers with long-term exposures to daynight rotating shift work (RSW). 14.2% of subjects developed MetS during follow-up. After 5 years, the workers with e-ALT had significantly unfavorable changes in MetS-components, and higher rates of MetS development, vs subjects with normal baseline ALT levels. Workers with both baseline e-ALT and 5-year persistent RSW (pRSW) exposure had the highest rate of MetS development. Also, e-ALT-plus-pRSW workers had a significant increase in MetS-components at follow-up, compared with the other subgroups. After controlling for potential confounders, e-ALT-plus-pRSW workers posed a significant risk for MetS development (odds ratio, 2.7; 95% confidence interval, 1.4-5.3, vs workers without baseline e-ALT nor pRSW). CONCLUSION: We suggest that all early middleaged male employees with e-ALT should be evaluated and managed for MetS. Particularly in terms of job arrangements, impacts of long-term RSW on MetS development should be assessed for all male employees having baseline e-ALT.

  14. Synthesis of [F-18]RGD-K5 by catalyzed [3+2] cycloaddition for imaging integrin alpha(v)beta(3) expression in vivo

    NARCIS (Netherlands)

    Mirfeizi, Leila; Walsh, Joe; Kolb, Hartmuth; Campbell-Verduyn, Lachlan; Dierckx, Rudi A.; Feringa, Ben L.; Elsinga, Philip H.; de Groot, Tjibbe; Sannen, Ivan; Bormans, Guy; Celen, Sofie


    In the last few years click chemistry reactions, and in particular copper-catalyzed cycloadditions have been used extensively for the preparation of new bioconjugated molecules such as F-18-radiolabeled radiopharmaceuticals for positron emission tomography (PET). This study is focused on the synthes

  15. Structural basis for distinctive recognition of fibrinogen [gamma]C peptide by the platelet integrin [alpha][subscript IIb][beta]3

    Energy Technology Data Exchange (ETDEWEB)

    Springer, Timothy A.; Zhu, Jianghai; Xiao, Tsan (Harvard-Med)


    Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to integrin {alpha}{sub IIb}{beta}{sub 3} on platelets, resulting in platelet aggregation. {alpha}{sub v}{beta}{sub 3} binding fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's {alpha} subunit. {alpha}{sub IIb}{beta}{sub 3} also binds to fibrinogen; however, it does so via an unstructured RGD-lacking C-terminal region of the {gamma} subunit ({gamma}C peptide). These distinct modes of fibrinogen binding enable {alpha}{sub IIb}{beta}{sub 3} and {alpha}{sub v}{beta}{sub 3} to function cooperatively in hemostasis. In this study, crystal structures reveal the integrin {alpha}{sub IIb}{beta}{sub 3}-{gamma}C peptide interface, and, for comparison, integrin {alpha}{sub IIb}{beta}{sub 3} bound to a lamprey {gamma}C primordial RGD motif. Compared with RGD, the GAKQAGDV motif in {gamma}C adopts a different backbone configuration and binds over a more extended region. The integrin metal ion-dependent adhesion site (MIDAS) Mg{sup 2+} ion binds the {gamma}C Asp side chain. The adjacent to MIDAS (ADMIDAS) Ca{sup 2+} ion binds the {gamma}C C terminus, revealing a contribution for ADMIDAS in ligand binding. Structural data from this natively disordered {gamma}C peptide enhances our understanding of the involvement of {gamma}C peptide and integrin {alpha}{sub IIb}{beta}{sub 3} in hemostasis and thrombosis.

  16. Integrin beta3 Leu33Pro polymorphism and risk of hip fracture: 25 years follow-up of 9233 adults from the general population

    DEFF Research Database (Denmark)

    Tofteng, Charlotte L; Bach-Mortensen, Pernille; Bojesen, Stig E


    OBJECTIVE: Integrin alphavbeta3 is essential for mature osteoclast function and therefore important for the development of osteoporosis and osteoporotic fractures. Integrin alphavbeta3 antagonists have antiresorptive effects in bone. We tested the hypothesis that the Leu33Pro polymorphism...

  17. Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease. (United States)

    Xiao, Wenbin; Ando, Tomoaki; Wang, Huan-You; Kawakami, Yuko; Kawakami, Toshiaki


    Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)-β3-dependent manner. Thus, PLC-β3-deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)- deficient mice. Here we show that Lyn/PLC-β3 doubly deficient lyn(-/-);PLC-β3(-/-) mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn(-/-);PLC-β3(-/-) mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr(536) and Tyr(564) is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr(564) by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr(536) in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-β3-mediated regulatory mechanism of SHP-1 and Stat5 activities.

  18. Interactions between an alpha2-adrenergic antagonist and a beta3-adrenergic agonist on the expression of UCP2 and UCP3 in rats.



    This experimental trial was devised to assess whether selective β3-adrenergic receptor (AR) stimulation and simultaneous blockade of α2-AR would affect thermoregulation. With this purpose, the individual and combined administration of a β3-AR agonist, trecadrine, and an α2-AR antagonist, yohimbine, were evaluated. Yohimbine produced a marked decrease (p < 0.001) in body temperature one hour after administration (5 mg kg−1, i.p.) and blocked the thermogenic effect of trecadrine (1 mg kg−1, i.p...

  19. Association of the beta3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: studies of 7605 middle-aged white people

    DEFF Research Database (Denmark)

    Gjesing, A. P.; Andersen, G; Borch-Johnsen, K;


    of type 2 diabetes and obesity in a relatively large, homogenous study population. METHODS: The Trp64Arg polymorphism was genotyped in 7605 Danish subjects using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Association was examined in case-control studies of obesity (1529...... cases and 6049 controls) and type 2 diabetes (1373 cases and 4742 controls) and quantitative trait analyses among 5822 individuals. Furthermore, the association of Trp64Arg with type 2 diabetes was examined in a meta-analysis. RESULTS: The Trp64Arg polymorphism was not associated with obesity. However...... (p=0.02). After sex stratification these associations were only present among women. Furthermore, the Arg-allele was borderline associated with type 2 diabetes in a meta-analysis of the present and 26 previous studies (p=0.06, OR1.27 (CI: 0.99-1.63)) (n=18891). CONCLUSION/INTERPRETATION: Trp64Arg...

  20. Nasute termite soldier frontal gland secretions. 1. Structure of Trinervi-2. beta. ,3. cap alpha. ,9. cap alpha. -triol 9-O acetate, a novel diterpene from Trinervitermes soldiers

    Energy Technology Data Exchange (ETDEWEB)

    Prestwich, G.D. (International Center of Insect Physiology and Ecology, Nairobi, Kenya); Tanis, S.P.; Springer, J.P.; Clardy, J.


    One of the major constituents, ''TG-2,'' of the soldier secretions of Trinervitermes gratiosus Sjostedt were studied by x-ray diffraction. The structure was determined to be a novel diterpene skeleton with a bridgehead double bond in an 11-membered ring. Bond angles and lengths were discussed, and a computer generated perspective drawing of the compound was presented. (DDA)

  1. Morgagni hernia with respiratory failure aggravated by noninvasive positive pressure ventilation: a case report and overview of the literature. (United States)

    Tone, Kazuya; Kiryu, Ikumi; Yoshida, Masahiro; Tsuboi, Kazuto; Takagi, Masamichi; Kuwano, Kazuyoshi


    An elderly woman diagnosed with multiple myeloma (MM) in 2007 had improved with chemotherapy. She had severe kyphosis and a diaphragmatic hernia (DH), but no respiratory symptoms. In 2011, because of thoracic deformity and emaciation, we advised her to continue the previously prescribed domiciliary noninvasive positive pressure ventilation (NPPV) therapy for chronic type II respiratory failure. However, she refused to continue NPPV. She was later admitted for deterioration in respiratory status and carbon dioxide (CO2) narcosis. We believed her low adherence to domiciliary NPPV caused CO2 narcosis; hence, we advised her to continue domiciliary NPPV and she complied. In May 2012, the now 79-year-old patient was admitted for acute exacerbation of chronic respiratory failure and CO2 narcosis. Chest imaging suggested that DH had caused a deterioration of her status. She underwent laparoscopic diaphragmatic hernia repair. Operative findings revealed a retrosternal hernia sac, and she was diagnosed as having a Morgagni hernia (MH). Her respiratory status subsequently improved. We hypothesize that NPPV increased intra-abdominal pressure, thereby worsening the MH and exacerbating respiratory failure. We believe that clinicians should be cautious when prescribing NPPV for MH patients.

  2. Investigation of Aggravating Psychosocial Factors on Health and Predictability of Smoking and Alcohol Use in Post Adolescent Students. (United States)

    Barmpagianni, Effrosyni; Travlos, Antonios; Kalokairinou, Athina; Sachlas, Athanasios; Zyga, Sofia


    Purpose of this study is to explore those factors which affect the health of students in postadolescent age, focusing on smoking and alcohol use, especially in regard to ways of predicting adoption of this behavior and its frequency to detect future users of tobacco and alcohol use but also high-risk groups, i.e. those people who are led to abuses. On the basis of the research part is the Theory of Planned Behaviour, the axes of which are to be investigated. Specifically, the factors evaluated, except for population parameters, behavioral attitudes, i.e. attitudes towards the behavior of tobacco use and alcohol regulations subjective perceptions and perceptions of control, perceived behavioral control and self-efficacy. Intention is explored to continue or start using tobacco and alcohol in the future and evaluate the behavior. The sample consisted of 138 students of postadolescent age, 18-25 years of both sexes, all of the University of Peloponnese and the Technological Educational Institute of Kalamata, Department of Sparta, Greece. The results of a series of statistical analysis, via SPSS 21.0 statistical program revealed the predictive power of perceived behavioral control and subjective norms to the intention of interpreting 64% of the variance of the latter, of the attitudes toward alcohol in relation to intention that interpret 69% of the variance, of the normative beliefs toward smoking with 69% range of interpretation to the dependent variable, of the perceived behavioral control of smoking with 72% and of the attitudes toward smoking with 77% of interpretation. The results demonstrate the significance and application in universities and technological educational institutes appropriate primary preventive interventions for students nonusers of tobacco and alcohol and appropriate programs of secondary and tertiary prevention in heavy users of tobacco and alcohol use and high-risk individual.

  3. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Zhen Wei


    Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

  4. Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis

    NARCIS (Netherlands)

    van Zwieten, Rob; van Oirschot, Brigitte A; Veldthuis, Martijn; Dobbe, Johannes G; Streekstra, Geert J; van Solinge, Wouter W; Schutgens, Roger E G; van Wijk, Richard


    In a family with mild dominant spherocytosis, affected members showed partial band 3 deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low pyruvate kinase activity. We investigated the contribution of partial PK defic

  5. 1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice. (United States)

    Son, Yeonghoon; Jeong, Ye Ji; Kwon, Jong Hwa; Choi, Hyung-Do; Pack, Jeong-Ki; Kim, Nam; Lee, Yun-Sil; Lee, Hae-June


    The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF-EMF) on health. In the present study, we investigated whether RF-EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aβ)-related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF-EMF- and sham-exposed groups, eight mice per group). The RF-EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y-maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non-spatial memory following 3-month RF-EMF exposure. Furthermore, Aβ deposition and APP and carboxyl-terminal fragment β (CTFβ) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aβ peptides were also investigated. In behavioral tests, mice that were exposed to RF-EMF for 3 months did not exhibit differences in spatial and non-spatial memory compared to the sham-exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF-EMF did not alter APP and CTFβ levels or Aβ deposition in the brains of the 5xFAD mice. These findings indicate that 3-month RF-EMF exposure did not affect Aβ-related memory impairment or Aβ accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391-399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.

  6. Farmer Resettlements and Water Energy Stresses Arising From Aggravating Drought Conditions in Mahaweli River Watershed, Sri Lanka (United States)

    Thabrew, L.


    Climate change is expected to cause significant changes in water quantity and water quality in river basins throughout the world, with particularly significant impacts in developing regions. Climate change effects are often exacerbated by other simultaneous activities in developing countries, such as population growth, reliance on subsistence agriculture, and expanding provision of electricity. Each of these activities requires access to readily-available freshwater. For example, population growth requires more water for irrigation as food production needs increase. Additionally, water is needed for generating electricity in hydropower facilities as well as other facilities, which require water to run steam turbines or to cool facilities. As such, many developing countries face the real and immediate need to anticipate and adapt to climatic stresses on water resources in both the agricultural and residential sectors. Water withdrawal in both of these sectors is largely driven by individual behaviors, such as electricity use in the home and irrigation practices on farmland, aggregated at the household, community, and regional level. Our ongoing project in Sri Lanka focuses on understanding aforementioned issues in coupled natural and human systems in the Mahaweli River Watershed (MWR) to inform decision-makers to streamline policies and strategies for effective adaptation to worsening drought conditions. MWR produces more than 60% of the rice demand and nearly 40% of the energy requirement of the country. Although irrigation is currently the sector that withdraws the most water, with government plans for resettling farmer communities and developing new urban centers in the region by 2030, electricity production is expected to compete for water against irrigation in the future. Thus, understanding the water-energy nexus is crucial to planning for conservation and efficiency. Through a pilot survey conducted by our interdisciplinary research team, in five locations in MWR, we collect information on household and farm level water and energy use, demand-side water management practices, and farmers' willingness and capacities to practice them. We use these self-reported pilot data together with water and energy utility company data to model increasing water-energy stresses in the watershed, and its effect on existing water allocation issues related to irrigation and power generation. Drawing upon the preliminary results of this work, this paper presents the emerging water-energy issues and plausible adaptation measures in MWR. This work will pave the way to understand the inherent interconnectivities of water energy stresses in multi-purpose watersheds in the developing world.

  7. Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis.

    NARCIS (Netherlands)

    Zwieten, R. van; Oirschot, B.A.J.A. van; Veldthuis, M.; Dobbe, J.G.; Streekstra, G.J.; Solinge, W.W. van; Schutgens, R.E.; Wijk, R. Gerth van


    In a family with mild dominant spherocytosis, affected members showed partial band 3 deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low pyruvate kinase activity. We investigated the contribution of partial PK defic

  8. Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.

    Directory of Open Access Journals (Sweden)

    Anouk A J Hamers

    Full Text Available Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS- and 2,4,6-trinitrobenzene sulfonic acid (TNBS-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.

  9. Deficiency for the chemokine monocyte chemoattractant protein-1 aggravates tubular damage after renal ischemia/reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Ingrid Stroo

    Full Text Available Temporal expression of chemokines is a crucial factor in the regulation of renal ischemia/reperfusion (I/R injury and repair. Beside their role in the migration and activation of inflammatory cells to sites of injury, chemokines are also involved in other processes such as angiogenesis, development and migration of stem cells. In the present study we investigated the role of the chemokine MCP-1 (monocyte chemoattractant protein-1 or CCL2, the main chemoattractant for monocytes, during renal I/R injury. MCP-1 expression peaks several days after inducing renal I/R injury coinciding with macrophage accumulation. However, MCP-1 deficient mice had a significant decreased survival and increased renal damage within the first two days, i.e. the acute inflammatory response, after renal I/R injury with no evidence of altered macrophage accumulation. Kidneys and primary tubular epithelial cells from MCP-1 deficient mice showed increased apoptosis after ischemia. Taken together, MCP-1 protects the kidney during the acute inflammatory response following renal I/R injury.

  10. Hypofibrinolytic State in Subjects with Type 2 Diabetes Mellitus Aggravated by the Metabolic Syndrome before Clinical Manifestations of Atherothrombotic Disease (United States)

    Aburto-Mejía, Elsa; Santiago-Germán, David; Martínez-Marino, Manuel; María Eugenia Galván-Plata; Almeida-Gutiérrez, Eduardo; Hernández-Juárez, Jesús; Alvarado-Moreno, Antonio; Leaños-Miranda, Alfredo


    Background. Metabolic and genetic factors induce plasminogen activator inhibitor type-1 (PAI-1) overexpression; higher PAI-1 levels decrease fibrinolysis and promote atherothrombosis. Aim. To assess PAI-1 antigen levels among subjects with type 2 diabetes mellitus (T2DM) plus Metabolic Syndrome (MetS) before clinical manifestations of atherothrombosis and the contribution of metabolic factors and 4G/5G polymorphism of PAI-1 gene on the variability of PAI-1. Methods. We conducted an observational, cross-sectional assay in a hospital in Mexico City from May 2010 to September 2011. MetS was defined by the International Diabetes Federation criteria. PAI-1 levels and 4G/5G polymorphism were determined by ELISA and PCR-RFLP analysis. Results. We enrolled 215 subjects with T2DM plus MetS and 307 controls. Subjects with T2DM plus MetS had higher PAI-1 levels than the reference group (58.4 ± 21 versus 49.9 ± 16 ng/mL, p = 0.026). A model with components of MetS explained only 12% of variability on PAI-1 levels (R2 = 0.12; p = 0.001), with β = 0.18 (p = 0.03) for hypertension, β = −0.16 (p = 0.05) for NL HDL-c, and β = 0.15 (p = 0.05) for NL triglycerides. Conclusion. Subjects with T2DM plus MetS have elevated PAI-1 levels before clinical manifestations of atherothrombotic disease. Metabolic factors have a more important contribution than 4G/5G polymorphism on PAI-1 plasma variability. PMID:28271069

  11. Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin. (United States)

    Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal


    Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

  12. One-punch Laws, Mandatory Minimums and ‘Alcohol-Fuelled’ as an Aggravating Factor: Implications for NSW Criminal Law

    Directory of Open Access Journals (Sweden)

    Julia Ann Quilter


    Full Text Available This article critically examines the New South Wales State Government’s latest policy response to the problem of alcohol-related violence and anxiety about ‘one punch’ killings: the recently enacted Crimes and Other Legislation Amendment (Assault and Intoxication Act 2014 (NSW. Based on an analysis of both the circumstances out of which it emerged, and the terms in which the new offences of assault causing death and assault causing death while intoxicated have been defined, I argue that the Act represents another example of criminal law ‘reform’ that is devoid of principle, produces a lack of coherence in the criminal law and, in its operation, is unlikely to deliver on the promise of effective crime prevention in relation to alcohol-fuelled violence.

  13. Hypofibrinolytic State in Subjects with Type 2 Diabetes Mellitus Aggravated by the Metabolic Syndrome before Clinical Manifestations of Atherothrombotic Disease

    Directory of Open Access Journals (Sweden)

    Elsa Aburto-Mejía


    Full Text Available Background. Metabolic and genetic factors induce plasminogen activator inhibitor type-1 (PAI-1 overexpression; higher PAI-1 levels decrease fibrinolysis and promote atherothrombosis. Aim. To assess PAI-1 antigen levels among subjects with type 2 diabetes mellitus (T2DM plus Metabolic Syndrome (MetS before clinical manifestations of atherothrombosis and the contribution of metabolic factors and 4G/5G polymorphism of PAI-1 gene on the variability of PAI-1. Methods. We conducted an observational, cross-sectional assay in a hospital in Mexico City from May 2010 to September 2011. MetS was defined by the International Diabetes Federation criteria. PAI-1 levels and 4G/5G polymorphism were determined by ELISA and PCR-RFLP analysis. Results. We enrolled 215 subjects with T2DM plus MetS and 307 controls. Subjects with T2DM plus MetS had higher PAI-1 levels than the reference group (58.4 ± 21 versus 49.9 ± 16 ng/mL, p=0.026. A model with components of MetS explained only 12% of variability on PAI-1 levels (R2 = 0.12; p=0.001, with β=0.18 (p=0.03 for hypertension, β=-0.16 (p=0.05 for NL HDL-c, and β=0.15 (p=0.05 for NL triglycerides. Conclusion. Subjects with T2DM plus MetS have elevated PAI-1 levels before clinical manifestations of atherothrombotic disease. Metabolic factors have a more important contribution than 4G/5G polymorphism on PAI-1 plasma variability.

  14. Exogenous administration of a recombinant variant of TWEAK impairs healing after myocardial infarction by aggravation of inflammation.

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    Christina Pachel

    Full Text Available BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14 are upregulated after myocardial infarction (MI in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. METHODS AND RESULTS: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK, mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. CONCLUSION: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.

  15. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice. (United States)

    Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F


    Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia.

  16. Neutrophil-Derived Myeloperoxidase Aggravates Non-Alcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Deficient Mice

    NARCIS (Netherlands)

    Rensen, Sander S.; Bieghs, Veerle; Xanthoulea, Sofia; Arfianti, Evi; Bakker, Jaap A.; Shiri-Sverdlov, Ronit; Hofker, Marten H.; Greve, Jan Willem; Buurman, Wim A.


    Background: Chronic inflammation and oxidative stress play fundamental roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Previously, we reported that myeloperoxidase (MPO), an aggressive oxidant-generating neutrophil enzyme, is associated with NASH severity in man. We now investigat

  17. Hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in a rat model of acute hyperammonemia

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Eefsen, Martin; Larsen, Fin Stolze;


    Intravenous infusion of magnesium sulfate prevents seizures in patients with eclampsia and brain edema after traumatic brain injury. Neuroprotection is achieved by controlling cerebral blood flow (CBF), intracranial pressure, neuronal glutamate release, and aquaporin-4 (Aqp4) expression....... These factors are also thought to be involved in the development of brain edema in acute liver failure. We wanted to study whether hypermagnesemia prevented development of intracranial hypertension and hyperperfusion in a rat model of portacaval anastomosis (PCA) and acute hyperammonemia. We also studied...... rats receiving ammonia infusion/vehicle and MgSO4) /saline. The effect of MgSO(4) on mean arterial pressure (MAP), intracranial pressure (ICP), CBF, cerebral glutamate and glutamine, and aquaporin-4 expression was studied. Finally, the effect of MgSO4 on MAP, ICP, and CBF was studied, using two...

  18. Direct recognition of Fusobacterium nucleatum by the NK cell natural cytotoxicity receptor NKp46 aggravates periodontal disease.

    Directory of Open Access Journals (Sweden)

    Stella Chaushu

    Full Text Available Periodontitis is a common human chronic inflammatory disease that results in the destruction of the tooth attachment apparatus and tooth loss. Although infections with periopathogenic bacteria such as Porphyromonas gingivalis (P. gingivalis and Fusobacterium nucleatum (F. nucleatum are essential for inducing periodontitis, the nature and magnitude of the disease is determined by the host's immune response. Here, we investigate the role played by the NK killer receptor NKp46 (NCR1 in mice, in the pathogenesis of periodontitis. Using an oral infection periodontitis model we demonstrate that following F. nucleatum infection no alveolar bone loss is observed in mice deficient for NCR1 expression, whereas around 20% bone loss is observed in wild type mice and in mice infected with P. gingivalis. By using subcutaneous chambers inoculated with F. nucleatum we demonstrate that immune cells, including NK cells, rapidly accumulate in the chambers and that this leads to a fast and transient, NCR1-dependant TNF-α secretion. We further show that both the mouse NCR1 and the human NKp46 bind directly to F. nucleatum and we demonstrate that this binding is sensitive to heat, to proteinase K and to pronase treatments. Finally, we show in vitro that the interaction of NK cells with F. nucleatum leads to an NCR1-dependent secretion of TNF-α. Thus, the present study provides the first evidence that NCR1 and NKp46 directly recognize a periodontal pathogen and that this interaction influences the outcome of F. nucleatum-mediated periodontitis.

