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Chronic Exposure (chronic + exposure)
Selected AbstractsInhibition of the Activity of Excitatory Amino Acid Transporter 4 Expressed in Xenopus Oocytes After Chronic Exposure to EthanolALCOHOLISM, Issue 7 2008Seung-Yeon Yoo Background:, The extracellular glutamate concentration is tightly controlled by excitatory amino acid transporters (EAATs). EAAT4 is the predominant EAAT in the cerebellar Purkinje cells. Purkinje cells play a critical role in motor coordination and may be an important target for ethanol to cause motor impairments. We designed this study to determine the effects of chronic ethanol exposure on the activity of EAAT4 and evaluate the involvement of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) in these effects. Methods:, EAAT4 was expressed in Xenopus oocytes following injection of EAAT4 mRNA. Oocytes were incubated with ethanol-containing solution for 24 to 96 hours. Membrane currents induced by l -aspartate were recorded using 2-electrode voltage clamps. Responses were quantified by integration of the current trace and reported in microCoulombs (,C). Results:, Ethanol dose- and time-dependently reduced EAAT4 activity. EAAT4 activity after a 96-hour exposure was significantly decreased compared to the control values at all concentrations tested (10 to 100 mM). Ethanol (50 mM) significantly decreased the Vmax (2.2 ± 0.2 ,C for control vs. 1.6 ± 0.2 ,C for ethanol, n = 18, p < 0.05) of EAAT4 for l -aspartate. Preincubation of ethanol-treated (50 mM for 96 hours) oocytes with phorbol-12-myrisate-13-acetate (100 nM for 10 minutes) abolished the ethanol-induced decrease in EAAT4 activity. While staurosporine (2 ,M for 1 hour) or chelerythrine (100 ,M for 1 hour) significantly decreased EAAT4 activity, no difference was observed in EAAT4 activity among the staurosporine, ethanol, or ethanol plus staurosporine groups. Similarly, EAAT4 activity did not differ among the chelerythrine, ethanol, or ethanol plus chelerythrine groups. Pretreatment of the oocytes with wortmannin (1 ,M for 1 hour) also significantly decreased EAAT4 activity. However, no difference was observed in the wortmannin, ethanol, or ethanol plus wortmannin groups. Conclusions:, The results of this study suggest that chronic ethanol exposure decreases EAAT4 activity and that PKC and PI3K may be involved in these effects. These effects of ethanol on EAAT4 may cause an increase in peri-Purkinje cellular glutamate concentration, and may be involved in cerebellar dysfunction and motor impairment after chronic ethanol ingestion. [source] Decrease in Langerhans Cells and Increase in Lymph Node Dendritic Cells Following Chronic Exposure of Mice to Suberythemal Doses of Solar Simulated RadiationPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2005Pauline McLoone ABSTRACT Exposure of certain strains of mice to ultraviolet radiation (UVR) causes suppression of some innate and adaptive immune responses. One such consequence of acute UVB exposure is a reduction in the number of Langerhans cells (LC) in the epidermis and an increase in dendritic cells (DC) in lymph nodes draining the irradiated skin sites. Exposure to chronic UVB irradiation also has effects on the immune system, but it is unknown what effects are caused by repeated doses of solar simulated radiation (SSR). Consequently, the main aims of the present study were to determine whether repeated exposure to low doses of SSR would lead to similar changes in these cell populations and whether chronic doses of SSR activate a protective photoadaptation mechanism. Groups of C3H/HeN mice were irradiated daily with 3.7 J/cm2 SSR from Cleo Natural lamps for 2, 10, 20, 30 or 60 days. Further groups of mice received an additional dose of 7.4 J/cm2 SSR on days 2, 10, 30 or 60 to test for photoadaptation. The numbers of LC in the epidermis and DC in the lymph nodes draining irradiated skin sites were counted 24 h after the final irradiation. With the exception of mice irradiated for only 2 days, LC were significantly reduced throughout the chronic irradiation protocol, and no recovery occurred. DC numbers were significantly increased in the draining lymph nodes of mice irradiated for 20 days and 60 days. [source] Depression gets old fast: do stress and depression accelerate cell aging?,DEPRESSION AND ANXIETY, Issue 4 2010Owen M. Wolkowitz M.D. Abstract Depression has been likened to a state of "accelerated aging," and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress-related depression may contribute to "accelerated aging," cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic,pituitary,adrenal axis (e.g., hyper- or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain-derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re-conceptualization of depression as a whole body disease rather than just a "mental illness," and to the rational development of new classes of medications to treat depression and its related medical comorbidities. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc. [source] Subcellular distribution of zinc in Daphnia magna and implication for toxicityENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2010Wen-Xiong Wang Abstract We examined the subcellular partitioning of zinc (Zn) in Daphnia magna both under acute and chronic exposures. In the acute Zn toxicity tests, the daphnids were exposed to different Zn concentrations for 48,h or to one lethal concentration (1,000,µg/L) for different durations (time to death for up to 47,h). Significant mortality of daphnids was observed when the newly accumulated Zn concentration reached a threshold level of approximately 40,µg/g wet weight (or 320,µg/g dry wt), approximately 3.5 times higher than the background tissue concentration (92,µg/g dry wt). Chronic exposure (14 d) to Zn resulted in nonobservable effect on survivorship and growth at newly accumulated tissue concentration of over 40,µg/g wet weight. With increasing Zn acute exposure, more Zn was partitioned into the cellular debris fraction, indicating that this fraction was presumably the first targeted site of binding for Zn upon entering the animals. The importance of other subcellular fractions either decreased accordingly or remained comparable. We found that the metal-sensitive fraction (Zn distribution in the organelles and heat-denatured proteins) did not predict the acute Zn toxicity in Daphnia. During chronic exposure, however, no major change of