RÉSUMÉ
High-volume, hydraulic fracturing (HVHF) is widely applied for natural gas and oil production from shales, coals, or tight sandstone formations in the United States, Canada, and Australia, and is being widely considered by other countries with similar unconventional energy resources. Secure retention of fluids (natural gas, saline formation waters, oil, HVHF fluids) during and after well stimulation is important to prevent unintended environmental contamination, and release of greenhouse gases to the atmosphere. Here, we critically review state-of-the-art techniques and promising new approaches for identifying oil and gas production from unconventional reservoirs to resolve whether they are the source of fugitive methane and associated contaminants into shallow aquifers. We highlight future research needs and propose a phased program, from generic baseline to highly specific analyses, to inform HVHF and unconventional oil and gas production and impact assessment studies. These approaches may also be applied to broader subsurface exploration and development issues (e.g., groundwater resources), or new frontiers of low-carbon energy alternatives (e.g., subsurface H2 storage, nuclear waste isolation, geologic CO2 sequestration).
Sujet(s)
Nappe phréatique , Fracturation hydraulique , Polluants chimiques de l'eau , Australie , Canada , Surveillance de l'environnement , Gaz , Gaz naturel , Champs de pétrole et de gazRÉSUMÉ
Free fatty acids (FFAs) can cause glucose intolerance and diabetes. Lipotoxicity to the pancreatic beta cells is considered to be a major underlying cause for this phenomenon. The aim of this study was to analyse the toxicity profile of FFAs in the human EndoC-ßH1 beta-cell line and to compare the results with isolated rat and human islets with special reference to the physiologically most prevalent FFAs palmitic acid (PA) and oleic acid (OA). Toxicity after a 2-day incubation with the different FFAs was analysed by the caspase-3 assay and confirmed by the propidium iodide and annexin V staining tests. The long-chain saturated PA (C16:0) and the monounsaturated OA (C18:1) were both toxic to human EndoC-ßH1 beta cells and pseudoislets, as well as to rat islets, and, as confirmed in a pilot experiment, also to human islets. Furthermore, OA provided no protection against the toxicity of PA. Likewise, elaidic acid (EA, the trans isomer of OA; trans-OA) was significantly toxic, in contrast to the non-metabolisable analogues methylated PA (MePA) and methylated OA (MeOA). Fatty acids with a chain length < C16 were not toxic in EndoC-ßH1 beta cells. Caspase-3 was also activated by linoleic acid (LA)(C18:2) but not by γ-linolenic acid (γ-LNA)(C18:3). Overall, only long-chain FFAs with chain lengths > C14, which generate hydrogen peroxide in the peroxisomal beta-oxidation, were toxic. This conclusion is also supported by the toxicity of the branched-chain FFA pristanic acid, which is exclusively metabolised in the peroxisomal beta-oxidation. The lack of a protective effect of the monounsaturated fatty acid OA has important consequences for a beta-cell protective lipid composition of a diet. A cardioprotective diet with a high OA content does not fulfil this requirement.
Sujet(s)
Acides gras monoinsaturés/toxicité , Cellules à insuline/effets des médicaments et des substances chimiques , Acide oléique/toxicité , Acide palmitique/toxicité , Animaux , Caspase-3/métabolisme , Lignée cellulaire , Humains , Cellules à insuline/métabolisme , Rats , Rats de lignée LEWRÉSUMÉ
This study investigates, for the first time, dual C-Cl isotope fractionation during anaerobic biodegradation of 1,2-dichloroethane (1,2-DCA) via dihaloelimination by Dehalococcoides and Dehalogenimonas-containing enrichment cultures. Isotopic fractionation of 1,2-DCA (εbulkC and εbulkCl) for Dehalococcoides (-33.0 ± 0.4 and -5.1 ± 0.1) and Dehalogenimonas-containing microcosms (-23 ± 2 and -12.0 ± 0.8) resulted in distinctly different dual element C-Cl isotope correlations (Λ = Δδ13C/Δδ37Cl ≈ εbulkC/εbulkCl), 6.8 ± 0.2 and 1.89 ± 0.02, respectively. Determined isotope effects and detected products suggest that the difference on the obtained Λ values for biodihaloelimination could be associated with a different mode of concerted bond cleavage rather than two different reaction pathways (i.e., stepwise vs concerted). Λ values of 1,2-DCA were, for the first time, determined in two field sites under reducing conditions (2.1 ± 0.1 and 2.2 ± 2.9). They were similar to the one obtained for the Dehalogenimonas-containing microcosms (1.89 ± 0.02) and very different from those reported for aerobic degradation pathways in a previous laboratory study (7.6 ± 0.1 and 0.78 ± 0.03). Thus, this study illustrates the potential of a dual isotope analysis to differentiate between aerobic and anaerobic biodegradation pathways of 1,2-DCA in the field and suggests that this approach might also be used to characterize dihaloelimination of 1,2-DCA by different bacteria, which needs to be confirmed in future studies.