  19. 77 FR 24415 - Inflation Adjustment of the Aggravated Maximum Civil Monetary Penalty for a Violation of a... (United States)


    ... Federal Railroad Administration 49 CFR Parts 209, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223...); 49 CFR 240.223(a), (b). Further, FRA is revising language in 49 CFR part 209, appendix A, ``Statement..., Transportation. 49 CFR Part 220 Communications, Penalties, Radio, Railroad safety, Reporting and...

  20. Aggravation of dyspnea in stage I non-small cell lung cancer patients following stereotactic body radiotherapy

    DEFF Research Database (Denmark)

    Paludan, Merete; Traberg Hansen, Anders; Petersen, Jørgen;


    In SBRT for NSCLC, highly potent radiation doses are delivered to patients with frequent pre-irradiatory compromise of pulmonary function. For the risk of pulmonary toxicity to be minimized during SBRT planning, data on its dose-volume dependency is needed. In the present study, we analyse the as...

  1. Deficiency for the chemokine monocyte chemoattractant protein-1 aggravates tubular damage after renal ischemia/reperfusion injury. (United States)

    Stroo, Ingrid; Claessen, Nike; Teske, Gwendoline J D; Butter, Loes M; Florquin, Sandrine; Leemans, Jaklien C


    Temporal expression of chemokines is a crucial factor in the regulation of renal ischemia/reperfusion (I/R) injury and repair. Beside their role in the migration and activation of inflammatory cells to sites of injury, chemokines are also involved in other processes such as angiogenesis, development and migration of stem cells. In the present study we investigated the role of the chemokine MCP-1 (monocyte chemoattractant protein-1 or CCL2), the main chemoattractant for monocytes, during renal I/R injury. MCP-1 expression peaks several days after inducing renal I/R injury coinciding with macrophage accumulation. However, MCP-1 deficient mice had a significant decreased survival and increased renal damage within the first two days, i.e. the acute inflammatory response, after renal I/R injury with no evidence of altered macrophage accumulation. Kidneys and primary tubular epithelial cells from MCP-1 deficient mice showed increased apoptosis after ischemia. Taken together, MCP-1 protects the kidney during the acute inflammatory response following renal I/R injury.

  2. Assessment of role of Porphyromonas gingivalis as an aggravating factor for chronic obstructive pulmonary disease patients with periodontitis

    Directory of Open Access Journals (Sweden)

    Roopa Madalli


    Full Text Available Introduction: Periodontitis is a chronic inflammatory disease associated with a number of lung conditions such as chronic obstructive pulmonary disease (COPD and pneumonia. Both chronic periodontitis (CP and COPD share similar risk factor profiles. Thus, recognition of interaction between periodontitis and COPD could lead to establishment of better preventive and therapeutic approaches. The microbial analysis of sputum from COPD patients with CP to detect periodontal pathogen Porphyromonas gingivalis (P. gingivalis both before and after nonsurgical periodontal therapy. Materials and Methods: The study group comprised 30 individuals diagnosed as COPD with CP. Periodontal indices, lung function test, and P. gingivalis in sputum were assessed before and 6 months after nonsurgical periodontal therapy. Results: A decrease in the count of P. gingivalis and decreased periodontal indices values were observed in COPD patients with periodontitis after nonsurgical periodontal therapy. Lung function test (forced expiratory volume in the first/forced vital capacity was improved in COPD patients with periodontitis after nonsurgical periodontal therapy. Conclusions: The study results suggest that nonsurgical periodontal therapy can be a part of treatment protocol in COPD patients because it helps in reducing the P. gingivalis count and improving the lung function.

  3. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice

    NARCIS (Netherlands)

    Hoekstra, H; Porte, RJ; Tian, Y; Jochum, W; Stieger, B; Moritz, W; Slooff, MJH; Graf, R; Clavien, PA


    Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resista

  4. Deficiency of the Complement Component 3 but Not Factor B Aggravates Staphylococcus aureus Septic Arthritis in Mice. (United States)

    Na, Manli; Jarneborn, Anders; Ali, Abukar; Welin, Amanda; Magnusson, Malin; Stokowska, Anna; Pekna, Marcela; Jin, Tao


    The complement system plays an essential role in the innate immune response and protection against bacterial infections. However, detailed knowledge regarding the role of complement in Staphylococcus aureus septic arthritis is still largely missing. In this study, we elucidated the roles of selected complement proteins in S. aureus septic arthritis. Mice lacking the complement component 3 (C3(-/-)), complement factor B (fB(-/-)), and receptor for C3-derived anaphylatoxin C3a (C3aR(-/-)) and wild-type (WT) control mice were intravenously or intra-articularly inoculated with S. aureus strain Newman. The clinical course of septic arthritis, as well as histopathological and radiological changes in joints, was assessed. After intravenous inoculation, arthritis severity and frequency were significantly higher in C3(-/-)mice than in WT controls, whereas fB(-/-)mice displayed intermediate arthritis severity and frequency. This was in accordance with both histopathological and radiological findings. C3, but not fB, deficiency was associated with greater weight loss, more frequent kidney abscesses, and higher bacterial burden in kidneys. S. aureus opsonized with C3(-/-)sera displayed decreased uptake by mouse peritoneal macrophages compared with bacteria opsonized with WT or fB(-/-)sera. C3aR deficiency had no effect on the course of hematogenous S. aureus septic arthritis. We conclude that C3 deficiency increases susceptibility to hematogenous S. aureus septic arthritis and impairs host bacterial clearance, conceivably due to diminished opsonization and phagocytosis of S. aureus.

  5. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    Zhen Wei; Xiao-Chun Chen; Yue Song; Xiao-Dong Pan; Xiao-Man Dai; Jing Zhang; Xiao-Li Cui


    Background:Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD),and cellular senescence is closely associated with aging and cognitive impairment.However,it remains blurred whether,in the AD brains,Aβ accelerates the neuronal.senescence and whether this senescence,in turn,impairs the cognitive function.This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.Methods:The 5XFAD mice and age-matched wild type mice,both raised from 1 to 18 months,were enrolled in the study.The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction.Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests.Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation.Aging-related proteins were detected by Western blotting analysis and immunofluorescence.Results:In 5XFAD mice,of all the DEGs,the senescence-associated marker p 16 was most significantly increased,even at the early age.It was mainly localized in neurons,with a marginal expression in astrocytes (labeled as glutamine synthetase),nil expression in activated microglia (labeled as Iba1),and negatively correlated with the spatial cognitive impairments of 5XFAD mice.oAβ (1-42) induced the production of senescence-related protein p 16,but not p53 in vitro,which was in line with the in vivo manifestation.Conclusions:oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice.Senescence-associated marker p 16 can serve as an indicator to estimate the cognitive prognosis for AD population.

  6. The Military Security Situation in 2015:Security Cooperation Made some Breakthroughs while Turmoil and Conflicts Became somewhat Aggravated

    Institute of Scientific and Technical Information of China (English)

    Meng Xiangqing; Zhou Peiqi; Zhang Chi


    In 2015 in the face of stability with some chaos in the world,one should not fear its sight being blotted out by floating clouds only if facing the situation with sober-mindedness and detailed analysisThe Global military security situation in2015 was stable as a whole,with obviously increasing uncertainties.Local conflicts and

  7. Deleted in liver cancer 2 (DLC2 was dispensable for development and its deficiency did not aggravate hepatocarcinogenesis.

    Directory of Open Access Journals (Sweden)

    Tai On Yau

    Full Text Available DLC2 (deleted in liver cancer 2, a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis.

  8. Endoplasmic reticulum stress-induced apoptosis in the penumbra aggravates secondary damage in rats with traumatic brain injur y

    Institute of Scientific and Technical Information of China (English)

    Guo-zhu Sun; Fen-fei Gao; Zong-mao Zhao; Hai Sun; Wei Xu; Li-wei Wu; Yong-chang He


    Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated, mitochondrial, and endo-plasmic reticulum stress pathways. Few studies have examined the endoplasmic reticulum-mediated apoptosis pathway in the penumbra after traumatic brain injury, and it remains unclear whether endoplasmic reticulum stress can activate the caspase-12-dependent apoptotic pathway in the traumatic penumbra. Here, we established rat models of lfuid percussion-induced traumatic brain injury and found that protein expression of caspase-12, caspase-3 and the endoplasmic reticulum stress marker 78 kDa glucose-regulated protein increased in the traumatic penumbra 6 hours after injury and peaked at 24 hours. Furthermore, numbers of terminal deoxynucleotidyl transferase-mediat-ed dUTP nick end labeling-positive cells in the traumatic penumbra also reached peak levels 24 hours after injury. These ifndings suggest that caspase-12-mediated endoplasmic reticulum-related apoptosis is activated in the traumatic penumbra, and may play an important role in the pathophysiology of secondary brain injury.

  9. Does Cisapride, as a 5HT4 Receptor Agonist, Aggravate the Severity of TNBS-Induced Colitis in Rat?

    Directory of Open Access Journals (Sweden)

    Azadeh Motavallian


    Full Text Available There is a pressing need for research that will lead to the reveal of targets designed to analyse the possible pathways for the treatment of IBD. Because of the probable involvement of serotonin in inflammatory conditions of intestine and the important role of 5HT4 receptors in GI function, the investigation of the role of 5HT4 receptors in the pathogenesis of IBD will be interesting. The aim of this study was to investigate the effects of cisapride, a 5HT4 receptor agonist, in trinitrobenzenesulfonic-acid-(TNBS induced rat colitis. Two hours subsequent to induction of colitis using TNBS in rats, cisapride (2 mg/kg, intraperitoneally (i.p; 4 mg/kg, orally (p.o and dexamethasone (1 mg/kg, i.p; 2 mg/kg, p.o were administrated for 6 days. Animals were thereafter euthanized; macroscopic, histological, and biochemical assessments and ELISA test were carried out on distal colon samples. Our data showed that dexamethasone treatment (i.p, p.o significantly decreased macroscopic and microscopic damage and also biochemical markers, but there were no significant differences in aforementioned parameters between cisapride (i.p or p.o and TNBS-treated rats. It can be deduced that because the severity of colitis produced by TNBS is massive (through various pathways, cisapride could not bring about more colitis damages through 5HT4 receptors. Based on the present study further researches are required for investigating the exact roles of 5HT4 receptors in the pathogenesis of ulcerative colitis.

  10. Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake

    NARCIS (Netherlands)

    Berg, S.A.A. van den; Heemskerk, M.M.; Geerling, J.J.; Klinken, J.B. van; Schaap, F.G.; Bijland, S.; Berbée, J.F.P.; Harmelen, V.J.A. van; Pronk, A.C.M.; Schreurs, M.; Havekes, L.M.; Rensen, P.C.N.; Dijk, K.W. van


    Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the lo

  11. Aquaporin-4 deficiency attenuates acute lesions but aggravates delayed lesions and microgliosis after cryoinjury to mouse brain

    Institute of Scientific and Technical Information of China (English)

    Wen-Zhen Shi; Chun-Zhen Zhao; Bing Zhao; Xiao-Liang Zheng; San-Hua Fang; Yun-Bi Lu; Wei-Ping Zhang; Zhong Chen; Er-Qing Wei


    Objective To determine whether aquaporin-4 (AQP4) regulates acute lesions,delayed lesions,and the associated microglial activation after cryoinjury to the brain.Methods Brain cryoinjury was applied to AQP4 knockout (KO)and wild-type mice.At 24 h and on days 7 and 14 after cryoinjury,lesion volume,neuronal loss,and densities of microglia and astrocytes were determined,and their changes were compared between AQP4 KO and wild-type mice.Results Lesion volume and neuronal loss in AQP4 KO mice were milder at 24 h following cryoinjury,but worsened on days 7 and 14,compared to those in wild-type mice.Besides,microglial density increased more,and astrocyte proliferation and glial scar formation were attenuated on days 7 and 14 in AQP4 KO mice.Conclusion AQP4 deficiency ameliorates acute lesions,but worsens delayed lesions,perhaps due to the microgliosis in the late phase.

  12. Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion. (United States)

    Kaiser, Melanie; Penk, Anja; Franke, Heike; Krügel, Ute; Nörenberg, Wolfgang; Huster, Daniel; Schaefer, Michael


    Effective therapeutic measures against the development of brain edema, a life-threatening complication of cerebral ischemia, are necessary to improve the functional outcome for the patient. Here, we identified a beneficial role of purinergic receptor P2X7 activation in acute ischemic stroke. Involvement of P2X7 in the development of neurological deficits, infarct size, brain edema, and glial responses after ischemic cerebral infarction has been analyzed. Neurologic evaluation, magnetic resonance imaging, and immunofluorescence assays were used to characterize the receptor's effect on the disease progress during 72 h after transient middle cerebral artery occlusion (tMCAO). Sham-operated animals were included in all experiments for control purposes. We found P2X7-deficient mice to develop a more prominent brain edema with a trend towards more severe neurological deficits 24 h after tMCAO. Infarct sizes, T2 times, and apparent diffusion coefficients did not differ significantly between wild-type and P2X7(-/-) animals. Our results show a characteristic spatial distribution of reactive glia cells with strongly attenuated microglia activation in P2X7(-/-) mice 72 h after tMCAO. Our data indicate that P2X7 exerts a role in limiting the early edema formation, possibly by modulating glial responses, and supports later microglia activation.

  13. Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure

    Directory of Open Access Journals (Sweden)

    Na Zhang


    Full Text Available Purpose. We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid. Methods. Eight-week-old MT-I/II knockout (MT-I/II KO mice and background-matched wild-type (WT mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx 3 expression were measured. Results. In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P>0.05, while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P>0.05. Conclusions. Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes.

  14. Enhancement of trichothecene mycotoxins of Fusarium oxysporum by ferulic acid aggravates oxidative damage in Rehmannia glutinosa Libosch (United States)

    Li, Zhen Fang; He, Chen Ling; Wang, Ying; Li, Ming Jie; Dai, Ya Jing; Wang, Tong; Lin, Wenxiong


    Rehmannia glutinosa is an important medicinal herb that cannot be replanted in the same field due to the effects of autotoxic substances. The effects of these substances on R. glutinosa in continuous cropping systems are unknown. In the present study, bioassays revealed that R. glutinosa exhibited severe growth restriction and higher disease indices in the FO+FA (F.oxysporum pretreated with ferulic acid) treatment. The increases in the contents of MDA and H2O2 were greater in the FA+FO treatment than in the FA or FO only treatments, respectively. Consistent with this result, the enzyme activities in the seedlings increased with treatment time. To identify the main factor underlying the increased pathogenicity of FO, macroconidia and trichothecene mycotoxins coproduced by FO were separated and used to treat R. glutinosa seedlings. The MDA and H2O2 contents were similar in the seedlings treated with deoxynivalenol and in the FA+FO treatment. Quantification of the relative expression of certain genes involved in Ca2+ signal transduction pathways suggested that trichothecene mycotoxins play an important role in the increased pathogenicity of FO. In conclusion, FA not only directly enhances oxidative damage in R. glutinosa but also increases wilting symptom outbreaks by promoting the secretion of trichothecene mycotoxins by FO. PMID:27667444

  15. Evaluación de los niveles del factor de crecimiento transformante beta 1 y beta 3 en plasma y líquido peritoneal de caballos con enfermedad abdominal aguda Evaluation of the transforming growth factor beta 1 and beta 3 levels in plasma and peritoneal fluid from horses with acute abdominal disease

    Directory of Open Access Journals (Sweden)

    D Argüelles


    Full Text Available Existe información escasa sobre moléculas presentes en el líquido peritoneal de caballos con cólico relacionadas con el desarrollo potencial de adherencias abdominales. Estudios en especies diferentes correlacionan niveles incrementados de las series del factor de crecimiento transformante beta (TGF-ß con la presencia de adherencias abdominales. Los objetivos de este estudio fueron: 1 documentar y comparar los niveles plasmáticos y del líquido peritoneal del TGF-ß1 y TGF-ß3 en caballos con enfermedad abdominal aguda y en caballos normales. 2 correlacionar los niveles de estos péptidos con los hallazgos del hemograma y los resultados citológicos y bioquímicos del líquido peritoneal. Se tomaron muestras de plasma y líquido peritoneal de 104 caballos con cólico (29 cólicos médicos (15 obstructivos simples y 14 inflamatorios y 65 cólicos quirúrgicos, de los cuales 30 padecían problemas isquémicos y 35 de problemas obstructivos simples y de 10 caballos sanos. En cada paciente se realizó un hemograma, análisis citológico de líquido peritoneal y determinación de los niveles plasmáticos y peritoneales de TGF-ß1 y TGF-ß3 mediante ELISA. Los niveles peritoneales de TGF-ß1 fueron estadísticamente más altos en los cólicos quirúrgicos isquémicos y en los cólicos médicos inflamatorios en comparación con los otros tipos de cólicos y con el grupo control. En conclusión, los niveles peritoneales de TGF-ß1 en caballos con crisis abdominal aguda están incrementados como respuesta a la inflamación. Los caballos con lesiones estrangulantes o peritonitis muestran alteración severa en niveles peritoneales de TGF-ß1.There is few information about the molecules present in the peritoneal fluid of horses with colic that are related to the potential development of abdominal adhesions. Studies carried out in different species correlate high levels of transforming growth factor beta (TGF-ß series with the presence of abdominal adhesions. The aims of this study were: 1 to document and compare the plasma and peritoneal fluid levels of TGF-ß1 and TGF-ß3 in horses with acute abdominal disease and normal horses, 2 to correlate the levels of these peptides with the hemogram values and the cytological and biochemical peritoneal fluid findings. Plasma and peritoneal fluid samples from 104 horses were obtained: 29 were medical colics (15 were obstructive simple colic and 14 were inflammatory colic, 65 underwent abdominal surgery (30 horses suffered from ischemic problems and 35 from non ischemic problems, and 10 were controls. A hemogram was performed and peritoneal fluid cytology and TGF-ß1 and TGF-ß3 plasma and peritoneal fluid levels were determined by ELISA. The TGF-ß1 peritoneal fluid levels were statistically (P < 0.05 higher in ischemic colics and inflammatory colics compared with controls and other type of surgical or medical colics. In conclusion, the levels of peritoneal fluid TGF-ß1 are elevated in horses with acute abdominal disease in response to inflammation. The horses with strangulating lesions and peritonitis show greater alterations of TGF-ß1 levels.

  16. The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. (United States)

    Matayoshi, Tetsutaro; Kamide, Kei; Takiuchi, Shin; Yoshii, Masayoshi; Miwa, Yoshikazu; Takami, Yoichi; Tanaka, Chihiro; Banno, Mariko; Horio, Takeshi; Nakamura, Satoko; Nakahama, Hajime; Yoshihara, Fumiki; Inenaga, Takashi; Miyata, Toshiyuki; Kawano, Yuhei


    The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.

  17. 肾上腺素β3受体调节大鼠逼尿肌舒张的机制%The mechanism of beta3-adrenoceptors mediated rat ditrusor relaxation

    Institute of Scientific and Technical Information of China (English)

    曹文锋; 王亮; 王庆堂; 杨航; 陈卫国; 李沙丹


    目的 探讨肾上腺能β3受体(β3-AR)调节逼尿肌舒张的机制.方法 应用激光共聚焦显微镜观察不同浓度β3-AR激动剂BRL37344A对氯化钾和咖啡因诱发的大鼠逼尿肌细胞钙荧光强度的变化,流式细胞仪测定β 3-AR激活后细胞内CaM活性变化.结果 较高浓度(1×10-6 mmol/L及1×10-4 mmol/L)的BRL37344A分别使氯化钾诱发的细胞内钙荧光强度的峰值下降了18.2%和28.3%,而低浓度BRL37344A对氯化钾诱发的细胞钙离子跨膜内流无显著影响;不同浓度的BRL37344对咖啡因诱发的细胞肌浆网内储存钙的释放均无明显影响(P>0.05).β3-AR激活后细胞内活性CaM含量明显增加.结论BRL37344A抑制电压门控钙通道的开放,减少钙离子跨膜内流.Ca2+-CaM信号传导途径参与了β 3-AR介导逼尿肌细胞舒张调节过程.%Objective To explore the mechanism of Pj-adrenoceptors on detrusor relaxation. Methods The effects of BRL37344A in different concentration on the change of intracellular Ca2* concentration induced by KG and caffeine were detected with confocal laser scanning microscopy by using Ca2* sensitive dye fluo-3AM as calcium fluorescent. The CaM fluorescence density determined. Results Higher concentration BRL37344A (10"6 mmol ?L ' and 10 "* mmol L) could inhibit Ca2* transsar-colemmal influx induced by KC1 ( peak Ca 2+ fluorescent intensity decreased 18.2% and 28.3% ), but low concentration BRL37344A did not(P >0.05). BRL37344A did not altered the amount of Ca2* releaes from intracellular stores responsed to caffeine. Afterp3-AR stimulated by BRL37344A, intracellular CaM activity relatively were increased. Conclusion The negative in-otropic effects of BRL37344A may be mediated by decrease Ca2 * transsarcolemmal influx through voltage-gated calcium channel. (S3-AR mediated detrusor relaxation was completed by the Ca2* -CaM signal pathway.

  18. Sheehan syndrome aggravated from inferior turbinectomy: a case report%下鼻甲术后加重席汉综合征一例

    Institute of Scientific and Technical Information of China (English)

    程建军; 乔泰峰; 安全梅; 用文明; 甄达



  19. High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis, Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide. (United States)

    Ghosh, Siddhartha S; Righi, Samuel; Krieg, Richard; Kang, Le; Carl, Daniel; Wang, Jing; Massey, H Davis; Sica, Domenic A; Gehr, Todd W B; Ghosh, Shobha


    A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.

  20. A novel role for APOBEC3: Susceptibility to sexual transmission of murine acquired immunodeficiency virus (mAIDS is aggravated in APOBEC3 deficient mice

    Directory of Open Access Journals (Sweden)

    Jones Philip H


    Full Text Available Abstract Background APOBEC3 proteins are host factors that restrict infection by retroviruses like HIV, MMTV, and MLV and are variably expressed in hematopoietic and non-hematopoietic cells, such as macrophages, lymphocytes, dendritic, and epithelia cells. Previously, we showed that APOBEC3 expressed in mammary epithelia cells function to limit milk-borne transmission of the beta-retrovirus, mouse mammary tumor virus. In this present study, we used APOBEC3 knockout mice and their wild type counterpart to query the role of APOBEC3 in sexual transmission of LP-BM5 MLV – the etiological agent of murine AIDs (mAIDs. Results We show that mouse APOBEC3 is expressed in murine genital tract tissues and gametes and that genital tract tissue of APOBEC3-deficient mice are more susceptible to infection by LP-BM5 virus. APOBEC3 expressed in genital tract tissues most likely plays a role in decreasing virus transmission via the sexual route, since mice deficient in APOBEC3 gene have higher genitalia and seminal plasma virus load and sexually transmit the virus more efficiently to their partners compared to APOBEC3+ mice. Moreover, we show that female mice sexually infected with LP-BM5 virus transmit the virus to their off-spring in APOBEC3-dependent manner. Conclusion Our data indicate that genital tissue intrinsic APOBEC3 restricts genital tract infection and limits sexual transmission of LP-BM5 virus.