the subcellular partitioning of Zn with increasing Zn exposure was documented. Zinc was mainly found in the organelles and heat-stable protein fractions during chronic exposure, suggesting that any subcellular repartitioning occurred primarily during acute exposure. Metallothioneins were induced upon chronic Zn exposure, but its induction evidently lagged behind the Zn accumulation. Our present study showed that the subcellular fractionation approach could not be readily used to predict the acute and chronic toxicities of Zn in Daphnia. A tissue-based Zn accumulation approach with a threshold Zn tissue concentration was better in predicting acute Zn toxicity. Environ. Toxicol. Chem. 2010; 29:1841,1848. © 2010 SETAC [source] Bidirectional modulation of visual plasticity by cholinergic receptor subtypes in the frog optic tectumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2003Chuan-Jiang Yu Abstract Cholinergic input to the optic tectum is necessary for visual map maintenance. To understand why, we examined the effects of activation of the different cholinergic receptor subtypes in tectal brain slices and determined whether the retinotectal map was affected by manipulations of their activity in vivo. Both ,-bungarotoxin sensitive and insensitive nicotinic receptor agonists increased spontaneous postsynaptic currents (sPSCs) in a subpopulation of patch-clamped tectal cells; application of subtype selective receptor antagonists reduced nicotine-induced increases in sPSCs. Activation of ,-bungarotoxin insensitive nicotinic receptors also induced substantial inward current in some cells. Muscarinic receptor mediated outward current responses were blocked by the M2-like muscarinic receptor antagonists himbacine or AF-DX 384 and mimicked by application of the M2-like agonist oxotremorine. A less frequently observed muscarinic response involving a change in sPSC frequency appeared to be mediated by M1-like muscarinic receptors. In separate experiments, pharmacological manipulation of cholinergic receptor subtype activation led to changes in the activity-dependent visual map created in the tectum by retinal ganglion cell terminals. Chronic exposure of the tectum to either ,-bungarotoxin insensitive, ,-bungarotoxin sensitive or M1-like receptor antagonists resulted in map disruption. However, treatment with the M2-like receptor antagonist, AF-DX 384, compressed the map. We conclude that nicotinic or M1-like muscarinic receptors control input to tectal cells while ,-bungarotoxin insensitive nicotinic receptors and M2-like muscarinic receptors change tectal cell responses to that input. Blockade of the different cholinergic receptor subtypes can have opposing effects on map topography that are consistent with expected effects on tectal cell activity levels. [source] Chronic exposure to increasing background ozone impairs stomatal functioning in grassland speciesGLOBAL CHANGE BIOLOGY, Issue 6 2009GINA MILLS Abstract Two species found in temperate calcareous and mesotrophic grasslands (Dactylis glomerata and Leontodon hispidus) were exposed to eight ozone treatments spanning preindustrial to post-2100 regimes, and late-season effects on stomatal functioning were investigated. The plants were grown as a mixed community in 14 L containers and were exposed to ozone in ventilated solardomes (dome-shaped greenhouses) for 20 weeks from early May to late September 2007. Ozone exposures were based on O3 concentrations from a nearby upland area, and provided the following seasonal 24 h means: 21.4, 39.9 (simulated ambient), 50.2, 59.4, 74.9, 83.3, 101.3 and 102.5 ppb. In both species, stomatal conductance of undamaged inner canopy leaves developing since a midseason cutback increased linearly with increasing background ozone concentration. Imposition of severe water stress by leaf excision indicated that increasing background ozone concentration decreased the ability of leaves to limit water loss, implying impaired stomatal control. The threshold ozone concentrations for these effects were 15,40 ppb above current ambient in upland UK, and were within the range of ozone concentrations anticipated for much of Europe by the latter part of this century. The potential mechanism behind the impaired stomatal functioning was investigated using a transpiration assay. Unlike for lower ozone treatments, apparently healthy green leaves of L. hispidus that had developed in the 101.3 ppb treatment did not close their stomata in response to 1.5 ,m abscisic acid (ABA); indeed stomatal opening initially occurred in this treatment. Thus, ozone appears to be disrupting the ABA-induced signal transduction pathway for stomatal control thereby reducing the ability of plants to respond to drought. These results have potentially wide-reaching implications for the functioning of communities under global warming where periods of soil drying and episodes of high vapour pressure deficit are likely to be more severe. [source] Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemiaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2005Neetu Tyagi Abstract Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de-methylation of methionine, in which s-adenosyl-methionine (SAM) is converted to s-adenosyl-homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH-hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+ -dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de-arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Ameliorative potential of resveratrol on proinflammatory cytokines, hyperglycemia mediated oxidative stress, and pancreatic ,-cell dysfunction in streptozotocin-nicotinamide-induced diabetic ratsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010P. Palsamy Chronic exposure of pancreatic ,-cells to supraphysiologic glucose causes adverse ,-cell dysfunction. Thus, the present study was aimed to investigate the hypothesis that oral administration of resveratrol attenuates hyperglycemia, proinflammatory cytokines and antioxidant competence and protects ,-cell ultrastructure in streptozotocin-nicotinamide-induced diabetic rats. Oral administration of resveratrol (5,mg/kg body weight) to diabetic rats for 30 days showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), TNF-,, IL-1,, IL-6, NF-,B p65 unit and nitric oxide (NO) with concomitant elevation in plasma insulin. Further, resveratrol treated diabetic rats elicited a notable attenuation in the levels of lipid peroxides, hydroperoxides and protein carbonyls in both plasma and pancreatic tissues. The diminished activities of pancreatic superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione-S-transferase (GST) as well as the decreased levels of plasma ceruloplasmin, vitamin C, vitamin E and reduced glutathione (GSH) in diabetic rats were reverted to near normalcy by resveratrol administration. Based on histological and ultrastructural observations, it is first-time reported that the oral administration of resveratrol may effectively rescue ,-cells from oxidative damage without affecting their function and structural integrity. The results of the present investigation demonstrated that resveratrol exhibits significant antidiabetic potential by attenuating hyperglycemia, enhancing insulin secretion and antioxidant competence in pancreatic ,-cells of diabetic rats. J. Cell. Physiol. 224: 423,432, 2010. © 2010 Wiley-Liss, Inc. [source] Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrityJOURNAL OF NEUROCHEMISTRY, Issue 2 2010Vamshi K. Manda J. Neurochem. (2010) 115, 515,525. Abstract Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia. [source] Chronic exposure to sub-lethal beta-amyloid (A,) inhibits the import of nuclear-encoded proteins to mitochondria in differentiated PC12 cells*JOURNAL OF NEUROCHEMISTRY, Issue 5 2007Daniel Sirk Abstract Studies on amyloid beta (A,|), the peptide thought to play a crucial role in the pathogenesis of Alzheimer's disease, have implicated mitochondria in A,-mediated neurotoxicity. We used differentiated PC12 cells stably transfected with an inducible green fluorescent protein (GFP) fusion protein containing an N,-terminal mitochondrial targeting sequence (mtGFP), to examine the effects of sub-lethal A, on the import of nuclear-encoded proteins to mitochondria. Exposure to sub-lethal A,25,35 (10 ,mol/L) for 48 h inhibited mtGFP import to mitochondria; average rates decreased by 20 ± 4%. Concomitant with the decline in mtGFP, cytoplasmic mtGFP increased significantly while mtGFP expression and intramitochondrial mtGFP turnover were unchanged. Sub-lethal A,1,42 inhibited mtGFP import and increased cytoplasmic mtGFP but only after 96 h. The import of two endogenous nuclear-encoded mitochondrial proteins, mortalin/mtHsp70 and Tom20 also declined. Prior to the decline in import, mitochondrial membrane potential (mmp), and reactive oxygen species levels were unchanged in A,-treated cells versus reverse phase controls. Sustained periods of decreased import were associated with decreased mmp, increased reactive oxygen species, increased vulnerability to oxygen-glucose deprivation and altered mitochondrial morphology. These findings suggest that an A,-mediated inhibition of mitochondrial protein import, and the consequent mitochondrial impairment, may contribute to Alzheimer's disease. [source] Alteration in G Proteins and Prolactin Levels in Pituitary After Ethanol and Estrogen TreatmentALCOHOLISM, Issue 5 2008Kirti Chaturvedi Background:, Chronic administration of ethanol increases plasma prolactin levels and enhances estradiol's mitogenic action on the lactotropes of the pituitary gland. The present study was conducted to determine the changes in the pituitary levels of G proteins during the tumor development following alcohol and ethanol treatments. Methods:, Using ovariectomized Fischer-344 female rats, we have determined ethanol and estradiol actions at 2 and 4 weeks on pituitary weight and pituitary cell contents of prolactin, Gs. Gq11, Gi1, Gi2, and Gi3 proteins. Western blots were employed to measure protein contents. Results:, Ethanol increased basal and estradiol-enhanced wet weight and the prolactin content in the pituitary in a time-dependent manner. Chronic exposure of estradiol increased the levels of Gs protein in the pituitary. Unlike estradiol, ethanol exposure did not show significant effect on the basal level of Gs protein, but moderately increased the estradiol-induced levels of this protein. Estradiol exposure enhanced Gq11 protein levels in the pituitary after 2 and 4 weeks, while ethanol treatment failed to alter these protein levels in the pituitary in control-treated or estradiol-treated ovariectomized rats. In the case of Gi1, estradiol but not ethanol increased the level of this protein at 4 weeks of treatment. However, estradiol and ethanol alone reduced the levels of both Gi2 and Gi3 proteins at 2 and 4 weeks of treatment. Ethanol also significantly reduced the estradiol-induced Gi2 levels at 4 weeks and Gi3 level at 2 and 4 weeks. Conclusions:, These results confirm ethanol's and estradiol's growth-promoting and prolactin stimulating actions on lactotropes of the pituitary and further provide evidence that ethanol and estradiol may control lactotropic cell functions by altering expression of specific group of G proteins in the pituitary. [source] Cellular Adaptation to Chronic Ethanol Results in Altered Compartmentalization and Function of the Scaffolding Protein RACK1ALCOHOLISM, Issue 10 2003Alicia J. Vagts Background: Previously, we found that acute ethanol induces the translocation of the scaffolding protein RACK1 to the nucleus. Recently, we found that nuclear RACK1 mediates acute ethanol induction of immediate early gene c-fos expression. Alterations in gene expression are thought to lead to long-term changes that ultimately contribute to the development of alcohol addiction and toxicity. Therefore, we sought to determine the effects of chronic exposure of cells to ethanol on the cellular compartmentalization of RACK1 and on c-fos messenger RNA (mRNA) and protein expression. Methods: Rat C6 glioma cells were used as the cell culture model. Immunohistochemistry was implemented to visualize the localization of RACK1 and to monitor the protein level of c-fos. Reverse-transcription polymerase chain reaction was used to measure c- fos mRNA levels. The Tat-protein transduction method was used to transduce recombinant Tat-RACK1 into cells as previously described. Results: Chronic exposure of cells to 200 mM ethanol for 24 and 48 hr resulted in the gradual re-distribution of RACK1 out of the nucleus. It is interesting to note that acute ethanol re-challenge immediately after chronic treatment did not result in RACK1 translocation to the nucleus, and nuclear compartmentalization of RACK1 in response to acute ethanol was detected only after 24 hr of withdrawal. Similar patterns were obtained for c-fos expression. Chronic exposure to ethanol did not result