  1. High temperature and vapor pressure deficit aggravate architectural effects but ameliorate non-architectural effects of salinity on dry mass production of tomato

    Directory of Open Access Journals (Sweden)

    Tsu-Wei eChen


    Full Text Available Tomato (Solanum lycopersicum L. is an important vegetable crop and often cultivated in regions exposed to salinity and high temperatures (HT which change plant architecture, decrease canopy light interception and disturb physiological functions. However, the long-term effects of salinity and HT combination (S+HT on plant growth are still unclear. A dynamic functional-structural plant model (FSPM of tomato was parameterized and evaluated for different levels of S+HT combinations. The evaluated model was used to quantify the contributions of morphological changes (architectural effects and physiological disturbances (non-architectural effects on the reduction of shoot dry mass under S+HT. The model predicted dynamic plant architecturale variables with high accuracy (> 85%, which ensured the reliability of the model analyses. HT enhanced architectural effects but reduced non-architectural effects of salinity on dry mass production. The stronger architectural effects of salinity under HT could not be counterbalanced by the smaller non-architectural effects. Therefore, long-term influences of HT on shoot dry mass under salinity were negative at the whole plant level. Our model analysis highlights the importance of plant architecture at canopy level in studying the plant responses to the environments and shows the merits of dynamic FSPMs as heuristic tools.

  2. CD1d knockout mice exhibit aggravated contact hypersensitivity responses due to reduced interleukin-10 production predominantly by regulatory B cells

    DEFF Research Database (Denmark)

    Fjelbye, Jonas; Antvorskov, Julie C; Buschard, Karsten


    Conflicting observations have been reported concerning the role of CD1d-dependent natural killer T (NKT) cells in contact hypersensitivity (CHS), supporting either a disease-promoting or downregulatory function. We studied the role of NKT cells in CHS by comparing the immune response in CD1d.......5% DNCB (w/v) on the ears fifteen days later. We demonstrate that CD1d KO mice, as compared with Wt littermates, have more pronounced infiltration of mononuclear cells in the skin (29.1% increase; P

  3. Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Hjalte Holm; Imai, Yosuke; Petersen, Kristian Kjær


    forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive...

  4. Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study

    DEFF Research Database (Denmark)

    Eriksson, J.W.; Jansson, P.A.; Carlberg, B.


    Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution....... Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg...

  5. Changes and effects of helper T cells and their effector molecules on disease aggravation in patients with chronic hepatitis B. MO Ruidong

    Institute of Scientific and Technical Information of China (English)



    Objective To investigate the role of helper T cell(Th)1,Th17 and Th22 and their effector molecules including interferon-gamma,interleukin(IL)-17 and IL-22in active phase of chronic hepatitis B(CHB)and acuteon-chronic liver failure(ACLF).Methods Forty-five CHB patients and 38 ACLF patients at Ruijin Hospital of Shanghai Jiaotong University School of Medicine were included,and 26 healthy controls(HC)were also enrolled.Fresh heparinized peripheral blood was obtained

  6. High Fat High Cholesterol Diet (Western Diet Aggravates Atherosclerosis, Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide.

    Directory of Open Access Journals (Sweden)

    Siddhartha S Ghosh

    Full Text Available A high fat meal, frequently known as western diet (WD, exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx or WD (Nx+WD. The controls were sham operated animals on normal diet (control and WD (WD. To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM, a known LPS antagonist, and curcumin (CU, a compound known to ameliorate chronic kidney disease (CKD, was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively. Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.

  7. Chloroquine aggravates Con A-induced autoimmune hepatitis%氯喹可加重Con A诱导的自身免疫性肝损伤

    Institute of Scientific and Technical Information of China (English)

    李延利; 王守杰; 唐媛; 张丽芸; 卢晓; 左大明; 陈政良


    氯喹(chloroquine,CQ)可抑制免疫反应,偶用于类风湿性关节炎、系统性红斑狼疮等自身免疫性疾病的治疗,但氯喹对自身免疫性肝炎的影响目前尚不明确.本研究拟探讨CQ对小鼠自身免疫性肝损伤的影响及可能机制.小鼠尾静脉注射Con A建立小鼠肝损伤模型,1h后,腹腔注射CQ或等体积PBS.观察小鼠生存状况,在不同时间点收集血清和肝组织,采用赖氏法检测血清谷丙转氨酶(GPT)水平;ELISA方法检测血清细胞因子IFN γ及TNF-α含量;HE染色观察肝脏病理损伤情况;免疫印迹检测小鼠肝脏自噬水平指标LC3-Ⅱ和P62.结果显示,Con A+CQ组小鼠血清中GPT水平显著高于Con A组,且病理切片染色显示Con A+CQ组肝脏损伤较Con A组更严重;Con A+CQ注射组小鼠的存活率明显低于仅注射Con A组(P<0.0001);Con A+CQ组小鼠血清中炎性细胞因子IFN-γ和TNF-α的分泌高于Con A组;CQ可抑制Con A刺激诱导的小鼠肝脏自噬水平升高.氯喹可加重Con A诱导的自身免疫性肝损伤,其机制可能是通过抑制肝脏自噬水平从而加剧小鼠肝脏损伤.

  8. Dynamic biogeochemical controls on river pCO2 and recent changes under aggravating river impoundment: An example of the subtropical Yangtze River (United States)

    Liu, Shaoda; Lu, Xi Xi; Xia, Xinghui; Zhang, Shurong; Ran, Lishan; Yang, Xiankun; Liu, Ting


    This paper highlights two aspects of the dynamic biogeochemical controls of riverine pCO2 in an increasingly impounded large subtropical river (the Yangtze): the terrestrial dominance through internal respiration of land-derived organic carbon and the influence of increased autotrophic activity in impounded areas on river pCO2. River pCO2 and total organic carbon (TOC) increase downstream on the main stem (pCO2: 528-1703 µatm; TOC: 137-263 µmol/L) and vary significantly among tributaries (464-3300 µatm; TOC: 109-340 µmol/L). pCO2 displays larger spatial variability than temporal variability and is spatially correlated with river organic carbon across the river (p 60%) do occur in impounded areas (especially in nutrient-rich rivers), but the decrease is mostly temporal and regional (~8% of the data points are significantly influenced, all from the upper reach and/or major tributaries). The paper concludes that terrestrial influence still dominates the pCO2 biogeochemistry in this increasingly intercepted and regulated river system.

  9. N-methyl-D-aspartic acid receptor 1 (NMDAR1) aggravates secondary inflammatory damage induced by hemin-NLRP3 pathway after intracerebral hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Xun Weng; Yan Tan; Xiang Chu; Xiao-Feng Wu; Rui Liu; Yue Tian; Lin Li


    Objective:Inflammation plays a critical role in secondary brain damage after intracerebral hemorrhage (ICH).However,the mechanisms of inflammatory injury following ICH are still unclear,particularly the involvement of NLRP3 inflammasome,which are crucial to sterile inflammatory responses.In this study,we aim to test the hypothesis that NLRP3 signaling pathway takes a vital position in ICH-induced secondary inflammatory damage and detect the role of N-methyl-D-aspartic acid receptor 1 (NMDAR1) in this progress.Methods:ICH was induced in mice by microinjection of hemin into the striatum.The protein levels of NMDAR1,NMDAR1 phosphorylation,NLRP3 and IL-1β were measured by Western blot.The binding of NMDAR1 to NLRP3 was detected by immunoprecipitation.Results:The expression of NMDAR1,NMDAR1 phosphorylation,NLRP3 and IL-1 β were rapidly increased after ICH.Hemin treatment enhanced NMDAR1 expression and NMDAR1 phosphorylation,as well in cultured microglial cells treated by hemin.Hemin up-regulated NLRP3 and IL-1β level,which was reversed by MK801 (NMDAR antagonist) in vitro.Hemin also promoted the binding of NMDAR1 to NLRP3.Conclusion:Our findings suggest that NMDAR1 plays a pivotal role in hemin-induced NLRP3-mediated inflammatory damage through synergistic activation.

  10. Excitotoxic median raphe lesions aggravate working memory storage performance deficits caused by scopolamine infusion into the dentate gyrus of the hippocampus in the inhibitory avoidance task in rats

    Directory of Open Access Journals (Sweden)

    Babar E.


    Full Text Available The interactions between the median raphe nucleus (MRN serotonergic system and the septohippocampal muscarinic cholinergic system in the modulation of immediate working memory storage performance were investigated. Rats with sham or ibotenic acid lesions of the MRN were bilaterally implanted with cannulae in the dentate gyrus of the hippocampus and tested in a light/dark step-through inhibitory avoidance task in which response latency to enter the dark compartment immediately after the shock served as a measure of immediate working memory storage. MRN lesion per se did not alter response latency. Post-training intrahippocampal scopolamine infusion (2 and 4 µg/side produced a more marked reduction in response latencies in the lesioned animals compared to the sham-lesioned rats. Results suggest that the immediate working memory storage performance is modulated by synergistic interactions between serotonergic projections of the MRN and the muscarinic cholinergic system of the hippocampus.

  11. Trans-Fatty Acids Aggravate Obesity, Insulin Resistance and Hepatic Steatosis in C57BL/6 Mice, Possibly by Suppressing the IRS1 Dependent Pathway

    Directory of Open Access Journals (Sweden)

    Xiaona Zhao


    Full Text Available Trans-fatty acid consumption has been reported as a risk factor for metabolic disorders and targeted organ damages. Nonetheless, little is known about the roles and mechanisms of trans-fatty acids in obesity, insulin resistance (IR and hepatic steatosis. Adult C57BL/6 male mice were fed with four different diets for 20 weeks: normal diet (ND, high fat diet (HFD, low trans-fatty acids diet (LTD and high trans-fatty acid diet (HTD. The diet-induced metabolic disorders were assessed by evaluating body weight, glucose tolerance test, hepatic steatosis and plasma lipid profiles post 20-week diet. Histological (H&E, Oil-Red-O staining and western blot analysis were employed to assess liver steatosis and potential signaling pathways. After 20-weeks of diet, the body weights of the four groups were 29.61 ± 1.89 g (ND, 39.04 ± 4.27 g (HFD, 34.09 ± 2.62 g (LTD and 43.78 ± 4.27 g (HTD (p < 0.05, respectively. HFD intake significantly impaired glucose tolerance, which was impaired further in the mice consuming the HTD diet. The effect was further exacerbated by HTD diet. Moreover, the HTD group exhibited significantly more severe liver steatosis compared with HFD group possibly through regulating adipose triglyceride lipase. The group consuming the HTD also exhibited significantly reduced levels of IRS1, phosphor-PKC and phosphor-AKT. These results support our hypothesis that consumption of a diet high in trans-fatty acids induces higher rates of obesity, IR and hepatic steatosis in male C57BL/6 mice, possibly by suppressing the IRS1dependent pathway.

  12. First molecular identification of Entamoeba polecki in a piglet in Japan and implications for aggravation of ileitis by coinfection with Lawsonia intracellularis. (United States)

    Matsubayashi, Makoto; Kanamori, Kenta; Sadahiro, Masayuki; Tokoro, Masaharu; Abe, Niichiro; Haritani, Makoto; Shibahara, Tomoyuki


    Parasitic Entamoeba spp. are found in many vertebrate species including humans, as well as many livestock including pigs. In pigs, three Entamoeba spp., E. suis, and E. polecki and E. histolytica as zoonotic species, have been identified, but their pathogenicity has not been fully characterized. Here, we report the bacteriological, virological, and histopathological examination of three piglets with chronic diarrhea. Two animals appeared to be additionally infected with Lawsonia intracellularis, which caused a characteristic proliferative ileitis. In the piglet infected with Entamoeba spp., the trophozoites (approximately 10-15 μm with one nucleus in their cytoplasm) invaded into the lamina propria and the disease was worsened by the formation of ulcers and pseudomembranes. Genetic analysis identified the parasite as E. polecki (99.5% identity). Although E. polecki in humans or animals might be less pathogenic in the case of a single infection, coinfections with other pathogens including L. intracellularis may increase the severity of the disease.

  13. TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis. (United States)

    Liao, Li; Su, Xiaoxia; Yang, Xiaohong; Hu, Chenghu; Li, Bei; Lv, Yajie; Shuai, Yi; Jing, Huan; Deng, Zhihong; Jin, Yan


    Decline of antioxidant defense after estrogen deficiency leads to oxidative damage in bone marrow-derived mesenchymal stem cells (BMMSCs), resulting a defect of bone formation in osteoporosis. Forkhead box O1 (FoxO1) protein is crucial for defending physiological oxidative damage in bone. But whether FoxO1 is involved in the oxidative damage during osteoporosis is largely unknown. In this study, we found that FoxO1 protein accumulation was decreased in BMMSCs of ovariectomized mice. The decrease of FoxO1 resulted in the suppression of manganese superoxide dismutase (Sod2) and catalase (Cat) expression and accumulation of reactive oxygen species (ROS), inhibiting the osteogenic differentiation of BMMSCs. The decline of FoxO1 protein was caused by tumor necrosis factor-alpha (TNF-α) accumulated after estrogen deficiency. Mechanistically, TNF-α activated NF-κB pathway to promote microRNA-705 expression, which function as a repressor of FoxO1 through post-transcriptional regulation. Inhibition of NF-κB pathway or knockdown of miR-705 largely prevented the decline of FoxO1-mediated antioxidant defense caused by TNF-α and ameliorated the oxidative damage in osteoporotic BMMSCs. Moreover, the accumulated ROS further activated NF-κB pathway with TNF-α, which formed a feed-forward loop to persistently inhibiting FoxO1 protein accumulation in BMMSCs. In conclusion, our study revealed that the decline of FoxO1 is an important etiology factor of osteoporosis and unclosed a novel mechanism of FoxO1 regulation by TNF-α. These findings suggested a close correlation between inflammation and oxidative stress in stem cell dysfunction during degenerative bone diseases.

  14. Vitamin K antagonism aggravates chronic kidney disease-induced neointimal hyperplasia and calcification in arterialized veins: role of vitamin K treatment? (United States)

    Zaragatski, Emma; Grommes, Jochen; Schurgers, Leon J; Langer, Stephan; Kennes, Lieven; Tamm, Miriam; Koeppel, Thomas A; Kranz, Jennifer; Hackhofer, Tina; Arakelyan, Karen; Jacobs, Michael J; Kokozidou, Maria


    Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins

  15. Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage

    NARCIS (Netherlands)

    Davidson, E.N.; Vitters, E.L.; Bennink, M.B.; Lent, P.L. van; Caam, A.P. van; Blom, A.B.; Berg, W.B. van den; Loo, F.A.J. van de; Kraan, P.M. van der


    OBJECTIVES: In osteoarthritis (OA) chondrocytes surrounding lesions express elevated bone morphogenetic protein 2 (BMP2) levels. To investigate the functional consequence of chondrocyte-specific BMP2 expression, we made a collagen type II dependent, doxycycline (dox)-inducible BMP2 transgenic mouse

  16. Ferrous sulfate, but not iron polymaltose complex, aggravates local and systemic inflammation and oxidative stress in dextran sodium sulfate-induced colitis in rats

    Directory of Open Access Journals (Sweden)

    Toblli JE


    Full Text Available Jorge E Toblli, Gabriel Cao, Margarita Angerosa Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina Background and aims: Iron deficiency is common in inflammatory bowel disease, yet oral iron therapy may worsen the disease symptoms and increase systemic and local oxidative stress. The aim of this study was to compare the effects of oral ferrous sulfate and iron polymaltose complex on inflammatory and oxidative stress markers in colitic rats.Methods: Animals were divided into four groups with ten animals each. Rats of three groups received dextran sodium sulfate to induce colitis and animals of two of these groups received 5 mg iron/kg of body weight a day, as ferrous sulfate or iron polymaltose complex, for 7 days. Gross colon anatomy, histology of colon and liver, stainings of L-ferritin, Prussian blue, hepcidin, tumor necrosis factor-α, and interleukin-6, as well serum levels of liver enzymes, inflammatory markers, and iron markers, were assessed.Results: Body weight, gross anatomy, crypt injury and inflammation scores, inflammatory parameters in liver and colon, as well as serum and liver hepcidin levels were not significantly different between colitic animals without iron treatment and colitic animals treated with iron polymaltose complex. In contrast, ferrous sulfate treatment caused significant worsening of these parameters. As opposed to ferrous sulfate, iron polymaltose complex caused less or no additional oxidative stress in the colon and liver compared to colitic animals without iron treatment.Conclusion: Iron polymaltose complex had negligible effects on colonic tissue erosion, local or systemic oxidative stress, and local or systemic inflammation, even at high therapeutic doses, and may thus represent a valuable oral treatment of iron deficiency in inflammatory bowel disease. Keywords: preclinical, oral iron treatment, tolerability, colonic tissue erosion, inflammatory bowel disease

  17. The in-vivo use of superparamagnetic iron oxide nanoparticles to detect inflammation elicits a cytokine response but does not aggravate experimental arthritis

    NARCIS (Netherlands)

    Vermeij, E.A.; Koenders, M.I.; Bennink, M.B.; Crowe, L.A.; Maurizi, L.; Vallee, J.P.; Hofmann, H.; Berg, W.B. van den; Lent, P.L. van; Loo, F.A. van de


    BACKGROUND: Superparamagnetic Iron Oxide Nanoparticles (SPION) are used in diagnostic imaging of a variety of different diseases. For such in-vivo application, an additional coating with a polymer, for example polyvinyl alcohol (PVA), is needed to stabilize the SPION and prevent aggregation. As the

  18. Liver-specific deletion of the signal transducer and activator of transcription 5 gene aggravates fatty liver in response to a high-fat diet in mice. (United States)

    Baik, Myunggi; Nam, Yoon Seok; Piao, Min Yu; Kang, Hyeok Joong; Park, Seung Ju; Lee, Jae-Hyuk


    Growth hormone (GH) signal is mediated by signal transducer and activator of transcription 5 (STAT5), which controls hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is clinically associated with a deficiency in GH. This study was performed to understand the role of local STAT5 signaling on hepatic lipid and glucose metabolism utilizing liver-specific STAT5 gene deletion (STAT5 LKO) mice under both normal diet and high-fat diet (HFD) feeding conditions. STAT5 LKO induced hepatic steatosis under HFD feeding, while this change was not observed in mice on normal diet. STAT5 LKO caused hyperglycemia, hyperinsulinemia, hyperleptinemia and elevated free fatty acid and cholesterol concentrations under HFD feeding but induced only hyperglycemia on normal diet. At the molecular level, STAT5 LKO up-regulated the expression of genes involved in lipid uptake (CD36), very low-density lipoprotein receptor (VLDLR), lipogenic stearoyl-CoA desaturase and adipogenic peroxisome proliferator-activated receptor gamma, in both diet groups. In response to HFD feeding, further increases in CD36 and VLDLR expression were found in STAT5 LKO mice. In conclusion, our study suggests that low STAT5 signaling on normal diet predisposes STAT5 LKO mice to early development of fatty liver by hyperglycemia and activation of lipid uptake and adipogenesis. A deficiency in STAT5 signaling under HFD feeding deregulates hepatic and body glucose and lipid metabolism, leading to the development of hepatic steatosis. Our study indicates that low STAT5 signaling, due to low GH secretion, may increase a chance for NAFLD development in elderly people.

  19. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

    DEFF Research Database (Denmark)

    Gavito, Ana Luisa; Bautista, Dolores; Suarez, Juan;


    High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the ...

  20. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress

    NARCIS (Netherlands)

    Fox, Julie M.; Long, Feng; Edeling, Melissa A.; Lin, Hueylie; van Duijl-Richter, Mareike K. S.; Fong, Rachel H.; Kahle, Kristen M.; Smit, Jolanda M.; Jin, Jing; Simmons, Graham; Doranz, Benjamin J.; Crowe, James E.; Fremont, Daved H.; Rossmann, Michael G.; Diamond, Michael S.


    We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphav

  1. 道光末年银贵钱贱的加剧及其社会影响%The Aggravation and Social Effect of Silver Costly and Cash Cheap in the Last Phase of Dao Guang

    Institute of Scientific and Technical Information of China (English)




  2. Knockout of the c-Jun N-terminal Kinase 2 aggravates the development of mild chronic dextran sulfate sodium colitis independently of expression of intestinal cytokines TNFα, TGFB1, and IL-6

    Directory of Open Access Journals (Sweden)

    Kersting S


    Full Text Available Sabine Kersting,1 Kirstin Reinecke,2 Christoph Hilgert,1 Monika S Janot,1 Elisabeth Haarmann,1 Martin Albrecht,1 Annette M Müller,3 Thomas Herdegen,2 Ulrich Mittelkötter,1 Waldemar Uhl,1 Ansgar M Chromik11Department of General and Visceral Surgery, St Josef Hospital, Ruhr-University of Bochum, Bochum, Germany; 2Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany; 3Department of Pediatric Pathology, Rheinische Friedrich-Wilhems-University of Bonn, Bonn, GermanyIntroduction: The c-Jun N-terminal kinases (JNKs are involved in signal transduction of inflammatory bowel diseases. The aim of this study was to examine the function of JNKs by using a low-dose dextran sulfate sodium (DSS model in JNK1 knockout mice (Mapk8–/–, JNK2 knockout mice (Mapk9–/–, and wild-type controls (WT1, WT2.Methods: The animals were evaluated daily using a disease activity index. After 30 days, the intestine was evaluated histologically with a crypt damage score. CD4+ and CD8+ cells were quantified using immunofluorescence. Analysis of tumor necrosis factor-a (TNFα, interleukin-6 (IL-6, and transforming growth factor ß1 (TGFB1 expression was carried out using LightCycler® real-time polymerase chain reaction.Results: Cyclic administration of low-dose DSS (1% was not able to induce features of chronic colitis in Mapk8–/– WT2 mice. By contrast, DSS administration significantly increased the disease activity index in WT1 and Mapk9–/– mice. In Mapk9–/– mice, the crypt damage score and the number of CD4+ and CD8+ cells as features of chronic colitis/inflammation were also significantly elevated. Expression of TNFα, IL-6, and TGFB1 was not altered by the JNK knockout.Conclusion: Administering DSS at a defined low concentration that is unable to induce colitis in WT animals leads to clinically and histologically detectable chronic colitis in Mapk9–/– mice. The reason for this disease-inducing effect resulting from the loss of JNK2 remains to be elucidated. Expression of TNFα, IL-6, and TGFB1 does not appear to be involved; proapoptotic JNK2 may prolong the activity of proinflammatory immune cells, leading to perpetuation of the inflammation.Keywords: inflammatory bowel diseases, proinflammatory cytokines, JNK knockout mice, T-cell immune response

  3. Evaluation of cardiac blood blow, metabolism and sympathetic nerve function in patients with cardiac failure using PET and SPECT. Prognostic diagnosis based on the analysis of aggravating factors of the disease

    Energy Technology Data Exchange (ETDEWEB)

    Ishida, Yoshio; Shimozu, Junko; Yasumura, Yoshio; Nagatani, Kenzo; Miyatake, Kunio [National Cardiovascular Center, Suita, Osaka (Japan)


    Focusing on the failure of energy metabolism, which is assumed to be attributed to the cardiac muscle disorder of a patient with cardiac failure, the characteristics and diagnostic significance of the metabolic disorders of cadiac muscles were investigated in those patients. The diagnostic efficacy of {beta}-methyl iodophenyl pentadecanoic acid (BMIPP) which is a imaging agent for lipid metabolism in the cardiac muscle was assessed in the clinical states of cardiac failure due to pulmonary hypertension. Even if there was a considerable increase in the mean pulmonary arterial pressure (mPAP), the initial accumulation of BMIPP linearly increased, similarly to the increase in the accumulation of MIBI, a blood flow agent. The initial accumulation of BMIPP was thought to reflect a thicken cardiac muscle and/or increased blood flow. Also, its washing-out rate was suggested to be usable as an clinical indicator to estimate the loading of ventricular pressure. (M.N.)