in an increase in mRNA or protein levels of c-fos. Furthermore, acute ethanol exposure did not increase c-fos protein levels in cells that were first treated chronically with ethanol. However, transduction of exogenous RACK1 expressed as a Tat-fusion protein was able to rescue c- fos mRNA expression after chronic ethanol exposure. Conclusions: Our data suggest that RACK1 nuclear compartmentalization and ethanol-induced c-fos expression are transient and are desensitized to ethanol during prolonged exposure to high concentrations. The desensitization is temporary, and RACK1 can respond to acute ethanol treatment after a 24-hr withdrawal period. Our data further suggest that the altered compartmentalization of RACK1 leads to differences in c-fos expression upon acute or chronic exposure to ethanol. In summary, RACK1 is an important molecular mediator of the acute and chronic actions of ethanol on the expression of c-fos. These findings could have implications for the molecular signaling pathways leading to pathologic states associated with alcoholism, including toxicity. [source] French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol®) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless MicePHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2010Yoshiyuki Kimura A French maritime pine bark extract, Flavangenol®, is widely used as a nutritional supplement for protection against atherosclerosis, hypertension, diabetes, etc. Chronic exposure to solar UV radiation damages skin, increasing cutaneous thickness, wrinkling and pigmentation, as well as reducing elasticity, and causes skin cancer. The aim of this study was to examine the effects of flavangenol on skin damage and the incidence of skin tumors caused by long-term UVB irradiation in melanin-possessing hairless mice. The oral administration of flavangenol (60, 200 or 600 mg kg,1, twice daily) significantly inhibited increases in skin thickness, and the formation of wrinkles and melanin granules, as well as increases in the diameter and length of skin blood vessels. Furthermore, it prevented increases in numbers of apoptotic, Ki-67-positive and 8-hydroxy-2,-deoxyguanosine (8-OHdG)-positive cells, and the expression of skin vascular endothelial growth factor (VEGF) induced by chronic UVB irradiation. The effect on these biomarkers was associated with a reduction in the incidence of tumors in mice. The antiphotoaging and anticarcinogenetic activities of flavangenol may be due to inhibition of the expression of Ki-67, 8-OHdG and VEGF through a scavenging effect on reactive oxygen species. [source] Involvement of Reactive Oxygen Species in TGF-,1-induced Tropoelastin Expression by Human Dermal FibroblastsPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 6 2009Won Seon Choi Chronic exposure to solar UV radiation causes marked changes in the dermal extracellular matrix that underlie the loss of resiliency and increased laxity observed in photoaged skin. In particular, the dermal elastin content increases substantially and the normal, well-organized elastic fibers are replaced by amorphous elastotic material. Transforming growth factor-,1 (TGF-,1) stimulates synthesis of elastin by dermal fibroblasts and may mediate the increase in elastin in chronically photodamaged skin. We investigated pathways involved in the TGF,,1-induced increase in tropoelastin (TE), the soluble elastin monomer and assessed the role of reactive oxygen species (ROS) in the regulation of TE mRNA. Antioxidants and an inhibitor of NADPH oxidase blocked TGF,,1-induced TE mRNA increase even when added 1.5 h after TGF-,1, although ROS were detected for only 30 min. The TE mRNA increase required activation of Smad4, shown using Smad4 siRNA, and also involved the ERK1/2, p38 and JNK MAP kinases but not PI3K. ROS did not enhance signaling through Smad2 but did enhance activation of p38 and ERK1/2 at 10 min after TGF-,1. These results indicate that Smad and MAPK pathways mediate TGF,,1-induced TE expression and that ROS are required for both early signal transduction and later steps that increase elastin. [source] Noninfectious dermatological diseases associated with chronic exposure to mine tailings in a Peruvian districtBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008W. Ramos Summary Background, Mine tailings are metallic wastes which are deposited in the environment due to mining activity. Long-term exposure to these metals is harmful to human health. Objective, To determine if chronic exposure to mine tailings constitutes a risk factor for the development of dermatological diseases in the district of San Mateo de Huanchor (Lima, Peru). Methods, An observational case,control study was carried out in the communities of Mayoc, Daza and Tamboraque (exposed to mine tailings, case group) located in the district of San Mateo de Huanchor, and also in the communities of Choccna and Caruya (not exposed to mine tailings, control group) located in the same district. Out of 230 adults, 121 were exposed and 109 were not exposed to mine tailings and out of 135 children, 71 were exposed and 64 were not exposed to mine tailings. Results, In the adult group, 71% of the exposed cases had some noninfectious dermatological disease while in the nonexposed group the frequency was 34% [P < 0·001; odds ratio (OR) 5·40; 95% confidence interval (CI) 3·02,9·68]. A statistically significant difference between groups was found for arsenical dermatitis, nonpruritic papulovesicular eruption, atopic dermatitis, contact dermatitis, seborrhoeic dermatitis and xerosis. In the paediatric population, 71 exposed and 64 nonexposed children were evaluated. Sixty-nine per cent of the exposed group had some noninfectious dermatological disease vs. 30% in the nonexposed group (P < 0·001; OR 6·00; 95% CI 2·71,13·31). A statistically significant difference between groups was found for xerosis and atopic dermatitis. Conclusion, Chronic exposure to mine tailings represents a risk factor for development of noninfectious dermatological diseases in both adults and children. [source] Autophagic pathways and metabolic stressDIABETES OBESITY & METABOLISM, Issue 2010S. Kaushik Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. [source] Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrationsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 5 2003Kanae Mure Abstract Arsenite is a human multisite carcinogen, but its mechanism of action is not known. We recently found that extremely low concentrations (,0.1 ,M) of arsenite transform human osteosarcoma TE85 (HOS) cells to anchorage-independence. In contrast to other carcinogens which transform these cells within days of exposure, almost 8 weeks of arsenite exposure are required for transformation. We decided to reexamine the question of arsenite mutagenicity using chronic exposure in a spontaneous mutagenesis assay we previously developed. Arsenite was able to cause a delayed increase in mutagenesis at extremely low concentrations (,0.1 ,M) in a dose-dependent manner. The increase in mutant frequency occurred after almost 20 generations of growth in arsenite. Transformation required more than 30 generations of continuous exposure. We also found that arsenite induced gene amplification of the dihydrofolate reductase (DHFR) gene in a dose-dependent manner. Since HOS cells are able to methylate arsenite at a very low rate, it was possible that active metabolites such as monomethylarsonous acid (MMAIII) contributed to the delayed mutagenesis and transformation in these cells. However, when the assay was repeated with MMAIII, we found no significant increase in mutagenesis or transformation, suggesting that arsenite-induced delayed mutagenesis and transformation are not caused by arsenite's metabolites, but by arsenite itself. Our results suggest that long-term exposure to low concentrations of arsenite may affect signaling pathways that result in a progressive genomic instability. Environ. Mol. Mutagen. 41:322,331, 2003. © 2003 Wiley-Liss, Inc. [source] Further characterization and validation of gpt delta transgenic mice for quantifying somatic mutations in vivoENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2001Roy R. Swiger Abstract The utility of any mutation assay depends on its characteristics, which are best discovered using model mutagens. To this end, we report further on the characteristics of the lambda-based gpt delta transgenic assay first described by Nohmi et al. ([1996]: Environ Mol Mutagen 28:465,470). Our studies show that the gpt transgene responds similarly to other transgenic loci, specifically lacZ and cII, after treatment with acute doses of N -ethyl- N -nitrosourea (ENU). Because genetic neutrality is an important factor in the design of treatment protocols for mutagenicity testing, as well as for valid comparisons between different tissues and treatments, a time-course study was conducted. The results indicate that the gpt transgene, like cII and lacZ, is genetically neutral in vivo. The sensitivities of the loci are also equivalent, as evidenced by spontaneous mutant frequency data and dose, response curves after acute treatment with 50, 150, or 250 mg/kg ENU. The results are interesting in light of transgenic target size and location and of host genetic background differences. Based on these studies, protocols developed for other transgenic assays should be suitable for the gpt delta. Additionally, a comparison of the gpt and an endogenous locus, Dlb-1, within the small intestine of chronically treated animals (94 ,g/mL ENU in drinking water daily) shows differential accumulation of mutations at the loci during chronic exposure. The results further support the existence of preferential repair at endogenous, expressed genes relative to transgenes. Environ. Mol. Mutagen. 37:297,303, 2001 © 2001 Wiley-Liss, Inc. [source] Air pollution in the city of Kolkata: Health effects due to chronic exposureENVIRONMENTAL QUALITY MANAGEMENT, Issue 2 2009Mrinal K. Ghose First page of article [source] Subcellular distribution of zinc in Daphnia magna and implication for toxicityENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2010Wen-Xiong Wang Abstract We examined the subcellular partitioning of zinc (Zn) in Daphnia magna both under acute and chronic exposures. In the acute Zn toxicity tests, the daphnids were exposed to different Zn concentrations for 48,h or to one lethal concentration (1,000,µg/L) for different durations (time to death for up to 47,h). Significant mortality of daphnids was observed when the newly accumulated Zn concentration reached a threshold level of approximately 40,µg/g wet weight (or 320,µg/g dry wt), approximately 3.5 times higher than the background tissue concentration (92,µg/g dry wt). Chronic exposure (14 d) to Zn resulted in nonobservable effect on survivorship and growth at newly accumulated tissue concentration of over 40,µg/g wet weight. With increasing Zn acute exposure, more Zn was partitioned into the cellular debris fraction, indicating that this fraction was presumably the first targeted site of binding for Zn upon entering the animals. The importance of other subcellular fractions either decreased accordingly or remained comparable. We found that the metal-sensitive fraction (Zn distribution in the organelles and heat-denatured proteins) did not predict the acute Zn toxicity in Daphnia. During chronic exposure, however, no major change of the subcellular partitioning of Zn with increasing Zn exposure was documented. Zinc was mainly found in the organelles and heat-stable protein fractions during chronic exposure, suggesting that any subcellular repartitioning occurred primarily during acute exposure. Metallothioneins were induced upon chronic Zn exposure, but its induction evidently lagged behind the Zn accumulation. Our present study showed that the subcellular fractionation approach could not be readily used to predict the acute and chronic toxicities of Zn in Daphnia. A tissue-based Zn accumulation approach with a threshold Zn tissue concentration was better in predicting acute Zn toxicity. Environ. Toxicol. Chem. 2010; 29:1841,1848. © 2010 SETAC [source] Acute and chronic toxicity of mercury to early life stages of the rainbow mussel, Villosa iris (Bivalvia: Unionidae)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2005Theodore W. Valenti Abstract Mercury (Hg) contamination is receiving increased attention globally because of human health and environmental concerns. Few laboratory studies have examined the toxicity of Hg on early life stages of freshwater mussels, despite evidence that glochidia and juvenile life stages are more sensitive to contaminants than adults. Three bioassays (72-h acute glochidia, 96-h acute juvenile, and 21-d chronic juvenile toxicity tests) were conducted by exposing Villosa iris to mercuric chloride salt (HgCl2). Glochidia were more sensitive to acute exposure than were juvenile mussels, as 24-, 48-, and 72-h