  4. 过表达解偶联蛋白-2基因加重原代肝细胞急性损伤%Overexpression of Uncoupling Protein 2 Aggravates Acute Primary Hepatocyte Damage

    Institute of Scientific and Technical Information of China (English)

    万赤丹; 程锐; 王春友; 王宏博; 王帅; 刘涛


    目的 研究解偶联蛋白-2(uncoupling protein-2,UCP-2)基因在肝细胞急性损伤过程中的作用.方法 构建小鼠UCP-2基因过表达慢病毒载体;二步胶原酶灌注法分离培养小鼠原代肝细胞;慢病毒感染肝细胞,使肝细胞中UCP-2基因表达上调;荧光显微镜镜检确定感染效率.Real time PCR检测UCP-2表达;肿瘤坏死因子-α(TNF-α)作用于病毒感染肝细胞24 h后.检测细胞上清液中谷丙转氨酶(ALT)和乳酸脱氢酶(LDH)水平;碘化丙啶(PI)染色流式细胞仪检测细胞凋亡,Western blot检测凋亡因子Caspase 3的活化.结果 Real time PCR检测证实目的 细胞中UCP-2表达上调;TNF-α作用后病毒感染的实验组上清液中ALT和LDH水平、细胞凋亡率、凋亡因子Caspase 3活化程度均高于对照组(均P<0.05).结论 UCP-2基因过度表达可加重肝细胞急性损伤.

  5. p18INK4C基因敲除加重顺铂诱导的小鼠急性肾损伤%p18INK4C depletion aggravates cisplatin-induced acute kidney injury in mice

    Institute of Scientific and Technical Information of China (English)

    谌卫; 张懿; 袁莉; 胡惠民; 梅长林


    目的 探讨周期素依赖性激酶抑制基因p18INK4C敲除对顺铂诱导的小鼠急性肾损伤(AKI)的影响,并分析其可能机制.方法 利用已引种的杂合p18INK4C基因敲除小鼠p18INK4C+/-繁育p18INK4C基因敲除小鼠P18INK4C-/-(KO组),以同窝野生型小鼠p18INK4C+/+作为对照(WT组).腹腔注射顺铂制备AKI模型,观察两组小鼠的存活情况,并检测给药后第2、3、5天血肌酐、尿素氮的变化及肾组织的病理变化.结果 WT组小鼠在第3天出现死亡,第7天存活率为46.7%(14/30).KO组小鼠自第2天出现死亡,至第7天全部死亡(100.0%,30/30).KO组的死亡率显著高于WT组(P<0.05).自给药后第2天起,KO组小鼠的肾功能恶化明显,此后继续加重.给药后第2、3、5天,KO组的尿素氮、肌酐均显著高于WT组(P值均<0.05).WT和KO组小鼠均以给药后第3天肾脏病变最为严重.结论 p18INK4C基因敲除加速了顺铂诱导的小鼠AKl的进展,可能与其增加小管上皮损伤及加剧炎性反应有关.

  6. Throbbing tinnitus in aberrant internal carotid artery aggravated by elevation of the jugular bulb. A case report; Pulsierender Tinnitus bei aberranter Arteria carotis interna in Kombination mit Hochstand des Bulbus venae jugularis. Kasuistik

    Energy Technology Data Exchange (ETDEWEB)

    Wilhelm, T. [Inst. fuer Roentgendiagnostik, Klinikum der Technischen Univ. Muenchen (Germany); Kirsten, R. [Inst. fuer Roentgendiagnostik, Klinikum der Technischen Univ. Muenchen (Germany); Kau, R.J. [Hals-Nasen-Ohrenklinik und Poliklinik, Klinikum der Technischen Univ. Muenchen (Germany)


    Vascular anomalies in the middle ear are rarely observed. They cause no symptoms in the majority of cases, although some may be associated with tinnitus. The false diagnosis of glomus tumour may lead to considerable problems, if surgery is performed. It is therefore necessary that precise pre-operative data are obtained, preferably based on contrast-enhanced computerized tomography. Subsequent 2D and 3D image reconstructions provide further vascular findings regarding the topographic and anatomic factors involved and eliminate the need for invasive angiography of the carotid artery or retrograde jugular venography to make a firm diagnosis. (orig.) [Deutsch] Gefaessanomalien im Mittelohr sind selten. Meist sind sie asymptomatisch, koennen aber assoziiert sein mit Tinnitus. Die Fehldiagnose eines Glomustumors kann im Rahmen einer Operation zu gravierenden Problemen fuehren. Eine exakte praeoperative Abklaerung ist deshalb notwendig und sollte als Computertomographie mit Kontrastmittelgabe durchgefuehrt werden. Die anschliessende 2D- und 3D-Bildwiedergabe klaert die topographisch-anatomischen Gefaessbeziehungen und erlaubt somit die Diagnosestellung ohne die frueher durchgefuehrte invasive Carotisangiographie oder retrograde Jugularisvenographie. (orig.)

  7. Contralaterai nephrectomy with disturbance of lymph circulation aggra-vate renal damage%肾淋巴管结扎对单肾切除大鼠的肾损害作用

    Institute of Scientific and Technical Information of China (English)

    柳刚; 孙玫; 李德祥; 张桃艳; 关广聚; 陈兵; 李学刚


    目的:探讨肾淋巴循环障碍及单侧肾脏切除对大鼠肾脏功能结构的损害.方法:雄性Wistar大鼠,随机分为3组:双肾淋巴管结扎组(2KL),左肾淋巴管结扎伴右肾切除组(1KL),假手术组(sham).分别在术后1、2、4、8周每组各处死6只.测定24 h尿蛋白和血尿肌酐.用PAS和Masson染色观察肾组织病理改变.用RT-PCR检测TGF-β1、Smad2/3、Ⅰ型胶原(col I)mRNA的表达量;用免疫组化和Western blotting方法检测组织col Ⅰ、TGF-β1、Smad2/3和磷酸化Smad2/3(P-Smad2/3)的蛋白表达量及主要表达部位.结果:2KL和1KL大鼠出现明显的蛋白尿和肾功能衰竭,1KL大鼠的肾脏损害尤其明显,随着时间推移逐渐加重,并出现明显的组织病理改变.2KL和1KL大鼠肾组织中col I、TGF-β1、Smad2/3、p-Smad2/3的蛋白和(或)基因表达水平也明显增高(P<0.01),且主要表达在肾小管上皮细胞及肾间质.1KL大鼠的表达也明显高于2KL大鼠.结论:肾淋巴循环障碍可导致大鼠肾脏功能及小管间质的损害,并随时间而加重.当淋巴循环障碍伴对侧肾切除时,损害明显加重.

  8. Quantitative expression of the homeobox and integrin genes in human gastric carcinoma. (United States)

    Rossi Degl'Innocenti, Duccio; Castiglione, Francesca; Buccoliero, Anna Maria; Bechi, Paolo; Taddei, Gian Luigi; Freschi, Giancarlo; Taddei, Antonio


    The homeobox (HOX) genes are a large family of regulator genes involved in the control of developmental processes and cell differentiation. The HOX genes encode transcription factors, and an increasing number of studies have shown that these genes may be implicated in the growth and the progression of many types of tumours. The present study investigated the expression of the HOX and integrin genes and their relationships in gastric carcinoma. We analyzed the RNA expression of 13 HOX genes from HOXA, C and D clusters and alphaV, alpha5 and alpha8 integrin genes in 24 gastric cancer samples by quantitative real-time PCR. The results showed that the HOXA2 gene and the alpha8 integrin gene had a lower expression in tumour samples than in normal gastric mucosas. The comparison between the HOX and integrin genes showed that HOXA2 and alphaV integrin expression presented the same trend in 83% of the samples. Moreover, in cancer samples that expressed the HOXD11 gene, the expression of alphaV integrin was lower with respect to normal mucosas. The different roles of HOX and integrin genes in gastric carcinoma remain to be fully elucidated. These findings suggest that the HOX genes may play a critical role in the genesis, maintenance and diffusion of gastric carcinoma.

  9. 重组转化生长因子β3基因对大鼠肝星状细胞Ⅰ型胶原表达的影响%Effects of transforming growth factor-beta 3 gene transfer on type I collagen synthesis of hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    周霞; 余姣; 李琪; 钱伟; 徐可树


    目的 观察转化生长因子β3基因(TGF β3)对大鼠肝星状细胞株(HSC-T6) Ⅰ型胶原合成的影响.方法 TGF β3表达质粒[pcDNA3.1(+)-TGF β3]和TGF β1表达质粒[pcDNA3.1(+)-TGF β1]的构建.通过脂质体介导方法,将pcDNA3.1(+)-TGF β1、pcDNA3.1(+)-TGF β3分别及共同转染体外培养的HSC-T6细胞,荧光定量PCR法及Western blot法分别检测转染后TGF β1、TGF β3、Ⅰ型胶原mRNA及蛋白质的表达.将pcDNA3.1(+)-TGF β1转染HSC-T6细胞,经G418筛选建立高表达TGF β1的HSC-T6细胞克隆,pcDNA3.1(+)-TGF β3转染克隆细胞,荧光定量PCR法检测转染后TGF β3、TGF β1及Ⅰ型胶原mRNA的表达,Western blot法检测TGF β1、Ⅰ型胶原蛋白的表达情况.结果 构建的pcDNA3.1(+)-TGF β3、pcDNA3.1(+) TGF β1质粒可转染HSC-T6细胞,转染率28.2%.pcDNA3.1(+)-TGF β3转染细胞后, I型胶原mRNA及蛋白的表达较空白组及对照组增加,以72 h增高最为明显(P《0.05),共转染组I型胶原mRNA及蛋白质的表达较pcDNA3.1(+)-TGF β1转染组明显降低(P《0.05).TGF β3转染克隆细胞后,TGF β1 mRNA表达较克隆组无明显改变(P》0.05),而蛋白质表达明显下降(P《0.05),I型胶原mRNA及蛋白质表达均较克隆组明显降低(P《0.05).结论 TGF β3基因转染正常培养的HSC-T6细胞,增加I型胶原的表达,转染高表达TGF β1的克隆组HSC-T6细胞, I型胶原表达明显降低,提示TGF β3对肝纤维化的发生有抑制作用.

  10. Transforming growth factor beta 1 and beta 3 expression during skin wound healing of rats%大鼠皮肤创伤修复过程中转化生长因子β1和β3的表达***

    Institute of Scientific and Technical Information of China (English)

    赵佳佳; 杨丕波; 韩传火; 刘加荣


    BACKGROUND: Transforming growth factor β plays a key role in the repair of tissue injury. OBJECTIVE: To investigate the expression level and distribution of transforming growth factor β1 and transforming growth factor β3 during healing of skin scarred wound. METHODS: The ful-thickness incised wound model was established in rats, 1.5-2.0 cm long to the fascia layer. Immunohistochemistry was used to quantitatively analyze the expression level and position of transforming growth factor β1 and transforming growth factor β3 in rats at 0, and 12 hours, 1, 2, 3, 4, 5, 6, and 7 days post injury. RESULTS AND CONCLUSION: Results showed that the transforming growth factor β1 and transforming growth factor β3 positive particles mainly distributed in cytoplasm of epithelial cel s and epithelial basilar membrane, macrophage and granulation tissue in the early stage of wound healing (1-5 days post injury). With prolonged time, the positive particles were mainly found in fibroblast and extracel ular matrix. The expression level of transforming growth factor β1 was up-regulated intensively during 1-5 days after injury, and transforming growth factor β3 was significantly expressed since 6 and 7 days post injury. That is, transforming growth factor β1 was earlier expressed than transforming growth factor β3 during wound healing. Results showed a close relationship between transforming growth factor β1 and col agen formation, as wel as wound repair. The expression level of transforming growth factor β3 was increased in the later stage of wound healing, indicating that transforming growth factor β3 may be related to the remodeling of the wound.%  背景:转化生长因子β在组织创伤修复中发挥核心和关键作用。目的:观察转化生长因子β1和转化生长因子β3在大鼠皮肤瘢痕性创伤愈合过程中表达量及表达部位的变化。方法:制备大鼠皮肤全层切伤模型,长度1.5-2.0 cm,深及筋膜层。于伤后0 h,12 h,1 d,2 d,3 d,4 d,5 d,6 d,7 d处死大鼠,取损伤部位皮肤,采用免疫组织化学染色检测各时间点转化生长因子β1和转化生长因子β3的表达,并进行定量分析。结果与结论:免疫组织化学染色显示,在创伤愈合的早期阶段(伤后1-5 d),转化生长因子β1和转化生长因子β3免疫阳性颗粒主要出现在上皮细胞、上皮基底层细胞胞浆、巨噬细胞等免疫细胞胞浆及肉芽组织中;随着创伤修复时间的持续,免疫阳性颗粒主要出现在真皮层的成纤维细胞及细胞外基质中。其中转化生长因子β1的表达在创伤后1-5 d最强,而转化生长因子β3在创伤后六七天时开始明显表达。可见在大鼠皮肤瘢痕性创伤愈合过程中,转化生长因子β1的表达先于转化生长因子β3,提示转化生长因子β1与胶原形成及创伤修复关系密切,而转化生长因子β3在愈合后期表达量有升高趋势,其可能与创伤后期的组织改建密切相关。

  11. β3肾上腺素能受体基因Trp64Arg多态性与蒙古族原发性高血压病相关性分析%Association of Beta 3 Adrenergic Receptor Gene Polymorphism and Essential Hypertension in Mongolian Population

    Institute of Scientific and Technical Information of China (English)

    张晓云; 魏芳婧; 徐力; 阴淑莹


    目的 检测蒙古族原发性高血压人群中β3肾上腺素能受体基因Trp64Arg多态性,探讨其与蒙古族人群原发性高血压病(EH)和其他心血管病危险因素的关系.方法 应用PCR技术检测原发性高血压病患者102例,健康体检者93例.比较两组Trp64Arg突变基因型和临床特征.结果 高血压病组与对照组β3-AR基因突变频率两者差异无统计学意义(P>0.05),基因Tr p 64Arg突变者的体质量指数显著高于正常基因型(P0. 05). In the patients group,body mass index(BMI)in patients with gene Trp64Arg mutation were significantly higher than that in patients with normal genotype(P<0. 05). Triglycerides,glucose,insulin,uric acid were significantly different between the two groups(P<0. 05). Conclusion Trp64Arg mutation may not be the determinants of the occurrence of hypertension. However, the gene mutation may be related to obesity,lipid metabolism,glucose metabolism and other risk factors.

  12. Transforming growth factor beta 3 induced odontoblast-like differentiation of stem cells from human exfoliated deciduous teeth%转化生长因子β3诱导人乳牙牙髓干细胞向成牙本质样细胞的分化

    Institute of Scientific and Technical Information of China (English)

    周慧; 林锦梅; 任飞; 刘建平; 章锦才; 徐平平; 杨勤; 陈晓春


    背景:转化生长因子β3与肝素联合作用后对人乳牙牙髓干细胞的增殖和矿化能力的作用目前仍有待研究。目的:探讨转化生长因子β3对人乳牙牙髓干细胞向成牙本质样细胞分化的作用。方法:采用酶消化法将人乳牙牙髓分离培养,获得人乳牙牙髓干细胞;对体外培养的第3代人乳牙牙髓干细胞单独加入25μg/L重组转化生长因子β3、10 U/mL 肝素,或者二者联合进行培养;通过Q-PCR和Western-blotting 方法,分别检测乳牙牙髓干细胞中牙本质涎磷蛋白基因及牙本质涎蛋白表达的情况;通过碱性磷酸酶试剂盒检测乳牙牙髓干细胞碱性磷酸酶活性的改变。结果与结论:乳牙牙髓干细胞在诱导体系中生长状态良好。25μg/L转化生长因子β3+10 U/mL肝素联合作用组的碱性磷酸酶活性明显增强,与转化生长因子β3单独作用组、肝素单独作用组以及对照组相比差异有显著性意义(P <0.01);转化生长因子β3+肝素联合作用组的茜素红染色呈强阳性,Q-PCR和Western-blotting结果均显示,转化生长因子β3+肝素联合作用组的牙本质涎磷蛋白 mRNA 和蛋白表达均明显升高。结果可见在转化生长因子β3与肝素联合作用的诱导下,可促进乳牙牙髓干细胞分化为成牙本质样细胞。%BACKGROUND:Studies have reported that the superfamily of transforming growth factors exert a role in the mineralization of various stem cells, but the combination effects of transforming growth factorβ3 and heparin on proliferation and mineralization ability of stem cells from human exfoliated deciduous teeth remains to be studied. OBJECTIVE:To explore the effect of transforming growth factorβ3 on odontoblast-like differentiation of stem cells from human exfoliated deciduous teeth. METHODS:Human deciduous teeth were col ected using enzyme digestion. The 3rd cells were incubated with 25μg/L recombinant human transforming growth factorβ3, 10 U/mL heparin or their combination. The dentin sialophosphoprotein mRNA and dentinsialoprotein expressions were detected by Q-PCR and western blot assay. Alkaline phosphatase activity was determined using alkaline phosphatase kit. RESULTS AND CONCLUSION:Stem cells from human exfoliated deciduous teeth grew wel after induction. The activity of alkaline phosphatase in the combination group was significantly higher than that in the transforming growth factorβ3, heparin and control groups (P<0.01). After combination induction, the cells were strongly positive for alizarin red staining. Results fromα-PCR and western blot assay showed that the expressions of dentin sialophosphoprotein were both remarkably increased at mRNA and protein levels. In summary, stem cells from human exfoliated deciduous teeth can differentiate into odontoblast-like cells under the induction of transforming growth factorβ3 plus heparin.

  13. NCBI nr-aa BLAST: CBRC-BTAU-01-1453 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-BTAU-01-1453 sp|Q9XT58|ADRB3_SHEEP Beta-3 adrenergic receptor (Beta-3 adrenoce...ptor) (Beta-3 adrenoreceptor) gb|AAG31165.1|AF314202_1 beta 3 adrenergic receptor [Ovis aries] gb|AAG31167.1|AF314204_1 beta 3 adrene...rgic receptor [Ovis aries] gb|ABB71185.1| beta 3 adrenergic reecptor [Ovis aries] Q9XT58 0.0 97% ...

  14. Fetal muscle gene transfer is not enhanced by an RGD capsid modification to high-capacity adenoviral vectors. (United States)

    Bilbao, R; Reay, D P; Hughes, T; Biermann, V; Volpers, C; Goldberg, L; Bergelson, J; Kochanek, S; Clemens, P R


    High levels of alpha(v) integrin expression by fetal muscle suggested that vector re-targeting to integrins could enhance adenoviral vector-mediated transduction, thereby increasing safety and efficacy of muscle gene transfer in utero. High-capacity adenoviral (HC-Ad) vectors modified by an Arg-Gly-Asp (RGD) peptide motif in the HI loop of the adenoviral fiber (RGD-HC-Ad) have demonstrated efficient gene transfer through binding to alpha(v) integrins. To test integrin targeting of HC-Ad vectors for fetal muscle gene transfer, we compared unmodified and RGD-modified HC-Ad vectors. In vivo, unmodified HC-Ad vector transduced fetal mouse muscle with four-fold higher efficiency compared to RGD-HC-Ad vector. Confirming that the difference was due to muscle cell autonomous factors and not mechanical barriers, transduction of primary myogenic cells isolated from murine fetal muscle in vitro demonstrated a three-fold better transduction by HC-Ad vector than by RGD-HC-Ad vector. We hypothesized that the high expression level of coxsackievirus and adenovirus receptor (CAR), demonstrated in fetal muscle cells both in vitro and in vivo, was the crucial variable influencing the relative transduction efficiencies of HC-Ad and RGD-HC-Ad vectors. To explore this further, we studied transduction by HC-Ad and RGD-HC-Ad vectors in paired cell lines that expressed alpha(v) integrins and differed only by the presence or absence of CAR expression. The results increase our understanding of factors that will be important for retargeting HC-Ad vectors to enhance gene transfer to fetal muscle.

  15. SwissProt search result: AK105506 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK105506 001-127-D12 (Q9JJZ9) Cyclic-nucleotide-gated cation channel beta 3 (CNG channel beta 3) (Cyclic... nucleotide gated channel beta 3) (Cone photoreceptor cGMP-gated channel beta subunit) (Cyclic... nucleotide-gated cation channel modulatory subunit) (Cyclic nucl CNGB3_MOUSE 4e-14 ...

  16. SwissProt search result: AK100739 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK100739 J023118D04 (Q9JJZ9) Cyclic-nucleotide-gated cation channel beta 3 (CNG channel beta 3) (Cyclic... nucleotide gated channel beta 3) (Cone photoreceptor cGMP-gated channel beta subunit) (Cyclic... nucleotide-gated cation channel modulatory subunit) (Cyclic nucl CNGB3_MOUSE 4e-18 ...

  17. Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. (United States)

    Wickham, T J; Tzeng, E; Shears, L L; Roelvink, P W; Li, Y; Lee, G M; Brough, D E; Lizonova, A; Kovesdi, I


    Alteration of the natural tropism of adenovirus (Ad) will permit gene transfer into specific cell types and thereby greatly broaden the scope of target diseases that can be treated by using Ad. We have constructed two Ad vectors which contain modifications to the Ad fiber coat protein that redirect virus binding to either alpha(v) integrin [AdZ.F(RGD)] or heparan sulfate [AdZ.F(pK7)] cellular receptors. These vectors were constructed by a novel method involving E4 rescue of an E4-deficient Ad with a transfer vector containing both the E4 region and the modified fiber gene. AdZ.F(RGD) increased gene delivery to endothelial and smooth muscle cells expressing alpha(v) integrins. Likewise, AdZ.F(pK7) increased transduction 5- to 500-fold in multiple cell types lacking high levels of Ad fiber receptor, including macrophage, endothelial, smooth muscle, fibroblast, and T cells. In addition, AdZ.F(pK7) significantly increased gene transfer in vivo to vascular smooth muscle cells of the porcine iliac artery following balloon angioplasty. These vectors may therefore be useful in gene therapy for vascular restenosis or for targeting endothelial cells in tumors. Although binding to the fiber receptor still occurs with these vectors, they demonstrate the feasibility of tissue-specific receptor targeting in cells which express low levels of Ad fiber receptor.