median lethal concentration values (LC50) for glochidia were >107, 39, and 14 ,g Hg/L, respectively. The 24-, 48-, 72-, and 96-h values for juveniles were 162, 135, 114, and 99 ,g Hg/L, respectively. In the chronic test, juveniles exposed to Hg treatments ,8 ,g/L grew significantly less than did control organisms. The substantial difference in juvenile test endpoints emphasizes the importance of assessing chronic exposure and sublethal effects. Overall, our study supports the use of glochidia as a surrogate life stage for juveniles in acute toxicity tests. However, as glochidia may be used only in short-term tests, it is imperative that an integrated approach be taken when assessing risk to freshwater mussels, as their unique life history is atypical of standard test organisms. Therefore, we strongly advocate the use of both glochidia and juvenile life stages for risk assessment. [source] Probabilistic risk assessment of reproductive effects of polychlorinated biphenyls on bottlenose dolphins (Tursiops truncatus) from the Southeast United States coastENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2002Lori H. Schwacke Abstract High levels of polychlorinated biphenyls (PCBs) have been reported in the tissues of some species of marine mammals. The high concentrations are of concern because a growing body of experimental evidence links PCBs to deleterious effects on reproduction, endocrine homeostasis, and immune system function. Much of the recent research has focused on determining the exposure of marine mammal populations to PCBs, but very little effort has been devoted to the actual risk assessments that are needed to determine the expected impacts of the documented exposures. We describe a novel risk assessment approach that integrates measured tissue concentrations of PCBs with a surrogate dose-response relationship and leads to predictions of health risks for marine mammals as well as to the uncertainties associated with these predictions. Specifically, we use PCB tissue residue data from three populations of bottlenose dolphins (Tursiops truncatus), study the feasibility of published dose-response data from a surrogate species, and combine this information to estimate the risk of detrimental reproductive effects in female dolphins. Our risk analyses for dolphin populations near Beaufort (NC, USA), Sarasota (FL, USA), and Matagorda Bay (TX, USA) indicate a high likelihood that reproductive success, primarily in primiparous females, is being severely impaired by chronic exposure to PCBs. Excess risk of reproductive failure, measured in terms of stillbirth or neonatal mortality, for primiparous females was estimated as 60% (Beaufort), 79% (Sarasota), and 78% (Matagorda Bay). Females of higher parity, which have previously off-loaded a majority of their PCB burden, exhibit a much lower risk. [source] Predicting intra-urban variation in air pollution concentrations with complex spatio-temporal dependencies,ENVIRONMETRICS, Issue 6 2010Adam A. Szpiro Abstract We describe a methodology for assigning individual estimates of long-term average air pollution concentrations that accounts for a complex spatio-temporal correlation structure and can accommodate spatio-temporally misaligned observations. This methodology has been developed as part of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), a prospective cohort study funded by the US EPA to investigate the relationship between chronic exposure to air pollution and cardiovascular disease. Our hierarchical model decomposes the space--time field into a "mean" that includes dependence on covariates and spatially varying seasonal and long-term trends and a "residual" that accounts for spatially correlated deviations from the mean model. The model accommodates complex spatio-temporal patterns by characterizing the temporal trend at each location as a linear combination of empirically derived temporal basis functions, and embedding the spatial fields of coefficients for the basis functions in separate linear regression models with spatially correlated residuals (universal kriging). This approach allows us to implement a scalable single-stage estimation procedure that easily accommodates a significant number of missing observations at some monitoring locations. We apply the model to predict long-term average concentrations of oxides of nitrogen (NOx) from 2005 to 2007 in the Los Angeles area, based on data from 18 EPA Air Quality System regulatory monitors. The cross-validated IR2 is 0.67. The MESA Air study is also collecting additional concentration data as part of a supplementary monitoring campaign. We describe the sampling plan and demonstrate in a simulation study that the additional data will contribute to improved predictions of long-term average concentrations. Copyright © 2009 John Wiley & Sons, Ltd. [source] PRECLINICAL STUDY: Electroacupuncture treatment reverses morphine-induced physiological changes in dopaminergic neurons within the ventral tegmental areaADDICTION BIOLOGY, Issue 4 2009Ling Hu ABSTRACT Chronic morphine administration decreases the size of dopamine (DA) neurons in the ventral tegmental area (VTA). These transient morphological changes are accompanied by a reduced sensitivity of morphine-induced conditioned place preference (CPP) after chronic exposure to the drug. In this study we examined alterations in the firing rate of DAergic neurons by means of extracellular recording following chronic morphine exposure and applied 100 Hz electroacupuncture (EA) treatment to reverse the reduced firing rate of these neurons. In the first set of experiments we show that in rats, which received chronic morphine treatment for 14 days, a small dose of morphine was not able to induce a CPP response anymore. However, the sensitivity to morphine was reinstated by consecutive EA treatment for 10 days. The electrophysiological response of VTA DA neurons to morphine was markedly reduced in chronic morphine-treated rats compared to saline-treated controls. A substantial recovery of the reactivity of VTA DA neurons to morphine was observed in rats that received 100 Hz EA for 10 days. Our findings suggest that 100 Hz EA is a potential therapy for the treatment of opiate addiction by normalizing the activity of VTA DA neurons. [source] Alcohol self-administration acutely stimulates the hypothalamic-pituitary-adrenal axis, but alcohol dependence leads to a dampened neuroendocrine stateEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2008Heather N. Richardson Abstract Clinical studies link disruption of the neuroendocrine stress system with alcoholism, but remaining unknown is whether functional differences in the hypothalamic-pituitary-adrenal (HPA) axis precede alcohol abuse and dependence or result from chronic exposure to this drug. Using an operant self-administration animal model of alcohol dependence and serial blood sampling, we show that long-term exposure to alcohol causes significant impairment of HPA function in adult male Wistar rats. Acute alcohol (voluntary self-administration or experimenter-administered) stimulated the release of corticosterone and its upstream regulator, adrenocorticotropic hormone, but chronic exposure sufficient to produce dependence led to a dampened neuroendocrine state. HPA responses to alcohol were most robust in ,low-responding' non-dependent animals (averaging < 0.2 mg/kg/session), intermediate in non-dependent animals (averaging ,0.4 mg/kg/session), and most blunted in dependent animals (averaging ,1.0 mg/kg/session) following several weeks of daily 30-min self-administration sessions, suggesting that neuroendocrine tolerance can be initiated prior to dependence and relates to the amount of alcohol consumed. Decreased expression of corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus and reduced sensitivity of the pituitary to CRF may contribute to, but do not completely explain, neuroendocrine tolerance. The present results, combined with previous studies, suggest that multiple adaptations to stress regulatory systems may be brought about by excessive drinking, including a compromised hormonal response and a sensitized brain stress response that together contribute to dependence. [source] Regulation of ,FosB transcriptional activity by Ser27 phosphorylationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2007Paula G. Ulery Abstract The transcription factor, ,FosB, is an important mediator of the long-term plasticity induced in brain by chronic exposure to drugs of abuse, stress, or several other psychoactive stimuli. We have previously demonstrated that the casein kinase 2 (CK2)-mediated phosphorylation of a highly conserved N-terminal serine (Ser27) plays a critical role in regulating ,FosB's unusual stability, while it does not affect that of the full-length FosB protein. In the present study, we analysed whether CK2 and Ser27 phosphorylation also play a role in regulating ,FosB's transcriptional activity. Our findings indicate that CK2 activation increases ,FosB's transactivation potential, while CK2 inhibition decreases it. Further, we show that preventing Ser27 phosphorylation by mutating the site to Ala results in a significant decrease in ,FosB transactivation, without affecting ,FosB's subcellular localization or DNA-binding affinity. In contrast, Ser27 does not seem to play a role in the transactivation potential of full-length FosB. These findings constitute the first evidence of a role for phosphorylation in ,FosB's transcriptional activity. [source] Activity-dependent modulation of GABAergic synapses in developing rat spinal networks in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Marcelo Rosato-Siri Abstract The role of activity-dependent plasticity in modulating inhibitory synapses was investigated in embryonic rat spinal cord slice cultures, by chronic exposure to non-NMDA receptor blockers. GABAergic synaptic efficacy in control and chronic-treated cultures was investigated by patch-recordings from visually identified spinal interneurons. In both culture groups proximal stimulation induced the appearance of postsynaptic currents (PSCs), which were fully antagonized by 20 µM bicuculline application and reverse polarity at potential values close to those reported for spontaneous GABAergic PSCs. In chronically treated cells GABAergic evoked PSCs displayed a larger failure rate and a smaller coefficient of variation of mean PSC amplitude, when compared to controls. As opposed to controls, chronic GABAergic evoked PSCs did not facilitate upon paired-pulse stimulation. Facilitation at chronic synapses was observed when extracellular calcium levels were decreased below physiological values (< 2 mM). Kainate was used to disclose any functional differences between control and treated slices. In accordance with the presynaptic action of kainate, the application of this drug along with GYKI, an AMPA receptor selective antagonist, changed, with analogous potency, short-term plasticity of GABAergic synapses from control and treated cultures. Nevertheless, in chronic cultures, the downstream effects of such activation unmasked short-term depression. Ultrastructural analysis of synapses in chronically treated cultures showed a reduction both in symmetric synapses and in the number of vesicles at symmetric terminals. Thus, based on electrophysiological and ultrastructural data, it could be suggested that during the development of spinal circuits, GABAergic synapses are modulated by glutamatergic transmission, and thus implying that excitatory transmission regulates the strength of GABAergic synapses. [source] Muscle afferent contributions to the cardiovascular response to isometric exerciseEXPERIMENTAL PHYSIOLOGY, Issue 6 2004James P. Fisher The cardiovascular response to isometric exercise is governed by both central and peripheral mechanisms. Both metabolic and mechanical stresses on the exercising skeletal muscle produce cardiovascular change, yet it is often overlooked that the afferent signal arising from the muscle can be modified by factors other than exercise intensity. This review discusses research revealing that muscle fibre type, muscle mass and training status are important factors in modifying this peripheral feedback from the active muscles. Studies in both animals and humans have shown that the pressor response resulting from exercise of muscle with a faster contractile character and isomyosin content is greater than that from a muscle of slower contractile character. Athletic groups participating in training programmes that place a high anaerobic load on skeletal muscle groups show attenuated muscle afferent feedback. Similarly, longitudinal studies have shown that specific local muscle training also blunts the pressor response to isometric exercise. Thus it appears that training may decrease the metabolic stimulation of muscle afferents and in some instances chronic exposure to the products of anaerobic