  18. Application of pressure perturbation calorimetry to lipid bilayers. (United States)

    Heerklotz, Heiko; Seelig, Joachim


    Pressure perturbation calorimetry (PPC) is a new method that measures the heat consumed or released by a sample after a sudden pressure jump. The heat change can be used to derive the thermal volume expansion coefficient, alpha(V), as a function of temperature and, in the case of phase transitions, the volume change, DeltaV, occurring at the phase transition. Here we present the first report on the application of PPC to determine these quantities for lipid bilayers. We measure the volume changes of the pretransition and main transition of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and the thermal expansivity of the fluid phase of DMPC and of two unsaturated lipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-phosphocholine. The high sensitivity of PPC instrumentation gives accurate data for alpha(V) and DeltaV even upon the application of relatively low pressures of approximately 5 bar.

  19. 吡哆醇对脑淋巴引流阻滞所致SAH后神经细胞凋亡加重的影响%Cerebral lymphatic blockage aggravates apoptosis of cortical neurons after SAH in rat and pyridoxine has a certain role in the mitigation

    Institute of Scientific and Technical Information of China (English)

    王轩; 陈锋; 高兵; 高向东; 贾丽丽; 杨明峰; 孙保亮


    目的 探讨脑淋巴引流阻滞(CLB)对蛛网膜下腔出血(SAH)后神经细胞凋亡的影响和吡哆醇的缓解作用及相关机制.方法 健康成年Wistar大鼠,随机分为正常对照组、SAH组、SAH+CLB组、SAH+CLB+吡哆醇组、SAH+CLB+生理盐水组.采用枕大池2次注血法建立SAH模型.于第2次注血3 d后检测相关指标.SAH+CLB+吡哆醇组于CLB术前30 min按50 mg·kg-1腹腔注射吡哆醇生理盐水溶液,每天以上述半量重复注射2次.采用TUNEL荧光标记法检测原位凋亡情况;免疫组织化学激光共聚焦检测大鼠皮层神经细胞Caspase-3和Bcl-2的蛋白表达.结果 ①与正常对照组比较,其余各组大鼠TUNEL阳性细胞表达均明显升高,而SAH+CLB组和SAH+CLB+生理盐水组又明显高于SAH组(P<0.01),SAH+CLB+吡哆醇组与SAH+CLB组比较表达有所减弱(P<0.01).②与正常对照组比较,其余各组大鼠皮层神经细胞Caspase-3蛋白表达均明显升高,而SAH+CLB组和SAH+CLB+生理盐水组最高,与SAH组比较差异具有显著性(P<0.01),SAH+CLB+吡哆醇组与SAH+CLB组比较表达有所减弱(P<0.01).③与正常对照组比较,其余各组大鼠皮层神经细胞Bcl-2蛋白表达均明显升高,而SAH+CLB组和SAH+CLB+生理盐水组明显低于SAH组(P<0.01),SAH+CLB+吡哆醇组较SAH+CLB组表达增强.结论 脑淋巴引流阻滞可以通过Caspase-3高表达和Bcl-2低表达加重SAH后大鼠皮层神经细胞的凋亡,而吡哆醇具有一定的缓解作用.

  20. Lentivirus-induced knockdown of low density lipoprotein receptor-related protein 1 aggravates cartilage damage in a rat model of osteoarthritis%慢病毒介导shRNA关节腔注射可加重骨关节炎的软骨破坏

    Institute of Scientific and Technical Information of China (English)

    杨二平; 彭飞; 梁杰; 杜远立


    BACKGROUND:Emerging evidence demonstrates that low density lipoprotein receptor-related protein 1 (LRP1)isinvolved in lipid metabolism and regulation of inflammatory reaction. OBJECTIVE:To explore the effectof lentivirus-induced knockdown of low density lipoprotein receptor-related protein 1 on cartilage damage and matrix metaloproteinase 13 in a rat model of osteoarthritis, so as to assess the role of low density lipoprotein receptor-related protein 1 in the pathogenesis of osteoarthritis. METHODS:Sixty-fourSprague-Dawleyratswere included andramdomlydivided into four groups (n=16 for each): negative control group, no surgery; sham-surgery group, onlythearticular cavity of the knee was exposed; osteoarthritisplus shLRP1 group, rat osteoarthritis models were established by cutting anterior cruciate ligament and removing the medial meniscus partly folowed by an intra-articular injection of lentivirus-mediated siRNA at 2 days after surgery, once a week for 2 consecutive weeks; osteoarthritis group,an intra-articular injection of the negative control lentivirus was performed after surgery. Rats inthe four groups started running on theself-made electric treadmil from 5 days after modeling, 30 minutes per day,totaly 500 meters. Cartilage damage and matrix metaloproteinase 13 expression in cartilage tissues were determined at 2, 4, 6 weeks after surgery. RESULTS AND CONCLUSION:Gross and pathological observations showed that lentivirus-induced knockdown of lowdensity lipoprotein receptor-related protein 1 aggravatedcartilage damage intherat model of osteoarthritis. At 6 weeks after surgery, Mankin’s scoreand matrix metaloproteinase 13 expression inthecartilage tissues in osteoarthritis plus shLRP1 groupweresignificantly increased compared with other three groups (P  目的:观察慢病毒介导的低密度脂蛋白受体相关蛋白1-shRNA对大鼠骨关节炎模型软骨破坏的影响,以及对软骨组织中基质金属蛋白酶13表达的作用,初步判断低密度脂蛋白受体相关蛋白1对体内实验骨关节炎发病进程中的作用。  方法:SD大鼠64只分为4组,每组16只。①对照组大鼠未做手术为阴性对照组。②假手术组大鼠显露关节腔后及关闭切口,不切断交叉韧带和半月板。③模型+shLRP1组大鼠切断前交叉韧带切断加内侧半月板部分切除制作骨关节炎模型,造模后2 d用慢病毒介导的siRNA关节腔注射,每周1次,连续2周。④骨关节炎模型组,造模后关节腔注射阴性对照慢病毒。4组大鼠造模后5d开始在自制的电动跑步机中跑步,每日跑步30 min,里程为500 m。造模2,4及6周处死各小组大鼠,观察软骨破坏程度和软骨组织中基质金属蛋白酶13表达。  结果与结论:①大体和病理切片观察发现:行关节腔注射慢病毒介导的siRNA抑制关节软骨的低密度脂蛋白受体相关蛋白1表达后,大鼠骨关节炎模型中软骨破坏加重,加速骨关节炎病程。②6周时:模型+shLRP1组Mankin’s评分明显高于其他3组(P<0.05),模型+shLRP1组软骨细胞基质金属蛋白酶13阳性率明显高于其他3组(P<0.05)。③结果说明:前叉韧带切断加内侧半月板部分切除并配合跑步机中慢跑锻炼能再现骨关节炎模型。慢病毒介导siRNA关节腔注射可干扰抑制关节软骨中的低密度脂蛋白受体相关蛋白1表达,对关节软骨有加重损伤的作用。

  1. Acute ethanol intoxication aggravates traumatic brain injury in rats and its relation to oxygen free radicals%急性乙醇中毒对大鼠颅脑损伤后神经系统的影响及其氧自由基损伤机制的研究

    Institute of Scientific and Technical Information of China (English)

    汤崇辉; 许信龙; 傅小君; 魏晓捷; 潘红松; 方战舰


    目的 探讨急性乙醇中毒对大鼠颅脑创伤后神经系统的影响及其氧自由基损伤机制.方法 Feeney法制作大鼠重型颅脑损伤模型,乙醇灌胃法建立急性乙醇中毒模型.48只雄性SD大鼠随机分为单纯急性乙醇中毒组(A组)、单纯颅脑创伤组(B组)、急性乙醇中毒合并颅脑创伤组(C组)和假手术组(D组)各12只.在伤后1、6、24、72h进行行为学评分;在伤后72h,各组随机取其中6只在麻醉下经心脏灌注4%多聚甲醛固定脑组织,TUNEL法测凋亡细胞数;其余6只快速断头取水肿带脑组织,测定脑组织内SOD活性及MDA含量.结果 C组大鼠的行为学评分最低,恢复最慢;其脑组织内MDA含量最高,SOD含量最低;其神经细胞凋亡最多.结论 急性乙醇中毒可加重颅脑创伤后氧自由基的损害,增加神经细胞的凋亡,影响神经功能的恢复.%Objective To investigate the influence of acute ethanol intoxication (AEI) on traumatic brain injury (TBI) in rats and its relation to oxygen free radicals.Methods Severe traumatic brain injury model was established by Feeny method in rats, and acute ethanol intoxication was induced by gastric gavage.Forty- eight male SD rats were randomly divided into 4 groups: acute ethanol intoxication group (A), traumatic brain injury group (B), acute ethanol intoxication with traumatic brain injury group (C) and sham operation group (D).The behavioral scores were examined at 1h, 6h, 24h and 72h after injury.After 72h, 6 rats from each group were sacrificed and brain specimens were collected.The apoptotic cells were detected by TUNEL method; the superoxide dismutase (SOD) and malondialdehyde (MDA) were determined.Data were analyzed by one- way ANOVA Results The behavior score of group C was the lowest (P<0.05) and delayed to recover (P<0.05).In group C the content of MDA was the highestand SODwas the lowest(P<0.05); the percentage ofapoptosis cells was the highest among 4 groups (P<0.05).Conclusion Acute ethanol intoxication exacerbates oxygen free radical damage after traumatic brain injury, increases neural cell apoptosis and affects the recovery of neurological function

  2. The study of selective segmental renal artery clamping aggravating pathological injury of the solitary-kidney in a porcine model%选择性肾段动脉钳夹阻断加重猪孤立肾缺血组织病理损伤的研究

    Institute of Scientific and Technical Information of China (English)

    徐述雄; 储铸钢; 王元林; 赵传祥; 徐元高; 石华; 李凯; 孙兆林; 夏术阶


    Objective To evaluate the effect of selective segmental renal artery clamping ( SSRAC) on the solitary-kidney, providing a foundamental basis for the using of SSRAC in partial nephrectomy. Methods A total of 18 pigs were randomized equally into 2 groups according to the method of renal artery clamping such as main renal artery clamping ( MRAC) group or SSRAC group.Each case underwent right radical nephrectomy and either MRAC or SSRAC for 60 minutes on the left kidney.Serum creatinine ( SCr) and blood urea nitrogen (BUN) were measured before surgery and at 6 time points thereafter (the 1st, 7th, 14th, 21st, 28th, 90th day).Magnetic resonance imaging was performed before surgery and at 4 time points thereafter (the 1st, 7th, 28th, 90th day) and T2 relaxation time and apparent diffusion coefficient (ADC) were determined.Inflammatory cell infiltration and interstitial fibrosis were detected using renal histology on the 1st and 90th day after operation.Results SCr and BUN of the two groups increased to peak value on the 1st day, and then decreased gradually to normal on the 90th day after the operation.On the 1st day, SCr [(266.43 ±31.12)umol/l] and BUN [(13.63 ±2.54)mmol/l)] of SSRAC group were significantly lower than that of MRAC [(386.37 ±40.40)umol/l,(26.83 ±5.96)mmol/l] (P0.05) on the 7th, 14th, 21st, 28th, 90th day.In the MRAC group, the T2 relaxation time of upper, middle and lower pole of the left kidney increased and the ADC decreased on the 1st day after operation.It arrived to the peak value on the 7th day, and decreased or increased respectively from then on to normal level on the 90th day.In the SSRAC group, there were no significant changes of T2 relaxation time and ADC in the upper and middle pole of left kidney (P>0.05), but it was similar to that in the MRAC group for lower pole.On the 1st, 7th, 28th day after operation, the T2 relaxation time of upper and middle pole of the left kidney in the MRAC group [(45.50 ±1.87),(51.82 ±2.27), and(40.37 ±1.93)ms ) ] were significantly higher than those in the SSRAC group [(36.67 ± 1.33),(35.15 ±1.27), and(37.48 ±1.37)ms](P0.05).On the 1st, 7th, 28th day after operation, the ADC of upper and middle pole of the left kidney in the MRAC group [(2.29 ±0.08) ×10 -3 mm2/s, (2.10 ±0.08) ×10 -3 mm2/s, (2.41 ±0.09) ×10 -3 mm2/s] were significantly lower than that of the SSRAC group [(2.69 ± 0.08) ×10 -3 mm2/s, ( 2.63 ±0.06 ) ×10 -3 mm2/s, ( 2.68 ±0.05 ) ×10 -3 mm2/s ] ( P <0.05 ) . However, on the 1st,7th, 28th, 90th day after operation, the ADC of lower pole of the left kidney in the SSRAC group [(1.93 ±0.08) ×10 -3mm2/s,(1.91 ±0.09) ×10-3mm2/s,(2.33 ±0.07) ×10 -3mm2/s, and (2.43 ±0.07) ×10 -3 mm2/s] were significantly lower than those of the MRAC group [ (2.37 ±0.05) ×10 -3 mm2/s, (2.06 ±0.07) ×10 -3 mm2/s, (2.46 ±0.09) ×10 -3 mm2/s, (2.61 ±0.08) ×10 -3 mm2/s](P<0.05).The whole left kidney in MRAC group experienced extensive tubular hydropic degeneration and limited inflammatory cell infiltration on the 1st day after operation.Moreover, renal tubular hydropic degeneration alleviated and no glomerular changes, fibrous tissue hyperplasia or inflammatory cell infiltration was found on the 90th day after operation.In SSRAC group, no changes were found in upper and middle pole of left kidney at the two time points, while the pathological injury of the lower pole of left kidney was more severe.Conclusions SSRAC has obvious protective effect on renal function in the early stage. However, compared with MRAC, the renal tissue injury in the ischemic area was more serious.Therefore, to protect renal function in partial nephrectomy, the ischemic renal area should be reduced as much as possible, even to zero-ischemic, when adopting SSRAC.%目的:探讨选择性肾段动脉钳夹阻断(SSRAC)对猪孤立肾的作用,为临床选用SSRAC提供理论基础。方法2012年5月至2015年6月选取18头猪,按照肾动脉阻断方式不同随机分成肾动脉主干钳夹阻断( MRAC)组和SSRAC组,每组9头。麻醉后切除右肾,MRAC组夹闭左侧肾动脉主干,SSRAC组夹闭左侧肾动脉下极支,60min后去除血管夹。术前及术后第1、7、14、21、28、90天抽血检测血肌酐( SCr)和尿素氮( BUN),术前及术后第1、7、28、90天进行MRI扫描检测T2弛豫时间和表观弥散系数( ADC)值;术后第1、90天取左肾行病理检查,观察炎症细胞浸润和肾间质纤维化情况。结果两组孤立肾猪采用不同方式行肾动脉阻断后,SCr和BUN均在术后第1天升到最高值,此后逐渐降低,在第90天时恢复到接近正常水平。术后第1天,SSRAC组SCr[(266.43±31.12)μmol/L]和BUN[(13.63±2.54)mmol/L]显著低于MRAC组的对应值[(386.37±40.40)μmol/L、(26.83±5.96)mmol/L](P<0.05);但术后第7、14、21、28、90天,两组SCr和BUN差异无统计学意义(P>0.05)。 MRAC组左肾上极和中极、下极T2弛豫时间在术后第1天升高,ADC在术后第1天下降,二者术后第7天均达峰值,此后逐渐分别下降和上升,在术后第90天恢复到术前水平。 SSRAC组术后各时间点左肾上极和中极T2弛豫时间和ADC与术前相比均无显著性变化( P>0.05),下极的变化趋势与MRAC组相似。术后第1、7、28天,MRAC组上极和中极T2弛豫时间分别为(45.50±1.87) ms、(51.82±2.27)ms和(40.37±1.93)ms,显著高于SSRAC组的对应值(36.67±1.33)ms、(35.15±1.27)ms和(37.48±1.37)ms(P<0.05);但是,MRAC组左肾下极T2弛豫时间(44.70±2.13)ms、(53.12±2.66)ms和(39.82±1.41) ms,显著低于SSRAC组的对应值(55.75±2.42) ms、(60.52±2.87)ms和(44.75±2.69)ms(P<0.05)。第90天,两组间T2弛豫时间差异无统计学意义(P>0.05)。术后第1、7、28天,MRAC组上极和中极ADC值分别为(2.29±0.08)×10-3 mm2/s 、(2.10±0.08)×10-3 mm2/s和(2.41±0.09)×10-3 mm2/s,显著低于SSRAC组的对应值(2.69±0.08)×10-3mm2/s、(2.63±0.06)×10-3mm2/s和(2.68±0.05)×10-3mm2/s(P<0.05);但在术后第1、7、28、90天,MRAC组左肾下极ADC值分别为(2.37±0.05)×10-3 mm2/s、(2.06±0.07)×10-3 mm2/s、(2.46±0.09)×10-3mm2/s和(2.61±0.08)×10-3mm2/s,均显著高于SSRAC组的对应值(1.93±0.08)×10-3 mm2/s、(1.91±0.09)×10-3 mm2/s、(2.33±0.07)×10-3 mm2/s和(2.43±0.07)×10-3 mm2/s(P<0.05)。 MRAC组术后第1天左肾上极和中极、下极广泛性肾小管水样变性,间质内少量炎细胞浸润,术后第90天,上述病变减轻;SSRAC组左肾上极和中极在两个时间点病理均无异常改变,但下极两个时间点的病理改变较MRAC组明显。结论 SSRAC对近期肾功能有明显的保护作用,但与MRAC比较,其缺血区域肾组织损伤更严重,提示肾部分切除术中行SSRAC时要尽可能缩小缺血区域,甚至做到零缺血,这样对保护肾功能更好。

  3. Toll-Like Receptor 3 Gene Deficiency Aggravates Carbon Tetrachloride-Induced Liver Fibrosis in Mice%Toll样受体3基因缺陷促进四氯化碳诱导的小鼠肝纤维化损伤

    Institute of Scientific and Technical Information of China (English)

    薛如意; 张丹瑛; 吴昊; 刘韬韬; 董玲; 沈锡中


    目的:探讨Toll样受体3(Toll‐like receptor 3,TLR3)基因缺陷对于四氯化碳诱导的肝纤维化小鼠模型肝纤维化损伤程度的影响。方法:将20只野生型雄性小鼠和20只T L R3基因缺陷型(T L R3‐/‐)雄性小鼠分别分为野生型对照组、野生型造模组、T L R3‐/‐对照组和T L R3‐/‐造模组,每组各10只。对照组腹腔注射玉米油,造模组腹腔注射四氯化碳。造模8周后采集血液标本,应用全自动生化分析仪检测血清丙氨酸氨基转移酶(alanine aminotransferase ,ALT)、天门冬氨酸氨基转移酶(aspar‐tate transaminase ,AST)、总胆红素(total bilirubin ,TBIL)、白蛋白(albumin ,ALB)水平;采用马松三色染色法对肝组织胶原沉积程度进行分析;采用α‐平滑肌肌动蛋白(alpha smooth muscle actin ,α‐SMA)免疫组织化学染色法检测肝星状细胞的激活情况;应用试剂盒检测肝组织中的羟脯氨酸含量;采用实时荧光定量PC R法检测肝组织中纤维化标志物Ⅰ型胶原、炎性因子[包括肿瘤坏死因子‐α(tumor necrosis factor‐α,TNF‐α)、白介素6(interleukin‐6,IL‐6)和单核细胞趋化因子1(monocyte chemotac‐tic protein‐1,MCP‐1)]以及促纤维化分子[包括转化生长因子‐β(transforming growth factor‐β,TGF‐β)、基质金属蛋白酶组织抑制因子1( tissue inhibitor of metalloproteinase 1,TIMP1)和血小板衍生生长因子受体(platelet‐derived growth factor recep‐tor ,PDGFR)]的表达。结果:TLR3基因缺陷对于四氯化碳诱导的肝纤维化小鼠血清中的ALT、AST、TBIL、ALB水平变化无影响。T L R3基因缺陷可加重四氯化碳诱导的肝组织胶原沉积和肝星状细胞激活;促进四氯化碳诱导的小鼠肝组织中羟脯氨酸的升高;使四氯化碳诱导的肝纤维化标志物Ⅰ型胶原增多,也使肝组织中炎性因子 TNF‐α、IL‐6和 MCP‐1以及促纤维化分子TGF‐β、TIMP1和PDGFR表达升高。结论:TLR3基因缺陷可促进四氯化碳诱导的肝纤维化小鼠肝组织中的胶原沉积和肝星状细胞激活,促进肝组织炎性因子释放,使肝促纤维化分子上调。以上提示,T L R3是肝纤维化病理过程中的一个保护性基因。%Objective:To investigate the effect of Toll‐like receptor 3(TLR3) gene deficiency on the degree of liver fibrosis in mouse model of carbon tetrachloride(CCl4 )‐induced liver fibrosis .Methods :A total of 20 wild‐type male mice and 20 male mice with TLR3 gene deficiency (TLR3‐/‐) were divided into wild‐type control group and wild‐type model group ,TLR3‐/‐ control group and TLR3‐/‐ model group ,respectively ,with 10 mice in each group .The control group was injected with corn‐oil by intraperitoneal injection while the model group was injected with CCl4 by intraperitoneal injection .After 8 weeks ,blood sample wascollectedandserumlevelofalanineaminotransferase(ALT),aspartatetransaminase(AST),totalbilirubin(TBIL),and albumin(Alb) was analyzed by automatic biochemical analyzer .And the degree of collagen deposition in liver tissue was evaluated by Masson trichrome staining .And the activation of hepatic stellate cells was detected by immunohistochemistry staining of α‐smooth muscle actin(α‐SMA).And hydroxyproline content of liver tissue was detected with detection kit . Furthermore ,real‐time fluorescence polymerase chain reaction was used to detect the expression of liver fibrotic marker type I collagen ,and inflammatory cytokines including tumor necrosis factor‐alpha (TNF‐α) , interleukin‐6 (IL‐6 ) and monocyte chemotactic protein‐1(MCP‐1) ,as well as pro‐fibrotic molecule including transforming growth factor‐beta (TGF‐β) ,tissue inhibitor of metalloproteinase 1(TIMP1) and platelet‐derived growth factor receptor(PDGFR) .Results:TLR3 gene deficiency had no effect on CCl4‐induced change regarding serum level of ALT ,AST ,TBIL ,ALB .TLR3 gene deficiency aggregated the CCl4‐induced collagen deposition and hepatic stellate cell activation in liver tissue .And it promoted the CCl4‐induced elevation of hydroxyproline content and expression increase of fibrotic marker type I collagen .Furthermore ,the expression increase of inflammatory cytokines including TNF‐α,IL‐6 and MCP‐1 ,as well as that of pro‐fibrotic molecule including TGF‐β,TIMP1 and PDGFR ,was promoted .Conclusions :TLR3 gene deficiency could promote liver collagen deposition and hepatic stellate cell activation in mouse model of CCl4‐induced liver fibrosis ,and it could promote inflammatory cytokine release and pro‐fibrotic molecule up‐regulation .All above suggest that TLR3 is a protective gene during liver fibrosis pathological process .

  4. Streptococcus pneumoniae capsular polysaccharide aggravate inflammation and tissue injury in acute otitis media of C57BL/6 mice%肺炎链球菌荚膜多糖加重C57BL/6小鼠中耳炎的炎症应答和中耳组织损伤

    Institute of Scientific and Technical Information of China (English)

    项云; 周爱娥; 王维; 王磊; 黄益飞; 金春芳; 王子萌; 尹一兵; 何於娟


    目的:研究肺炎链球菌(Streptococcus pneumoniae,荚膜多糖(capsular polysaccharide,CPS)对C57BL/6小鼠急性中耳炎的炎症应答和组织损伤的作用.方法:首先通过同源重组的方式构建TIGR4△cps菌株,然后经鼓膜穿刺,分别接种5μl/耳的TIGR4和TIGR4△cps于C57BL/6小鼠的双侧中耳腔,对照组采用相同方法接种等体积无菌磷酸盐缓冲液(phosphate buffered saline,PBS).观察小鼠发病情况,分别于感染后1、3、5d制备中耳组织切片,HE染色观察中耳组织损伤及炎性细胞浸润变化,同时收集中耳灌洗液(middle ear lavage fluids,MELF),检测MELF中细菌载量、炎性细胞数量和细胞因子含量.结果:成功构建了TIGR4△cps菌株.与TIGR4组相比,TIGR4△cps组小鼠中耳上皮的损伤更轻,中性粒细胞募集减少(第1天时P=0.004;第3天时P=0.000;第5天时P=0.000),MELF中细胞因子TNF-α和IL-6水平更低(第1天时P=0.076、P=0.000;第3天时P=0.002、P=-0.003;第5天时P=0.000、P=0.000),但细菌清除更快(第1天时t=2.659,P=0.029;第3天时t=3.717,P=0.006).结论:在 TIGR4致小鼠急性中耳炎过程中,CPS具有加重炎症应答和组织损伤,并导致宿主对S.pn的清除减慢的作用.

  5. AQP1慢病毒载体成功转染心肌细胞后加重体外循环后心肌细胞水肿%Lentiviral-AQP1 vector successfully transfect the myocytes and aggravate the myocardiac edema after cardiopulmonary bypass

    Institute of Scientific and Technical Information of China (English)

    闫玉梅; 丁芳宝; 梅举; 孙锟


    目的 探讨水通道蛋白-1(AQP1)慢病毒载体可否成功转染心肌细胞,转染成功的心肌细胞在体外循环结束后,不同时点AQP1表达变化及与心肌水肿的关系.方法 健康成年羊36只,分为空载体组和AQP1慢病毒转染组.根据羊AQP1mRNA全基因设计酶切引物,克隆到慢病毒表达载体中,与其它包装载体共转染293T细胞产生病毒载体并测定病毒滴度.体外循环期间将空载体或AQP1病毒悬液注射入左心室心肌组织,体外循环结束后不同时间点(2、6、12、24、48、72 h)取材,每个时间点3只.应用realtimePCR、WesternBlot、ELASE、流式细胞仪(FACS)和干湿重法等检测AQP1慢病毒载体是否成功转染心肌细胞,成功转染体外循环后不同时间点AQP1表达变化和心肌水肿程度.结果 成功构建AQP1慢病毒载体并转染心肌细胞,体外循环后不同时间点AQP1表达变化趋势和心肌水肿程度与空载体组心肌表达变化趋势一致,但程度较高,差异有统计学意义(P<0.05).结论 AQP1慢病毒载体可成功转染心肌细胞,AQP1高表达的心肌组织在体外循环后不同时间点AQP1的表达和水肿程度变化趋势不变,但均较空载体转染组程度高.AQP1表达量与心肌水肿程度正相关.%Objective Construct the lentiviral AQP1 vector and explore whether it can transfect the myocyte or not,then test the law of the AQP1 expression and the edema in the successfully transducted myocytes after cardiopulmonary bypass in sheeps.Methods Design cleavage primer according to ovine AQP1mRNA,clone it into expressing vector and transducated into the 293T cells with other packing vectors to produce the lentiviral AQP1 vector,then test the virus titer.36 adult healthy sheeps are randomly divided into blank or AQP1-lentiviral transfected group,blank or AQP1-lentiviral vector suspension was injected in the ventricle tissue of healthy adult sheeps during cardiopulmonary bypass and take specimen in different time points (2,6,12,24,48,72 h)after extracorporeal circulation,3 in each group.Realtime-PCR WesternBlot ELISA FACS immumofluorescent and Dry/Wet methods are emploied to detect the expression of AQP1 and the according degree of edema.Results lentiviral AQP1 vector was successfully construced and transducated into the myocytes.The tranducated groups have the same trend of AQP1 of expression and cardiac edema after cardiopulmonary bypass compared to the blank vector group,but the degree is heavier(P < 0.05).Conclusion Lentivral AQP1 vector can successfully transfect the myoctyes,and the overexpressed myocardial tissue have the same trend of AQP1 expression and edema after cardiopulmonary bypass,but with a heaver degree.The expression of aquaporins was positively relevant to the edema.

  6. bFGF influences human articular chondrocyte differentiation

    DEFF Research Database (Denmark)

    Schmal, H; Zwingmann, J; Fehrenbach, M


    FGF concentrations in supernatants of primary human articular chondrocytes peaked immediately after isolation and then declined. In a dose-dependent manner, bFGF enhanced cell amplification and viability. BFGF induced a decrease in the apoptotic cell population, while the number of proliferating cells remained...... in monolayer. bFGF-dependent cell proliferation, production of collagen type II and aggrecan were monitored 10 days after isolation. Furthermore, effect of bFGF on cell cycle, cell morphology, and mRNA expression of integrins and chondrogenic markers determined by real time PCR were analyzed. RESULTS: b...... unchanged. Supplementation of cell culture with bFGF reduced collagen type II mRNA by 49%, but increased expression of the integrin alpha(2) by 70%. bFGF did not significantly regulate the integrins alpha(1), alpha(5), alpha(10), alpha(v) and type I collagen. bFGF reduced the amount of collagen type II...

  7. Tissue-penetrating delivery of compounds and nanoparticles into tumors. (United States)

    Sugahara, Kazuki N; Teesalu, Tambet; Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Agemy, Lilach; Girard, Olivier M; Hanahan, Douglas; Mattrey, Robert F; Ruoslahti, Erkki


    Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to alphav integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.

  8. None of the integrins known to be present on the mouse egg or to be ADAM receptors are essential for sperm-egg binding and fusion

    DEFF Research Database (Denmark)

    He, Zhi-Yong; Brakebusch, Cord; Fässler, Reinhard;


    Antibody inhibition and alpha6beta1 ligand binding experiments indicate that the egg integrin alpha6beta1 functions as a receptor for sperm during gamete fusion; yet, eggs null for the alpha6 integrin exhibit normal fertilization. Alternative integrins may be involved in sperm-egg binding...... and fusion and could compensate for the absence of alpha6beta1. Various beta1 integrins and alphav integrins are present on mouse eggs. Some of these integrins are also reported to be receptors for ADAMs, which are expressed on sperm. Using alpha3 integrin null eggs, we found that the alpha3beta1 integrin...... was not essential for sperm-egg binding and fusion. Oocyte-specific, beta1 integrin conditional knockout mice allowed us to obtain mature eggs lacking all beta1 integrins. We found that the beta1 integrin null eggs were fully functional in fertilization both in vivo and in vitro. Furthermore, neither anti...

  9. Immunomodulatory effects of a set of amygdalin analogues on human keratinocyte cells. (United States)

    Baroni, A; Paoletti, I; Greco, R; Satriano, R A; Ruocco, E; Tufano, M A; Perez, J J


    Peptide T (PT) is an octapeptide shown to resolve psoriatic lesions. Our previous investigations suggest that keratinocytes play an important role in conditioning the therapeutic effects of the PT in psoriasis. However, peptides are not good therapeutic agents, because they exhibit poor absorption, are easily metabolized and are immunogenic. Using computational methods, the natural product amygdalin was identified as peptidomimetic of PT. However, amygdalin exhibits a toxic profile due to its cyanide group. To overcome this deleterious effect, we synthesized analogues lacking the cyanide group. Human keratinocytes were treated with PT or with three different peptidomimetics of PT. To study its effects on the expression of HSP-70, TGF-beta, alpha-v integrin, ICAM-1 and cytokines, we analysed the protein levels by Western blot and ELISA. Our results show that the different peptidomimetics of PT tested exhibit a similar biological behaviour in regard to the overexpression of HSP-70, TGF-beta and alpha-v integrin than the native peptide. TNF-alpha is overexpressed by PT and SVT-03018; between the other two analogs, SVT-03016 do not produce any significant change in regard to the control, while SVT-03017 shows only a moderate increase in regard to control. SVT-03018 provokes a remarkable upregulation of IL-10, stronger than SVT-03016, SVT-03017 and PT. All the other three analogues reduce comparably to the PT, the expression of ICAM-1 and do not increase the release of proinflammatory cytokines. The results highlighted that the three analogues of amygdalin with the cyanide group removed exhibit the same biological effects of PT. Therefore, they can be considered peptidomimetics, suggesting their possible use in the treatment of psoriasis.

  10. Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis. (United States)

    Carriero, Maria Vincenza; Longanesi-Cattani, Immacolata; Bifulco, Katia; Maglio, Ornella; Lista, Liliana; Barbieri, Antonio; Votta, Giuseppina; Masucci, Maria Teresa; Arra, Claudio; Franco, Renato; De Rosa, Mario; Stoppelli, Maria Patrizia; Pavone, Vincenzo


    The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser(88)-Arg-Ser-Arg-Tyr(92) is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH(2) (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe-dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an alphav integrin-dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/alphav association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein-expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy.

  11. Differences between scar and dermal cultured fibroblasts derived from a patient with recurrent abdominal incision wound herniation. (United States)

    Boemi, L; Allison, G M; Graham, W P; Krummel, T M; Ehrlich, H P


    Fibroblasts were derived from dermis and scar of a 47-year-old white man with a recurrent incisional hernia as a result of fractured ribs. The scar was thin and stretched, suggesting a defect in the maturation of granulation tissue. After surgical repair, biopsy specimens of discarded scar and skin were used to generate fibroblast cell lines. Fibroblasts maintained in medium containing 10% fetal bovine serum and antibiotic were studied between their third and eighth passage. By phase contrast microscopy, no structural differences were obvious, but it was noted that to pass scar fibroblasts, a more aggressive trypsin regimen was required. Immunohistologic and Western blot analysis of patient scar fibroblasts showed (1) more a smooth muscle actin within stress fibers, (2) increased expression of the vitronectin integrin receptor alpha(v) (CD 51), and (3) reduced expression of the collagen integrin receptor alpha2 (CD 49b). The expression of vinculin from focal adhesions or a tubulin from microtubules was the same among cell lines. Contractions of scar and dermal fibroblast-populated collagen lattice were compared. At 24 hours, contractions were 69 percent with newborn fibroblasts (normal); 68 percent for patient dermal fibroblasts; and only 48 percent for patient scar fibroblasts. The retarded contraction of scar fibroblast-populated collagen lattice was significant (p > or = 0.002). Myosin ATPase activity, critical for lattice contraction, and cell migration were equivalent among all cell lines. A plausible mechanism for the retardation of scar lattice contraction is disruption of fibroblasts and collagen interactions, for which the attachment of cells to collagen is altered. It is proposed that either the decrease in the expression of collagen integrin receptor alpha2 (CD 49b), an increase in the expression of the vitronectin receptor alpha(v) (CD 51), or a combination of both is responsible for disruption of collagen fibroblast interactions.

  12. Immunohistochemistry of adhesion molecules, metalloproteinases and NO-synthases in extravillous trophoblast of tubal pregnancy. (United States)

    Dubernard, G; Galtier-Fougairolles, M; Cortez, A; Uzan, S; Challier, J C


    Trophoblast invasion in uterine pregnancy is fine-tuned for the remodelling of the uterine wall and its vascularization. Tubal pregnancy, which occurs in a limited number of patients, involves a dramatic trophoblast invasion in a context of a poor decidualization. By studying the histology of the extravillous trophoblast (EVC) in the anchoring villi, the Ki67 labelling, the location of several adhesion markers (cytokeratin-7, alpha1, alpha6, alphaV, beta1, beta4 integrin subunits and E-cadherin, V/E-cadherin), metalloproteinases (MMP-2, 9 and11), NOS2 and 3, we aimed to detect the specificity of tubal compared to intrauterine pregnancies. No difference could be observed between meso or anti-salpingial trophoblast proliferation or invasion using Ki67. Cytokeratin-7 allowed detection of spindle-shape EVCs and we identified some decidualized stromal cells. Integrins alpha1, beta1 and alphaV, and V/E-cadherin were expressed mainly in the distal EVC correspondingly to intrauterine pregnancy, with a poor expression of alpha1. Integrins alpha6 and beta4, E-cadherin were detected in the distal EVC in contrast to uterine pregnancy. MMP-2, 9, 11 were also shown in distal EVC. NOS2 and 3 labelled the perivascular EVC and NOS3 the endothelial cells of the tubal vessels. These changed distributions of adhesion molecules and MMP together with that of the basic and inducible NOS expressions could be related to mechanical effects in superficial implantation or to a failure of decidualization in tubal pregnancies.

  13. 宣肺平喘、温阳利水法对肺心病急性加重期合并周围性水肿ADH的影响%The Effectiveness of the Therapy Dispersing Lung-Qi to Relive Asthma, Warming Yang to Promote Diuresis on the Level of ADH of Patients with Cor Pulmonale in Acute Aggravate Stage, Combined with Peripheral Hydrops

    Institute of Scientific and Technical Information of China (English)

    卢云; 张晓云; 黄宁; 陈绍宏


    目的 通过多中心、随机、对照、平行、单盲临床研究,对宣肺平喘、温阳利水法治疗肺心病急性加重期合并周围性水肿疗效进行评价,并观察其对抗利尿激素(ADH)的影响.方法 以肺心病急性发作期合并周围性水肿的患者为对象,随机分为两组.治疗组采用中西医结合方案治疗,对照组予以西医常规加安慰剂治疗,两组均治疗14d.比较两组疗效性指标与ADH值情况.结果 治疗组在总体疗效、改善症状体征、纠正电解质紊乱、纠正酸碱失衡等方面优于对照组.两组治疗后均无明显副作用.同时治疗组在降低血清ADH水平方面优于对照组.结论 针对肺心病急性发作期合并周围性水肿的中西医结合治疗可能具有提高总体疗效、改善症状体征、纠正电解质紊乱、纠正酸碱失衡优势,同时对ADH的分泌有一定的抑制作用,提示抑制ADH分泌可能是宣肺平喘、温阳利水法治疗肺心病急性加重期合并周围性水肿的部分机理.

  14. Can Institutional Investors Aggravate the Effect of Stock Markets on Physical Economic?--- Based on the Perspective of the Effect of Investor Sentiment on Corporate Investment%机构投资者是股票市场影响实体经济的助推器吗?--基于投资者情绪对公司资本投资的视角

    Institute of Scientific and Technical Information of China (English)

    花贵如; 刘志远; 郑凯


    Inefficient capital markets affect the corporate physical investment.Which role can institutional investors play?Does it affect the relationships between investor sentiment and corporate investment?From the perspective of behavioral corporate finance,this paper theoretically analyzes and empirically studies the questions.It is found that in the listed compa-nies holding institutional investor,investor sentiment has a significant effect on corporate investment.Institutional investors do play an adjustment role through the intermediate channel of managerial optimism.The results can help to identify the roles of institutional investors in China’s capital market which is important to make policy about institutional investor,and to under-stand the information handed by institutional investor and evade the “expert trap”in the decision-making process.%“资本市场并非有效”,股票市场上投资者情绪对公司的实体投资行为具有重大影响。被监管层寄予厚望的机构投资者从中扮演了什么角色?上述重大影响的助推器抑或制衡器,深层的作用机理又是什么?运用行为公司金融理论,研究发现,公司资本投资决策倾向于遵循机构投资者的“专家意见”,机构投资者是投资者情绪影响公司资本投资的“助推器”,“管理者信心”是上述助推功能得以发挥的重要渠道。上述研究发现有助于从微观企业的视角,有效识别机构投资者在股票市场影响实体经济中的角色,为监管层在“后金融危机时代”制定和执行有关机构投资者的政策提供依据;也有益于公司管理层科学理解机构投资者传递的信息,合理规避决策过程中的“专家陷阱”。

  15. Yeast Interacting Proteins Database: YBR288C, YGR261C [Yeast Interacting Proteins Database

    Lifescience Database Archive (English)

    Full Text Available bait (1) Rows with this bait as prey (0) YGR261C APL6 Beta3-like subunit of the yeast AP-3 complex; functio...rey (0) Prey ORF YGR261C Prey gene name APL6 Prey description Beta3-like subunit of the ye

  16. LM potencies: one of the hidden treasures of the sixth edition of the Organon. (United States)

    De Schepper, L


    50 millesimal (LM) potencies have great advantages for all patients, not just those who are hypersensitive because of their great power to heal without major aggravations. Before discussing their advantages this paper describes what LM potencies are, and how they are administered, then addresses two questions: why do we want to avoid aggravations if most homeopaths look for aggravation to know if the remedy is working? And if LM potencies are indeed superior, why are they still relatively unknown and unused?

  17. Monocyte adhesion induced by multi-walled carbon nanotubes and palmitic acid in endothelial cells and alveolar-endothelial co-cultures

    DEFF Research Database (Denmark)

    Cao, Yi; Roursgaard, Martin; Jacobsen, Nicklas Raun;


    Free palmitic acid (PA) is a potential pro-atherogenic stimulus that may aggravate particle-mediated cardiovascular health effects. We hypothesized that the presence of PA can aggravate oxidative stress and endothelial activation induced by multi-walled carbon nanotube (MWCNT) exposure in vitro. We...

  18. Triterpenoidal glycosides from Justicia betonica. (United States)

    Kanchanapoom, Tripetch; Noiarsa, Pawadee; Ruchirawat, Somsak; Kasai, Ryoji; Otsuka, Hideaki


    dFrom the aerial portion of Justicia betonica L., four triterpenoidal glycosides (justiciosides A-D) were isolated. Their structures were established through chemical and NMR spectroscopic analyses as olean-12-ene-1beta,3beta,11alpha,28-tetraol 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, olean-12-ene-1beta,3beta,11alpha,28-tetraol 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, 11alpha-methoxy-olean-12-ene-1beta,3beta,28-triol 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, 11alpha-methoxy-olean-12-ene-1beta,3beta,28-triol 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, respectively.

  19. Auto-modulation of neuroactive steroids on GABA A receptors: a novel pharmacological effect. (United States)

    Wegner, Florian; Rassler, Cornelia; Allgaier, Clemens; Strecker, Karl; Wohlfarth, Kai


    GABA(A) receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA(A) receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (alpha1beta3delta, alpha1beta3gamma2L, alpha6beta3delta, alpha6beta3gamma2L) and at GABA(A) receptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5alpha-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at alpha1beta3gamma2L, alpha6beta3gamma2L, and alpha6beta3delta subtypes while it enhanced potentiation at alpha1beta3delta isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABA(A) receptor sites containing the delta subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.

  20. Redshift-Space Distortions with the Halo Occupation Distribution I: Numerical Simulations

    CERN Document Server

    Tinker, J L; Zheng, Z; Tinker, Jeremy L.; Weinberg, David H.; Zheng, Zheng


    We show how redshift-space distortions of the galaxy correlation function or power spectrum can constrain the matter density parameter Omega_m and the linear matter fluctuation amplitude sigma_8. We improve on previous treatments by adopting a fully non-linear description of galaxy clustering and bias, which allows us to break parameter degeneracies by combining large-scale and small- scale distortions. We consider different combinations of Omega_m and sigma_8 and find parameters of the galaxy halo occupation distribution (HOD) that yield nearly identical galaxy correlation functions in real space. We use these HOD parameters to populate the dark matter halos of large N-body simulations, from which we measure redshift-space distortions on small and large scales. We include a velocity bias parameter alpha_v that allows the velocity dispersions of satellite galaxies in halos to be systematically higher or lower than those of dark matter. Large-scale distortions are determined by the parameter combination beta =...

  1. Fibrolamellar carcinoma of the liver: composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules. (United States)

    Scoazec, J Y; Flejou, J F; D'Errico, A; Fiorentino, M; Zamparelli, A; Bringuier, A F; Feldmann, G; Grigioni, W F


    We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.

  2. Mapping of amino acid residues responsible for adhesion of cell culture-adapted foot-and-mouth disease SAT type viruses. (United States)

    Maree, Francois F; Blignaut, Belinda; de Beer, Tjaart A P; Visser, Nico; Rieder, Elizabeth A


    Foot-and-mouth disease virus (FMDV) infects host cells by adhering to the alpha(V) subgroup of the integrin family of cellular receptors in a Arg-Gly-Asp (RGD) dependent manner. FMD viruses, propagated in non-host cell cultures are reported to acquire the ability to enter cells via alternative cell surface molecules. Sequencing analysis of SAT1 and SAT2 cell culture-adapted variants showed acquisition of positively charged amino acid residues within surface-exposed loops of the outer capsid structural proteins. The fixation of positively charged residues at position 110-112 in the beta F-beta G loop of VP1 of SAT1 isolates is thought to correlate with the acquisition of the ability to utilise alternative glycosaminoglycan (GAG) molecules for cell entry. Similarly, two SAT2 viruses that adapted readily to BHK-21 cells accumulated positively charged residues at positions 83 and 85 of the beta D-beta E loop of VP1. Both regions surround the fivefold axis of the virion. Recombinant viruses containing positively charged residues at position 110 and 112 of VP1 were able to infect CHO-K1 cells (that expresses GAG) and demonstrated increased infectivity in BHK-21 cells. Therefore, recombinant SAT viruses engineered to express substitutions that induce GAG-binding could be exploited in the rational design of vaccine seed stocks with improved growth properties in cell cultures.

  3. Melanoma cultures show different susceptibility towards E1A-, E1B-19 kDa- and fiber-modified replication-competent adenoviruses. (United States)

    Schmitz, M; Graf, C; Gut, T; Sirena, D; Peter, I; Dummer, R; Greber, U F; Hemmi, S


    Replicating adenovirus (Ad) vectors with tumour tissue specificity hold great promise for treatment of cancer. We have recently constructed a conditionally replicating Ad5 AdDeltaEP-TETP inducing tumour regression in a xenograft mouse model. For further improvement of this vector, we introduced four genetic modifications and analysed the viral cytotoxicity in a large panel of melanoma cell lines and patient-derived melanoma cells. (1) The antiapoptotic gene E1B-19 kDa (Delta19 mutant) was deleted increasing the cytolytic activity in 18 of 21 melanoma cells. (2) Introduction of the E1A 122-129 deletion (Delta24 mutant), suggested to attenuate viral replication in cell cycle-arrested cells, did not abrogate this activity and increased the cytolytic activity in two of 21 melanoma cells. (3) We inserted an RGD sequence into the fiber to extend viral tropism to alphav integrin-expressing cells, and (4) swapped the fiber with the Ad35 fiber (F35) enhancing the tropism to malignant melanoma cells expressing CD46. The RGD-fiber modification strongly increased cytolysis in all of the 11 CAR-low melanoma cells. The F35 fiber-chimeric vector boosted the cytotoxicity in nine of 11 cells. Our results show that rational engineering additively enhances the cytolytic potential of Ad vectors, a prerequisite for the development of patient-customized viral therapies.