metabolism may blunt the sensitivity of the muscle metaboreflex. There may be surprising parallels between the local muscle conditions induced in athletes training for longer sprint events (e.g. 400 m) and by the low-flow conditions in, for example, the muscles of chronic heart failure patients. Whether their similar attenuations in muscle afferent feedback during exercise are due to decreased metabolite accumulation or to a desensitization of the muscle afferents is not yet known. [source] Chronic effects of polychlorinated dibenzofurans on mink in laboratory and field environmentsINTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue 2 2009Matthew J Zwiernik Abstract Mink are often used as a sentinel species in ecological risk assessments of chemicals such as polychlorinated biphenyls (PCBs), dibenzo- p -dioxins (PCDDs), and dibenzofurans (PCDFs) that cause toxicity mediated through the aromatic hydrocarbon receptor. Considerable toxicological information is available on the effects of PCBs and PCDDs on mink, but limited toxicological information is available for PCDFs. Thus, exposure concentrations at which adverse effects occur could not be determined reliably for complex mixtures in which PCDFs dominate the total calculated concentration of 2,3,7,8-tetrachlorodibenzo- p -dioxin equivalent (TEQ). Two studies were conducted to evaluate the potential toxicity of PCDFs to mink. The first was a chronic exposure, conducted under controlled laboratory conditions, in which mink were exposed to 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF) concentrations as great as 2.4 × 103 ng 2,3,7,8-TCDF/kg wet-weight (ww) diet or 2.4 × 102 ng TEQ2006-WHO-mammal/kg ww diet. In that study, transient decreases in body masses of kits relative to the controls was the only statistically significant effect observed. The second study was a 3-y field study during which indicators of individual health, including hematological and morphological parameters, were determined for mink exposed chronically to a mixture of PCDDs and PCDFs under field conditions. In the field study, there were no statistically significant differences in any of the measured parameters between mink exposed to a median estimated dietary dose of 31 ng TEQ2006-WHO-mammal/kg ww and mink from an upstream reference area where they had a median dietary exposure of 0.68 ng TEQ2006-WHO-mammal/kg ww. In both studies, concentrations of TEQ2006-WHO-mammal to which the mink were exposed exceeded those at which adverse effects, based on studies with PCDD and PCB congeners, would have been expected. Yet in both instances where PCDF congeners were the sole or predominant source of the TEQ2006-WHO-mammal, predicted adverse effects were not observed. Taken together, the results of these studies suggest that the values of the mammalian-specific toxicity equivalency factors suggested by the World Health Organization overestimate the toxic potency of PCDFs to mink. Therefore, hazard cannot be accurately predicted by making comparisons to toxicity reference values derived from exposure studies conducted with PCBs or PCDDs in situations where mink are exposed to TEQ mixtures dominated by PCDFs. [source] Review Article: A new wrinkle on old skin: the role of elastic fibres in skin ageingINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 5 2010A. K. Langton Synopsis Cutaneous ageing is the result of two distinct, biological processes which may occur concurrently: (i) the passage of time, termed intrinsic ageing and (ii) environmental influences, termed extrinsic ageing. Intrinsic ageing of the skin is a slow process which causes changes in tissue structure and impairs function in the absence of additional biological, chemical and physical factors. The clinical features of intrinsically aged skin are not usually evident until old age when, although smooth and unblemished, the skin surface appears pale and is characterized by fine wrinkles with occasional exaggerated expression lines. Functionally, intrinsically aged skin is dry and less elastic than more youthful skin. In contrast, extrinsically aged skin is exemplified by deep, coarse wrinkles, mottled hyperpigmentation and a marked loss of elasticity and recoil. The two major environmental influences which induce extrinsic ageing are: (i) chronic exposure to solar ultraviolet (UV) irradiation (termed photoageing) and (ii) smoking. This review discusses the changes associated with the ageing process in the skin, with particular emphasis on the role played by the elastic fibre network in maintaining dermal function. The review concludes with a discussion of a short-term assay for independent assessment of the efficacy of anti-ageing cosmetic products using the elastic fibre component fibrillin-1 as a biomarker of extracellular matrix repair. Résumé Le vieillissement Cutané est le résultat de deux processus biologiques distincts, qui peuvent se produire concurremment : i) le passage de temps, désigné comme vieillissement intrinsèque et ii) les influences environnementales, désignées comme vieillissement extrinsèque. Le vieillissement intrinsèque de la peau est un processus lent provoquant des changements de la structure et détériorant la fonction tissulaire sans facteurs biologiques, chimiques ou physiques supplémentaires. Les caractéristiques cliniques de la peau intrinsèquement âgée sont peu visibles avant la vieillesse où, bien que lisse et impeccable, la surface de la peau apparaît pâle et marquée par des rides notables et des lignes d'expression exagérées. Au niveau fonctionnel, la peau intrinsèquement âgée est sèche et moins d'élastique que la peau plus jeune. Au contraire, la peau extrinsèquement âgée est caractérisée par des rides profondes, grossières, une hyperpigmentation en taches et une perte marquée d'élasticité. Les deux influences environnementales majeures à l'origine du vieillissement extrinsèque sont : i) l'exposition chronique aux ultra-violets (UV) et ii) l'exposition tabagique. Cette revue envisage les changements associés au processus de vieillissement cutané, avec une attention particulière sur le rôle joué par le réseau élastique dans le maintien de la fonction dermique. Cette analyse se termine par une discussion à propos d'un essai d'évaluation de l'efficacité de produits cosmétiques anti-âges utilisant un composant de fibre élastique la fibrillin-1 comme bio marqueur de la réparation de la matrice extracellulaire. [source] | ||||||||||||||||||||||||||||||||||