  4. Erythroblastic Islands: Specialized Mircoenvironmental Niches forErythropoiesis

    Energy Technology Data Exchange (ETDEWEB)

    Chasis, Joel Anne


    This review focuses on current understanding of molecular mechanisms operating within erythroblastic islands including cell-cell adhesion, regulatory feedback, and central macrophage function. RECENT FINDINGS: Erythroblasts express a variety of adhesion molecules and recently two interactions have been identified that appear to be critical for island integrity. Erythroblast macrophage protein, expressed on erythroblasts and macrophages, mediates cell-cell attachments via homophilic binding. Erythroblast intercellular adhesion molecule-4 links erythroblasts to macrophages through interaction with macrophage alphav integrin. In intercellular adhesion molecule-4 knockout mice, erythroblastic islands are markedly reduced, whereas the erythroblast macrophage protein null phenotype is severely anemic and embryonic lethal. Retinoblastoma tumor suppressor (Rb) protein stimulates macrophage differentiation by counteracting inhibition of Id2 on PU.1, a transcription factor that is a crucial regulator of macrophage differentiation. Rb-deficient macrophages do not bind Rb null erythroblasts and the Rb null phenotype is anemic and embryonic lethal. Lastly, extruded nuclei rapidly expose phosphatidylserine on their surface, providing a recognition signal similar to apoptotic cells. SUMMARY: Although understanding of molecular mechanisms operating within islands is at an early stage, tantalizing evidence suggests that erythroblastic islands are specialized niches where intercellular interactions in concert with cytokines play critical roles in regulating erythropoiesis.

  5. Human rhinovirus 14 enters rhabdomyosarcoma cells expressing icam-1 by a clathrin-, caveolin-, and flotillin-independent pathway. (United States)

    Khan, Abdul Ghafoor; Pickl-Herk, Angela; Gajdzik, Leszek; Marlovits, Thomas C; Fuchs, Renate; Blaas, Dieter


    Intercellular adhesion molecule 1 (ICAM-1) mediates binding and entry of major group human rhinoviruses (HRVs). Whereas the entry pathway of minor group HRVs has been studied in detail and is comparatively well understood, the pathway taken by major group HRVs is largely unknown. Use of immunofluorescence microscopy, colocalization with specific endocytic markers, dominant negative mutants, and pharmacological inhibitors allowed us to demonstrate that the major group virus HRV14 enters rhabdomyosarcoma cells transfected to express human ICAM-1 in a clathrin-, caveolin-, and flotillin-independent manner. Electron microscopy revealed that many virions accumulated in long tubular structures, easily distinguishable from clathrin-coated pits and caveolae. Virus entry was strongly sensitive to the Na(+)/H(+) ion exchange inhibitor amiloride and moderately sensitive to cytochalasin D. Thus, cellular uptake of HRV14 occurs via a pathway exhibiting some, but not all, characteristics of macropinocytosis and is similar to that recently described for adenovirus 3 entry via alpha(v) integrin/CD46 in HeLa cells.

  6. Endometrial receptivity: expression of alpha3beta1, alpha4beta1 and alphaVbeta1 endometrial integrins in women with impaired fertility. (United States)

    Skrzypczak, J; Mikołajczyk, M; Szymanowski, K


    Advances in immunohistochemical methods with the specificity of poly- and monoclonal antibodies allow the description of the endometrial receptivity, which is characterized by the ability of secretion of phase specific proteins and glikoproteins by epithelial and stromal cells. We studied the differences in the expression of alpha3beta1, alpha4beta1 and alphaVbeta1 integrins in endometrium of women with recurrent miscarriages and women with unexplained infertility. The endometrial tissue was collected during hysteroscopy performed between 7th and 9th day after ovulation. The immunohistochemical evaluation of alpha3beta1, alpha4beta1 and alphaVbeta1 integrin expression was determined in all endometrial biopsies. Staining intensity of alpha3beta1 in glandular epithelium and endometrial stroma was similar in both groups. In women with recurrent miscarriages we noted a lower concentrations of the alpha4beta1 and alphaVbeta1 integrins during the midluteal phase than in women with unexplained infertility. Moreover, integrins alpha4beta1 and alphaVbeta1 were expressed more frequently in glandular epithelium and endometrial stroma of women with unexplained infertility than those of women with recurrent miscarriages. However, alphaV(2)1 staining in endometrial stroma was stronger than that of alpha4beta1. It can be concluded, that these integrins may play an important role in the implantation process.

  7. Asthma phenotypes modify the impact of environmetnal factors on lung function (United States)

    Previous studies have examined the role of childhood asthma phenotypes based on clinical history on asthma severity and symptom aggravation by environmental risk factors. The current study focuses on the associations between lung function in childhood and environmental factors an...

  8. 77 FR 28225 - Sentencing Guidelines for United States Courts (United States)


    ... example, assault, kidnapping, and murder. As a result, the guidelines generally have addressed these...; Attempted Murder), 2A2.2 (Aggravated Assault) and 2A4.1 (Kidnapping, Abduction, Unlawful Restraint)....

  9. 综合康复治疗贝尔面瘫瘫32例%Treatment of Bell facial paralysis by comprehensive rehabilitation therapy

    Institute of Scientific and Technical Information of China (English)



    Background:Bell facial paralysis is characterized by acutely peripheral facial paralysis.Simple approaches can aggravate symptoms and induce permanent facial paralysis.Optimal therapy time may be missed.Comprehensive therapy is effective in treating the condition.

  10. Renal failure induces telomere shortening in the rat heart

    NARCIS (Netherlands)

    Wong, L. S.; Windt, W. A.; Roks, A. J.; van Dokkum, R. P.; Schoemaker, R. G.; de Zeeuw, D.; Henning, R. H.


    Background. Renal failure aggravates pathological cardiac remodelling induced by myocardial infarction (MI). Cardiac remodelling is associated with telomere shortening, a marker for biological ageing. We investigated whether mild and severe renal failure shorten cardiac telomeres and excessively sho


    Institute of Scientific and Technical Information of China (English)

    WERNER Buck


    @@ Problems with extreme floods have been aggravated in Germany mainly due to loss of flood retaining areas caused by river regulation measures in former centuries, and by intensified use of the former natural flood plains.

  12. 19 CFR 122.183 - Denial of access. (United States)


    ...; (xxxiii) Illegal use or possession of firearms or explosives; (xxxiv) Any violation of a U.S. immigration... property; (H) Aggravated assault; (I) Bribery; or (J) Illegal possession of a controlled...

  13. μ-opioid Receptor-Mediated Alterations of Allergen-Induced Immune Responses of Bronchial Lymph Node Cells in a Murine Model of Stress Asthma

    Directory of Open Access Journals (Sweden)

    Kaori Okuyama


    Conclusions: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.

  14. [Short-term memory processes during delayed visual differentiation after bilateral removal of the 7th field of the parietal cortex in Rhesus macaca]. (United States)

    Dudkin, K N; Chueva, I V; Makarov, F N; Orlov, I V


    Extirpation of the parietal cortex area 7 aggravated delayed visual discrimination of all visual attributes including shape, colour and spatial relationship in adult rhesus monkeys. Oxymetacil improved the shape and colour discrimination alone.

  15. The Affect of Drug Trafficking in West Africa on the National Security Interests of the United States of America (United States)


    Armada Revolucionarias de Colombia [Revolutionary Armed Forces of Columbia] TCO Transnational Criminal Organization TOC Transnational Organized greater drug dependence by the local population, increasing and aggravating health risks like Human Immunodeficiency Virus and hepatitis C, and...

  16. Mainstreaming climate adaptation into development assistance: rationale, institutional barriers and opportunities in Mozambique

    NARCIS (Netherlands)

    Sietz, D.; Boschütz, M.; Klein, R.J.T.


    In Mozambique, weather extremes threaten development progress, while pronounced poverty aggravates the climate vulnerability of the population. With the country being a major recipient of official development assistance, Mozambique's development strongly depends on donor investments. Against this ba

  17. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference

    Directory of Open Access Journals (Sweden)

    Zohreh Zamani


    Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.

  18. The Optimal Dentition of the Periodontitis Patient

    DEFF Research Database (Denmark)

    Melsen, Birte; Laursen, Morten Godtfredsen


    This article focuses on the evolution of orthodontic treatment possibilities developed for degenerating dentitions in adult patients. Indications for such therapy comprise dentition suffering from an aggravation of a malocclusion, horizontal loss of periodontal tissue support, elongation and...

  19. 34 CFR Appendix A to Subpart D of... - Crime Definitions in Accordance With the Federal Bureau of Investigation's Uniform Crime... (United States)


    ... necessary that injury result from an aggravated assault when a gun, knife, or other weapon is used which... to the unlawful possession, sale, use, growing, manufacturing, and making of narcotic drugs....

  20. Repetitive Stress Injuries (United States)

    ... tendon from the kneecap attaches to the shinbone. Patellofemoral syndrome. This is a softening or breaking down of kneecap cartilage. Squatting, kneeling, and climbing stairs and hills can aggravate pain around the knee. Shin splints. This term refers ...

  1. Admitting acute ischemic stroke patients to a stroke care monitoring unit versus a conventional stroke unit : a randomized pilot study

    NARCIS (Netherlands)

    Sulter, Geert; Elting, Jan Willem; Langedijk, Marc; Maurits, Natasha M; De Keyser, Jacques


    BACKGROUND AND PURPOSE: Pathophysiological considerations and observational studies indicate that elevated body temperature, hypoxia, hypotension, and cardiac arrhythmias in the acute phase of ischemic stroke may aggravate brain damage and worsen outcome. METHODS: Both units were organized with the

  2. Decreased magnesium level and membrane potential of glaucoma patients

    Directory of Open Access Journals (Sweden)

    Johnkennedy Nnodim


    The result probably suggests, that decrease in magnesium aggravates glaucoma while decrease in membrane potential could cause poor energy transmission and hence affect ocular blood flow. Hence, decreased magnesium and membrane potential levels contributes greatly to glaucoma.


    Disruption of the respiratory epithelium contributes to the progression of a variety of respiratory diseases that are aggravated by exposure to air pollutants, specifically traffic-based pollutants such as diesel exhaust particles (DEP). Recognizing that lung repair following inj...

  4. Semiannual Report to the Congress. October 1, 2010 - March 31, 2011 (United States)


    decade, Congress passed legislation to ad­ dress its concern regarding allegations of con­ tractor and U.S. Forces’ involvement in sexual slavery , human...forfeiture of all pay and allowances, and dismissal from the service. Aggravated Sexual Contact and Aggravated Sexual Abuse of a Child Overview: An...investigation conducted by Army CID disclosed that an Army staff sergeant had sexual relations with a 14 year- old child on multiple occasions when

  5. The underinvestment problem under conglomeration

    Directory of Open Access Journals (Sweden)

    Jacques A. Schnabel


    Full Text Available This theoretical paper explores whether the underinvestment problem is aggravated or ameliorated by the formation of a pure conglomerate. It establishes that the answer depends critically on the volatility of corporate assets. If volatility is low, conglomeration ameliorates the underinvestment problem, whereas if volatility is high, conglomeration aggravates the underinvestment problem. These analytical results are then invoked as a potential explanation for the ambiguous conclusions of empirical studies that delve into the existence of a conglomerate discount.

  6. Exacerbation of Bloody Diarrhea as a Side Effect of Mesalamine Treatment of Active Ulcerative Colitis


    Yuichi Shimodate; Kunihiro Takanashi; Eriko Waga; Tomoki Fujita; Shinichi Katsuki; Masafumi Nomura


    Mesalamine has been used as the first-line therapy for the treatment of ulcerative colitis (UC) because of its efficacy and fewer side effects. However, earlier study showed that mesalamine occasionally causes diarrhea. We are presenting a patient with active UC in whom bloody diarrhea accompanied by abdominal pain and fever occurred and the symptoms were aggravated after administration of mesalamine. In order to clarify the reason of symptoms aggravation, drug lymphocyte stimulation test and...

  7. 霉菌性脊柱炎1例报告%Infectious spondylitis: a case report

    Institute of Scientific and Technical Information of China (English)

    朴虎男; 李芳英; 吴光; 金舜容


    @@ 1 Clinical data A man aged 40 years old was admitted to our hospital for 10 days due to aggravation of satiety of upper abdomen as well as vomiting, nausea. Satiety developed without apparent predisposing cause 2 months ago and aggravated after meals. Nausea and vomiting occurred 10 days ago,2 to 3 times a day. After a period of time, dry vomiting became predominated accompanied by occasional dull pain of upper abdomen.

  8. Complete obstruction of right side lymphatic of lower limb%右下肢淋巴管完全性阻塞案

    Institute of Scientific and Technical Information of China (English)

    尚军; 孟苏华


    @@ A patient, female, aged 65 years, paid her visit on 18thJanuary, 2008.She complained of edema, soreness and heaviness of right side of lower limb for 9 years,aggravated for half a year.The right side of lumbus and lower limb were injured in an accident 9 years ago.Although the function was basically recovered after treatment, edema appeared at right side of lower limb, aggravated day by day, and difficulty of walking with heavy sensation occurred.

  9. Steroidal saponins from the aerial parts of Dracaena draco and their cytostatic activity on HL-60 cells. (United States)

    Mimaki, Y; Kuroda, M; Ide, A; Kameyama, A; Yokosuka, A; Sashida, Y


    Chemical examination of the aerial parts of Dracaena draco has led to the isolation of a total of nine steroidal saponins, including five new ones. The structures of the new saponins were determined by spectral data and a few chemical transformations to be (23S,24S)-spirosta-5,25(27)-diene-1 beta,3 beta,23,24-tetrol 1-O-{O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranosyl)-(1-->2)-alpha-L -arabinopyranosyl} 24-O-beta-D-fucopyranoside, (23S,24S)-spirosta-5,25(27)-diene-1 beta,3 beta, 23,24-tetrol 1-O-{O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L -arabinopyranoside}, (23S,24S)-spirosta-5,25(27)-diene-1 beta,3 beta,23,24-tetrol 1-O-{O-(4-O- acetyl-alpha-L-rhamnopyranosyl)-(1-->2)-alpha-L-arabinopyransoide} , (23S)-spirosta-5,25(27)-diene-1 beta,3 beta,23-triol 1-O-{O-alpha-L- rhamnopyranosyl)-(1-->2)-alpha-L-arabinopyranoside} and (23S,24S)-spirosta-5,25(27)-diene-1 beta,3 beta,23-triol 1-O-{O-(4-O-acetyl-alpha-L-rhamnopyranosyl)-(1-->2)-alpha-L- arabinopyranoside}. The isolated saponins were evaluated for their cytostatic activity on leukemia HL-60 cells.

  10. Differential regulation of phosphoinositide metabolism by alphaVbeta3 and alphaVbeta5 integrins upon smooth muscle cell migration. (United States)

    Paulhe, F; Racaud-Sultan, C; Ragab, A; Albiges-Rizo, C; Chap, H; Iberg, N; Morand, O; Perret, B


    Smooth muscle cell migration is a key step of atherosclerosis and angiogenesis. We demonstrate that alpha(V)beta(3) and alpha(V)beta(5) integrins synergistically regulate smooth muscle cell migration onto vitronectin. Using an original haptotactic cell migration assay, we measured a strong stimulation of phosphoinositide metabolism in migrating vascular smooth muscle cells. Phosphatidic acid production and phosphoinositide 3-kinase IA activation were triggered only upon alpha(V)beta(3) engagement. Blockade of alpha(V)beta(3) engagement or phospholipase C activity resulted in a strong inhibition of smooth muscle cell spreading on vitronectin. By contrast, blockade of alpha(V)beta(5) reinforced elongation and polarization of cell shape. Moreover, Pyk2-associated tyrosine kinase and phosphoinositide 4-kinase activities measured in Pyk2 immunoprecipitates were stimulated upon cell migration. Blockade of either alpha(V)beta(3) or alpha(V)beta(5) function, as well as inhibition of phospholipase C activity, decreased both Pyk2-associated activities. We demonstrated that the Pyk2-associated phosphoinositide 4-kinase corresponded to the beta isoform. Our data point to the metabolism of phosphoinositides as a regulatory pathway for the differential roles played by alpha(V)beta(3) and alpha(V)beta(5) upon cell migration and identify the Pyk2-associated phosphoinositide 4-kinase beta as a common target for both integrins.

  11. Hemostatic effects of recombinant DisBa-01, a disintegrin from Bothrops alternatus. (United States)

    Kauskot, Alexandre; Cominetti, Marcia R; Ramos, Oscar H P; Bechyne, Iga; Renard, Jean-Marie; Hoylaerts, Marc F; Crepin, Michel; Legrand, Chantal; Selistre-de-Araujo, Heloisa S; Bonnefoy, Arnaud


    A monomeric RGD-disintegrin was recently identified from a cDNA library from the venom gland of Bothrops alternatus. The corresponding 12 kDa-recombinant protein, DisBa-01, specifically interacted with alpha(v)beta3 integrin and displayed potent anti-metastatic and anti-angiogenic properties. Here, the interaction of DisBa-01 with platelet alphaIIb beta3 integrin and its effects on hemostasis and thrombosis were investigated. DisBa-01 bound to Chinese Hamster Ovary (CHO) cells expressing beta3 or alphaIIb beta3 and promoted their adhesion and the adhesion of resting platelets onto glass coverslips. The disintegrin inhibited the binding of FITC-fibrinogen and FITC-PAC-1 to ADP-stimulated platelets and inhibited ADP-, TRAP- and collagen-induced aggregation of murine, rabbit or human platelets. In a flow chamber assay, DisBa-01 inhibited and reverted platelet adhesion to immobilized fibrinogen. DisBa-01 inhibited the phosphorylation of FAK following platelet activation. The intravenous injection of DisBa-01 in C57Bl6/j mice, prolonged tail bleeding time as well as thrombotic occlusion time in mesenteric venules and arterioles following vessel injury with FeCl3. In conclusion, DisBa-01 antagonizes the platelet alphaIIb beta3 integrin and potently inhibits thrombosis.

  12. In vitro derby imaging of cancer biomarkers using quantum dots. (United States)

    Ko, Mee Hyang; Kim, Soonhag; Kang, Won Jun; Lee, Jung Hwan; Kang, Hyungu; Moon, Sung Hwan; Hwang, Do Won; Ko, Hae Young; Lee, Dong Soo


    Semiconductor quantum dots (QDs), which have broad absorption with narrow emission spectra, are useful for multiplex imaging. Here, fluorescence derby imaging using dual color QDs conjugated by the AS1411 aptamer (targeting nucleolin) and the arginine-glycine-aspartic acid (targeting the integrin alpha(v)beta(3)) in cancer cells is reported. Simultaneous fluorescence imaging of cellular distribution of nucleolin and integrin alpha(v)beta(3) using QDs enables easy monitoring of separate targets in the cancer cells and the normal healthy cells. These results suggest the feasibility of a concurrent visualization of QD-based multiple cancer biomarkers using small molecules such as aptamer or peptide ligands.

  13. The effect of microstructure on the fracture toughness of titanium alloys (United States)

    Vanstone, R. H.; Low, J. R., Jr.; Shannon, J. L., Jr.


    The microstructure of the alpha titanium alloy Ti-5Al-2.5Sn and the metastable beta titanium alloy Beta 3 was examined. The material was from normal and extra low interstitial grade plates which were either air-cooled or furnace-cooled from an annealing treatment. Beta 3 was studied in alpha-aged and omega-aged plates which were heat treated to similar strength levels. Tensile and plane strain fracture toughness tests were conducted at room temperature on the alpha-aged material. The microstructure and fracture mechanisms of alloys were studied using optical metallography, electron microscopy, microprobe analyses, and texture pole figures. Future experiments are described.

  14. Internalization of coxsackievirus A9 is mediated by {beta}2-microglobulin, dynamin, and Arf6 but not by caveolin-1 or clathrin. (United States)

    Heikkilä, Outi; Susi, Petri; Tevaluoto, Tuire; Härmä, Heidi; Marjomäki, Varpu; Hyypiä, Timo; Kiljunen, Saija


    Coxsackievirus A9 (CAV9) is a member of the human enterovirus B species within the Enterovirus genus of the family Picornaviridae. It has been shown to utilize alphaV integrins, particularly alphaVbeta6, as its receptors. The endocytic pathway by which CAV9 enters human cells after the initial attachment to the cell surface has so far been unknown. Here, we present a systematic study concerning the internalization mechanism of CAV9 to A549 human lung carcinoma cells. The small interfering RNA (siRNA) silencing of integrin beta6 subunit inhibited virus proliferation, confirming that alphaVbeta6 mediates the CAV9 infection. However, siRNAs against integrin-linked signaling molecules, such as Src, Fyn, RhoA, phosphatidylinositol 3-kinase, and Akt1, did not reduce CAV9 proliferation, suggesting that the internalization of the virus does not involve integrin-linked signaling events. CAV9 endocytosis was independent of clathrin or caveolin-1 but was restrained by dynasore, an inhibitor of dynamin. The RNA interference silencing of beta2-microglobulin efficiently inhibited virus infection and caused CAV9 to accumulate on the cell surface. Furthermore, CAV9 infection was found to depend on Arf6 as both silencing of this molecule by siRNA and the expression of a dominant negative construct resulted in decreased virus infection. In conclusion, the internalization of CAV9 to A549 cells follows an endocytic pathway that is dependent on integrin alphaVbeta6, beta2-microglobulin, dynamin, and Arf6 but independent of clathrin and caveolin-1.

  15. Identification of HI-like loop in CELO adenovirus fiber for incorporation of receptor binding motifs. (United States)

    Logunov, Denis Y; Zubkova, Olga V; Karyagina-Zhulina, Anna S; Shuvalova, Eugenia A; Karpov, Andrei P; Shmarov, Maxim M; Tutykhina, Irina L; Alyapkina, Yulia S; Grezina, Natalia M; Zinovieva, Natalia A; Ernst, Lev K; Gintsburg, Alexsandr L; Naroditsky, Boris S


    Vectors based on the chicken embryo lethal orphan (CELO) avian adenovirus (Ad) have two attractive properties for gene transfer applications: resistance to preformed immune responses to human Ads and the ability to grow in chicken embryos, allowing low-cost production of recombinant viruses. However, a major limitation of this technology is that CELO vectors demonstrate decreased efficiency of gene transfer into cells expressing low levels of the coxsackie-Ad receptor (CAR). In order to improve the efficacy of gene transfer into CAR-deficient cells, we modified viral tropism via genetic alteration of the CELO fiber 1 protein. The alphav integrin-binding motif (RGD) was incorporated at two different sites of the fiber 1 knob domain, within an HI-like loop that we identified and at the C terminus. Recombinant fiber-modified CELO viruses were constructed containing secreted alkaline phosphatase (SEAP) and enhanced green fluorescent protein genes as reporter genes. Our data show that insertion of the RGD motif within the HI-like loop of the fiber resulted in significant enhancement of gene transfer into CAR-negative and CAR-deficient cells. In contrast, CELO vectors containing the RGD motif at the fiber 1 C terminus showed reduced transduction of all cell lines. CELO viruses modified with RGD at the HI-like loop transduced the SEAP reporter gene into rabbit mammary gland cells in vivo with an efficiency significantly greater than that of unmodified CELO vector and similar to that of Ad type 5 vector. These results illustrate the potential for efficient CELO-mediated gene transfer into a broad range of cell types through modification of the identified HI-like loop of the fiber 1 protein.

  16. The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Gian Carlo Alghisi

    Full Text Available Cilengitide is a high-affinity cyclic pentapeptdic alphaV integrin antagonist previously reported to suppress angiogenesis by inducing anoikis of endothelial cells adhering through alphaVbeta3/alphaVbeta5 integrins. Angiogenic endothelial cells express multiple integrins, in particular those of the beta1 family, and little is known on the effect of cilengitide on endothelial cells expressing alphaVbeta3 but adhering through beta1 integrins. Through morphological, biochemical, pharmacological and functional approaches we investigated the effect of cilengitide on alphaVbeta3-expressing human umbilical vein endothelial cells (HUVEC cultured on the beta1 ligands fibronectin and collagen I. We show that cilengitide activated cell surface alphaVbeta3, stimulated phosphorylation of FAK (Y(397 and Y(576/577, Src (S(418 and VE-cadherin (Y(658 and Y(731, redistributed alphaVbeta3 at the cell periphery, caused disappearance of VE-cadherin from cellular junctions, increased the permeability of HUVEC monolayers and detached HUVEC adhering on low-density beta1 integrin ligands. Pharmacological inhibition of Src kinase activity fully prevented cilengitide-induced phosphorylation of Src, FAK and VE-cadherin, and redistribution of alphaVbeta3 and VE-cadherin and partially prevented increased permeability, but did not prevent HUVEC detachment from low-density matrices. Taken together, these observations reveal a previously unreported effect of cilengitide on endothelial cells namely its ability to elicit signaling events disrupting VE-cadherin localization at cellular contacts and to increase endothelial monolayer permeability. These effects are potentially relevant to the clinical use of cilengitide as anticancer agent.

  17. [Cerebral ischemia and histamine]. (United States)

    Adachi, Naoto


    Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.

  18. Light baryon masses with dynamical twisted mass fermions

    CERN Document Server

    Alexandrou, C; Blossier, B; Brinet, M; Carbonell, J; Dimopoulos, P; Drach, V; Farchioni, F; Frezzotti, R; Guichon, P; Herdoiza, G; Jansen, K; Korzec, T; Koutsou, G; Liu, Z; Michael, C; Pène, O; Shindler, A; Urbach, C; Wenger, U


    We present results on the mass of the nucleon and the Delta using two dynamical degenerate twisted mass quarks. The evaluation is performed at four quark masses corresponding to a pion mass in the range of about 300-600 MeV on lattices of 2.1-2.7 fm. We check for cut-off effects by evaluating these baryon masses on lattices of spatial size 2.1 fm at beta=3.9 and beta=4.05 and on a lattice of 2.4 fm at beta=3.8. The values we find are compatible within our statistical errors. Lattice results are extrapolated to the physical limit using continuum chiral perturbation theory. Performing a combined fit to our lattice data at beta=3.9 and beta=4.05 we find a nucleon mass of 964\\pm 28 (stat.) \\pm 8 (syst.) MeV. The nucleon mass at the physical point provides an independent determination of the lattice spacing. Using heavy baryon chiral perturbation theory at O(p^3) we find a_{\\beta=3.9}=0.0890\\pm 0.0039(stat.) \\pm 0.0014(syst.) fm, and a_{\\beta=4.05}= 0.0691\\pm 0.0034(stat.) \\pm 0.0010(syst.) fm, in good agreement w...

  19. Different Recovery Profiles of Coagulation Factors, Thrombin Generation, and Coagulation Function After Hemorrhagic Shock in Pigs (United States)


    automated water delivery system. On day 2, the animals were tranquilized with diazepam (0.5 mg/kg intramuscularly) before being transferred to the study room...Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa (alphaIIb/beta3

  20. Dicty_cDB: Contig-U13620-1 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available lobus solfataricus P2, com... 35 2.3 ( Q62318 ) RecName: Full=Transcription intermediary factor 1-beta;... 3...motif-cont... 34 3.9 ( O08629 ) RecName: Full=Transcription intermediary factor 1

  1. Disease: H00431 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available tion of the posterior longitudinal ligament of spine (OPLL) is an osteogenetic disorder of the spine found a...ts causes myelopathy in patients with OPLL. Genetic linkage studies revealed gene...s encoding collagens, nucleotide pyrophosphatase, and TGF-beta3 in association with susceptibility to the disea

  2. RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

    NARCIS (Netherlands)

    Temming, K; Molema, G; Kok, RJ


    During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to a(v)beta(3)-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to coupl

  3. SwissProt search result: AK111213 [KOME

    Lifescience Database Archive (English)

    Full Text Available 1,3-GalTase 3) (Beta3Gal-T3) (b3Gal-T3) (Galactosylgalactosylglucosylceramide beta-D-acetyl-galactosaminyltr...ansferase) (UDP-N-acetylgalactosamine:globotriaosylceramide beta-1,3-N-a B3GT3_MUSSI 5e-11 ...

  4. SwissProt search result: AK064329 [KOME

    Lifescience Database Archive (English)

    Full Text Available 1,3-GalTase 3) (Beta3Gal-T3) (b3Gal-T3) (Galactosylgalactosylglucosylceramide beta-D-acetyl-galactosaminyltr...ansferase) (UDP-N-acetylgalactosamine:globotriaosylceramide beta-1,3-N-a B3GT3_HUMAN 2e-11 ...

  5. SwissProt search result: AK101244 [KOME

    Lifescience Database Archive (English)

    Full Text Available ,3-GalTase 3) (Beta3Gal-T3) (b3Gal-T3) (Galactosylgalactosylglucosylceramide beta-D-acetyl-galactosaminyltra...nsferase) (UDP-N-acetylgalactosamine:globotriaosylceramide beta-1,3-N-ace B3GT3_RAT 6e-12 ...

  6. SwissProt search result: AK101169 [KOME

    Lifescience Database Archive (English)

    Full Text Available ,3-GalTase 3) (Beta3Gal-T3) (b3Gal-T3) (Galactosylgalactosylglucosylceramide beta-D-acetyl-galactosaminyltra...nsferase) (UDP-N-acetylgalactosamine:globotriaosylceramide beta-1,3-N-a B3GT3_MOUSE 3e-15 ...

  7. GABA receptor subunit composition relative to insecticide potency and selectivity. (United States)

    Ratra, G S; Casida, J E


    Three observations on the 4-[(3)H]propyl-4'-ethynylbicycloorthobenzoate ([(3)H]EBOB) binding site in the gamma-aminobutyric acid (GABA) receptor indicate the specific target for insecticide action in human brain and a possible mechanism for selectivity. First, from published data, alpha-endosulfan, lindane and fipronil compete for the [(3)H]EBOB binding site with affinities of 0.3--7 nM in both human recombinant homooligomeric beta 3 receptors and housefly head membranes. Second, from structure-activity studies, including new data, GABAergic insecticide binding potency on the pentameric receptor formed from the beta 3 subunit correlates well with that on the housefly receptor (r=0.88, n=20). This conserved inhibitor specificity is consistent with known sequence homologies in the housefly GABA receptor and the human GABA(A) receptor beta 3 subunit. Third, as mostly new findings, various combinations of alpha 1, alpha 6, and gamma 2 subunits coexpressed with a beta 1 or beta 3 subunit confer differential insecticide binding sensitivity, particularly to fipronil, indicating that subunit composition is a major factor in insecticide selectivity.

  8. Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

    DEFF Research Database (Denmark)

    Andersen, G; Overgaard, J; Albrechtsen, Anders;


    The 825C>T polymorphism in the gene encoding the G protein beta3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with d...

  9. Yuehchukene, a Novel Anti-implantation Indole Alkaloid from Murraya paniculata. (United States)

    Kong, Y C; Ng, K H; Wat, K H; Wong, A; Saxena, I F; Cheng, K F; But, P P; Chang, H T


    Yuehchukene, 11beta-(3'-indolyl-7,9alpha,9beta-trimethyl-5beta,8,9,10beta-tetrahydroindano-[2,3- B]indole, a novel dimeric indole alkaloid from the roots of MURRAY A PANICULATA has potent anti-implantation activity in rats at 3 mg/kg P. O. dosing on pregnancy day 2.

  10. Domain Modeling: NP_389647.1 [SAHG[Archive

    Lifescience Database Archive (English)

    Full Text Available NP_389647.1 chr10 Solution structure of the talin F3 domain in complex with a chime...ric beta3 integrin-PIP kinase peptide- minimized average structure p2h7eb_ chr10/NP_389647.1/NP_389647.1_apo_752-786.pdb psi-blast 0 ...

  11. The frequency of dietary references in homeopathic consultations. (United States)

    Filho, Rubens Dolce


    A retrospective quantitative study on dietary references found in medical records of 2753 patients attending consultations from 10/1/1994 to 5/31/2007 was conducted. The symptoms found in the rubrics relating to food and drink aggravation and amelioration, aversion and craving of homeopathic repertories reflect diets at different places and times and do not correspond fully, to contemporary gastronomy. Desires for sweet and spicy foods were statistically more frequent, revealing the prevailing taste for such food among the studied population. Food cravings should be carefully analyzed before considering them as indications for choosing homeopathic therapy, they are less significant than aversions, aggravations and ameliorations.

  12. Recurrence of Panic Attacks after Influenza Vaccination: Two Case Reports (United States)

    Kim, Han-Joon; Jeon, Sang-Won; Yoon, Ho-Kyoung


    Human influenza is a contagious respiratory illness caused by the influenza virus. The influenza vaccination is recommended annually, but several adverse effects related to allergic reactions have been reported. Panic attacks are also known to occur, but no case of a panic attack adverse effect has been reported in South Korea. We present two cases of panic disorder patients whose symptoms were aggravated by the influenza vaccination. We assumed that dysregulation of T-lymphocytes in panic disorder patients could have a role in activating various kinds of cytokines and chemokines, which then can lead to panic attack aggravation. PMID:27776395

  13. 肺心病患者脑循环动力学的研究%Study of cerebrovascular activity in patients with pulmonary heart disease

    Institute of Scientific and Technical Information of China (English)

    李金双; 左剑; 荆春明; 韩云辉


    Objective To investigate cerebrovascular activity (CVA) change of pulmonary heart disease patients.Methods To measure CAV of acute stage and compare with CAV of remission stage and control group with CAV tester.Results Average cerebral blood flow velocity,maximal blood velocity,minimal blood velocity and minimal blood flow of pulmonary heart disease patients decrease apparently (P0.05).Conclusion CVA of pulmonary heart disease patients is disorder in different degree,and this disorder aggravate as aggravating of state of disease.

  14. 2014 ebola outbreak: media events track changes in observed reproductive number. (United States)

    Majumder, Maimuna S; Kluberg, Sheryl; Santillana, Mauricio; Mekaru, Sumiko; Brownstein, John S


    In this commentary, we consider the relationship between early outbreak changes in the observed reproductive number of Ebola in West Africa and various media reported interventions and aggravating events. We find that media reports of interventions that provided education, minimized contact, or strengthened healthcare were typically followed by sustained transmission reductions in both Sierra Leone and Liberia. Meanwhile, media reports of aggravating events generally preceded temporary transmission increases in both countries. Given these preliminary findings, we conclude that media reported events could potentially be incorporated into future epidemic modeling efforts to improve mid-outbreak case projections.

  15. The use of religion in death penalty sentencing trials. (United States)

    Miller, Monica K; Bornstein, Brian H


    Both prosecutors and defense attorneys have presented religious appeals and testimony about a defendant's religious activities in order to influence capital jurors' sentencing. Courts that have objected to this use of religion fear that religion will improperly influence jurors' decisions and interfere with their ability to weigh aggravators and mitigators. This study investigated the effects of both prosecution and defense appeals. Prosecution appeals did not affect verdict decisions; however, use of religion by the defense affected both verdicts and the weighing of aggravators and mitigators. These results could be due to differences in perceived sincerity and remorse that are conveyed in the various appeals.

  16. Parenting among Low-Income, African American Single Mothers with Preschool-Age Children: Patterns, Predictors, and Developmental Correlates. (United States)

    McGroder, Sharon M.


    Examined dimensions and patterns of parenting among 193 low-income African American single mothers with preschoolers. Identified four parenting patterns (aggravated but nurturant, cognitively stimulating, patient and nurturant, and low nurturance). Found that maternal well-being and sociodemographic characteristics accounted for 93 percent of…

  17. An Analysis of China's Fertilizer Policies: Impacts on the Industry, Food Security, and the Environment

    NARCIS (Netherlands)

    Li, Y.X.; Zhang, W.F.; Ma, L.; Huang, G.Q.; Oenema, O.; Zhang, F.S.; Dou, Z.X.


    China has made remarkable strides in recent decades to grow enough food to feed 20% of the world's population with only 9% of the world's arable land. Meanwhile, the nation is experiencing exacerbated air and water pollution problems. Agricultural growth and the pollution aggravation are closely lin

  18. Environmental Health: High-level Strategy and Leadership Needed to Continue Progress toward Protecting Children from Environmental Threats. Report to Congressional Requesters. GAO-10-205 (United States)

    Stephenson, John B.


    Exposure to toxic chemicals or environmental pollutants may harm the health of the nation's 74 million children and contribute to increases in asthma and developmental impairments. In 2007, 66 percent of children lived in counties exceeding allowable levels for at least one of the six principal air pollutants that cause or aggravate asthma,…

  19. Ulnarisneuropati hos fjerkræslagteriarbejder

    DEFF Research Database (Denmark)

    Svendsen, Susanne Wulff; Juhl, Anne


    -25 kg with flexion of the elbow, pronation of the forearm, and ulnar deviation of the wrist. A nerve conduction study indicated ulnar neuropathy just distal to the elbow. Surgery at this level alleviated the symptoms, but shortly after his return to work, he changed jobs because of aggravation...

  20. Communication Design Education: Could Nine Reflections Be Sufficient? (United States)

    van der Waarde, Karel; Vroombout, Maurits


    Situation: Graphic design education is subject to substantial changes. Changes in professional practice and higher education aggravate insecurities about the contents and structure of courses, assessment criteria, relations between practice, research and theory and teaching methods. Assumption: Graphic design education (visual communication design…

  1. Establishment of a mammalian cell line suitable for industrial production of recombinant protein using mutations induced by high-energy beam radiation


    Chida, Yasuhito; Takagi, Keiichi; Terada, Satoshi


    Mammalian cells are extensively used for production of biopharmaceuticals. Most cells used in industry have infinite proliferative capacity, which provides a high number of cells and corresponding productivity. However, infinite cells will continue to multiply even after cell density reaches sufficient levels. This excess proliferation aggravates the culture environment and induces low productivity. Therefore, after cell density reaches sufficient levels, downregulation of proliferation would...

  2. Menopause versus aging: The predictor of obesity and metabolic aberrations among menopausal women of Karnataka, South India

    Directory of Open Access Journals (Sweden)

    Shruti Dasgupta


    Conclusions: Menopausal transition brings about anomalies in total body composition characterized by an increased body fat mass and central adiposity. This creates a compatible atmosphere for abnormal metabolism and aggravated cardio metabolic risk factors. Thus, menopausal status and associated obesity is the major predictor of metabolic aberrations over age in menopausal women.

  3. In vitro evaluation of the antibacterial activity of fenugreek seed (Trigonella foenum-graecum) crude extracts against a rabbit Escherichia coli isolate (United States)

    Post-weaned rabbits are sensitive to digestive disorders some of which may be due or aggravated by enteric bacteria, such as Escherichia coli (E. coli). Fenugreek (Trigonella foenum-graecum) is a medicinal plant known for its various pharmacological properties, including its antibacterial activity. ...

  4. Hair removal in hirsute women with normal testosterone levels: a randomized controlled trial of long-pulsed diode laser vs. intense pulsed light

    DEFF Research Database (Denmark)

    Haak, C S; Jensen, Pernille Nymann; Pedersen, A T;


    Hirsutism is a common disorder in women of reproductive age, and androgen disturbances may aggravate the condition. Limited evidence exists regarding efficacy of hair removal in this specific population and no data are available for patients with verified normal testosterone levels....

  5. Treatment options for hyperthyroidism. (United States)

    Wartofsky, L


    Antithyroid drugs induce sustained remission in only 55% of cases. Radioiodine, the overwhelming choice of specialists, may pose risks, including aggravation of ophthalmopathy. Surgical ablation should be considered only if a highly skilled surgeon is available. Thyroid storm requires aggressive management, and definitive treatment is needed for toxic adenoma or toxic multinodular goiter.

  6. Sensitivity of water scarcity events to ENSO-driven climate variability at the global scale

    NARCIS (Netherlands)

    Veldkamp, T.I.E.; Eisner, S.; Wada, Y.; Aerts, J.C.J.H.; Ward, P.J.


    Globally, freshwater shortage is one of the most dangerous risks for society. Changing hydro-climatic and socioeconomic conditions have aggravated water scarcity over the past decades. A wide range of studies show that water scarcity will intensify in the future, as a result of both increased consum

  7. Effect of central corticotropin releasing factor on hepatic circulation in rats: the role of the CRF2 receptor in the brain



    Backgrounds: Corticotropin releasing factor (CRF) is distributed in the central nervous system and acts as a neurotransmitter to regulate gastric functions through vagal-muscarinic pathways. We have recently demonstrated that central CRF aggravates experimental acute liver injury in rats. In the present study, the central effect of CRF on hepatic circulation was investigated.

  8. 44 CFR 206.171 - Crisis counseling assistance and training. (United States)


    ... organizations which are located in or do business primarily in the major disaster area. (f) Immediate services... population, including the types of services to be offered, an estimate of the length of time for which mental... was caused or aggravated by the major disaster or its aftermath; or (ii) He/she may benefit...

  9. MultiNeuron - Neural Networks Simulator for Medical, Physiological, and Psychological Applications


    Gorban, A. N.; Rossiyev, D. A.; M. G. Dorrer


    This work describes neural software applied in medicine and physiology to: - investigate and diagnose immune deficiencies; diagnose and study allergic and pseudoallergic reactions; forecast emergence or aggravation of stagnant cardiac insufficiency in patients with cardiac rhythm disorders; forecast development of cardiac arrhythmia after myocardial infarction; reveal relationships between the accumulated radiation dose and a set of immunological, hormonal, and bio-chemical parameters of ...

  10. CLON: Overlay Networks and Gossip Protocols for Cloud Environments (United States)

    Matos, Miguel; Sousa, António; Pereira, José; Oliveira, Rui; Deliot, Eric; Murray, Paul

    Although epidemic or gossip-based multicast is a robust and scalable approach to reliable data dissemination, its inherent redundancy results in high resource consumption on both links and nodes. This problem is aggravated in settings that have costlier or resource constrained links as happens in Cloud Computing infrastructures composed by several interconnected data centers across the globe.

  11. Impact of the Decontrol of Silver Concentrate Processing Trade on China’s Lead Market

    Institute of Scientific and Technical Information of China (English)


    In early June,two lead factories of Henan Jinli,and Yuguang Gold&Lead announced they have obtained silver concentrate Processing Handbook.Market analysts considered that decontrol on contract processing of silver ore will aggravate the pressure on lead ingot supply in China.

  12. 49 CFR 225.19 - Primary groups of accidents/incidents. (United States)


    ... equipment accidents/incidents are collisions, derailments, fires, explosions, acts of God, and other events... following outcomes, and this outcome is a new case or a significant aggravation of a pre-existing injury or... of Transportation (49 CFR 1.49(g) and (m)) Editorial Note: For Federal Register citations...

  13. Restricted Liberty, Parental Choice and Homeschooling (United States)

    Merry, Michael S.; Karsten, Sjoerd


    In this paper the authors carefully study the problem of liberty as it applies to school choice, and whether there ought to be restricted liberty in the case of homeschooling. They examine three prominent concerns that might be brought against homeschooling, viz., that it aggravates social inequality, worsens societal conflict and works against…

  14. Restricted liberty, parental choice and homeschooling

    NARCIS (Netherlands)

    Merry, M.S.; Karsten, S.


    In this paper the authors carefully study the problem of liberty as it applies to school choice, and whether there ought to be restricted liberty in the case of homeschooling. They examine three prominent concerns that might be brought against homeschooling, viz., that it aggravates social inequalit

  15. The U.S. Military and the Philippines after 11 September 2001: Why Size, Reform, and Goodwill Still Matter (United States)


    Indians and “mixed bloods” is widespread, aggravated by a Salvadoran culture predisposed to violence and machismo . iv Economically, years of steady...violence and the carrying of weapons, including machetes, is common even among the elite. Finally, the expectations of machismo ; fearlessness


    Institute of Scientific and Technical Information of China (English)

    Wang Zhongmao; Dong Bo; Fu Xiaofeng; Rong Jiashu


    @@ Most of the oil reservoirs in Jilin province occur in fractured sandstone with low permeability and heavy heterogeneity. In addition, with fracture development, the artificial fractures around producing wells and water injection wells have been increased, further aggravating the heterogeneity of oil reservoirs.

  17. The impact of area deprivation on parenting stress

    NARCIS (Netherlands)

    Spijkers, Willem; Jansen, Danielle E. M. C.; Reijneveld, Sijmen A.


    Background: Area deprivation negatively affects health and lifestyles, among which child behaviours. The latter may aggravate the effects of area deprivation on parental health due to higher rates of parenting stress. However, evidence on the influence of the living environment on parenting stress i

  18. Should Colleges Be Sued for Harboring Intolerance? (United States)

    Sanders, Steve


    Gregory A. Love, then a student at Morehouse College, in Atlanta, was beaten in 2002 with a baseball bat by a fellow student in a dormitory shower after Love made what his attacker perceived as a homosexual advance. The attacker was later convicted of aggravated assault and battery. Love sued Morehouse, arguing that the institution was liable for…

  19. Transcranial Doppler evaluation function to vessel function of hypertension and diabetes patients%经颅多谱勒对高血压和糖尿病患者血管功能的评估

    Institute of Scientific and Technical Information of China (English)



    @@ Background:Hypertension and diabetes are independent and main risk factors of cerebral vascular lesion.These two diseases can interact and aggravate cerebral vascular lesion when they exist together.We can know lesion characteristics and hemodynamics change by transcranial Doppler (TCD).We examed 186 hypertension and diabetes cases by TCD,and compared their result.

  20. 76 FR 45007 - Sentencing Guidelines for United States Courts (United States)


    ... directives in section 1079A of the Dodd-Frank Wall Street Reform and Consumer Protection Act, Public Law...) Continuation of its multi-year study of the statutory and guideline definitions of ``crime of violence... conflicts regarding whether any offense is categorically a ``crime of violence'', ``aggravated...