Sujet(s)
Dépollution biologique de l'environnement , Isotopes du carbone , Fractionnement chimique , Chloroflexi/métabolisme , CinétiqueRÉSUMÉ
Phenoxy acid herbicides and their potential metabolites represent industrial or agricultural waste that impacts groundwater and surface waters through leaching from old landfills throughout the world. Fate assessment of dichlorprop and its putative metabolite 4-CPP (2-(4-chlorophenoxy)propionic acid) is frequently obstructed by inconclusive evidence from redox conditions, heterogeneous geologic settings (e.g. clay till) and ambiguous parent-daughter relationships (i.e. 4-CPP may be daughter product or impurity of dichlorprop). For the first time, a combination of four methods was tested to assess transformation of phenoxy acids at a contaminated landfill (Risby site): analysis of (i) parent and daughter compound concentrations, (ii) enantiomer ratios (iii) compound-specific isotope analysis and (iv) enantiomer-specific isotope analysis. Additionally, water isotopes and chloride were used as conservative tracers to delineate two distinct groundwater flow paths in the clay till. Metabolite concentrations and isotope ratios of chlorinated ethenes demonstrated dechlorination activity in the area with highest leachate concentrations (hotspot) indicating favorable conditions also for dechlorination of dichlorprop to 4-CPP and further to phenoxypropionic acid. Combined evidence from concentrations, enantiomer ratios and isotope ratios of dichlorprop and 4-CPP confirmed their dechlorination in the hotspot and gave evidence for further degradation of 4-CPP downgradient of the hotspot. A combination of 4-CPP enantiomer and isotope analysis indicated different enantioselectivity and isotope fractionation, i.e. different modes of 4-CPP degradation, at different locations. This combined information was beyond the reach of any of the methods applied alone demonstrating the power of the new combined approach.
Sujet(s)
Eau douce/composition chimique , Sédiments géologiques/composition chimique , Herbicides/analyse , Modèles chimiques , Phénoxy-acétates/analyse , Polluants chimiques de l'eau/analyse , Acide 2,4-dichlorophénoxy-acétique/analogues et dérivés , Acide 2,4-dichlorophénoxy-acétique/analyse , Acide 2,4-dichlorophénoxy-acétique/composition chimique , Acide 2,4-dichlorophénoxy-acétique/métabolisme , Acide 4-chloro-2-méthylphénoxy-acétique/analogues et dérivés , Acide 4-chloro-2-méthylphénoxy-acétique/analyse , Acide 4-chloro-2-méthylphénoxy-acétique/composition chimique , Acide 4-chloro-2-méthylphénoxy-acétique/métabolisme , Silicates d'aluminium/composition chimique , Isotopes du carbone , Argile , Danemark , Deutérium , Surveillance de l'environnement/méthodes , Nappe phréatique , Halogénation , Herbicides/composition chimique , Herbicides/métabolisme , Isotopes de l'oxygène , Phénoxy-acétates/composition chimique , Phénoxy-acétates/métabolisme , Éthers phényliques/analyse , Éthers phényliques/composition chimique , Éthers phényliques/métabolisme , Propionates/analyse , Propionates/composition chimique , Propionates/métabolisme , Rivières , Stéréoisomérie , Polluants chimiques de l'eau/composition chimique , Polluants chimiques de l'eau/métabolisme , Pollution chimique de l'eauRÉSUMÉ
Neighboring springs draining fractured-rock aquifers can display large differences in water quality and flow regime, depending on local variations of the connectivity and the aperture size distribution of the fracture network. Consequently, because homogeneous equivalent parameters cannot be assumed a priori for the entire regional aquifer, the vulnerability to pollution of such springs has to be studied on a case by case basis. In this paper, a simple lumped-parameter model usually applied to estimate the mean transit time of water (or tracer) is presented. The original exponential piston-flow model was modified to take land-use distribution into account and applied to predict the evolution of atrazine concentration in a series of springs draining a fractured sandstone aquifer in Luxembourg, where despite a nationwide ban in 2005, atrazine concentrations still had not begun to decrease in 2009. This persistence could be explained by exponentially distributed residence times in the aquifer, demonstrating that in some real world cases, models based on the groundwater residence time distribution can be a powerful tool for trend reversal assessments as recommended for instance by current European Union guidelines.
Sujet(s)
Atrazine/composition chimique , Modèles théoriques , Sources naturelles/composition chimique , Polluants chimiques de l'eau/composition chimiqueRÉSUMÉ
Previous studies have shown that homocysteine (HC) has a detrimental impact on insulin secretion and pancreatic beta cell function. The aim of the present study was to determine the role of reactive oxygen species (ROS) in the in vitro toxic effects of HC on insulin secretion and function of BRIN-BD11 insulin-secreting cells. In this study, insulin secretion from BRIN-BD11 cells was determined radioimmunologically, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and glucokinase activity by a glucose phosphorylation assay following culture with HC plus alloxan (Alx). Treatment with HC resulted in concentration-dependent inhibition of insulin secretion induced by glucose and other insulinotropic agents. HC in combination with Alx resulted in a more pronounced decline in insulin secretion, including that induced by 20â mM alanine, by 43% (P<0.001) and 30â mM KCl by 60% (P<0.001), compared with control culture. The glucokinase phosphorylating capacity in cells cultured with HC plus Alx was significantly lower, compared with control cells. The cells also displayed a significant 84% (P<0.001) decline in cell viability. Prolonged, 72-h culture of insulin-secreting cells with HC followed by 18-h culture without HC did not result in full restoration of beta cell responses to insulinotropic agents. In vitro oxygen consumption was enhanced by a combination of Alx with HC. The study arrived at the conclusion that HC generates ROS in a redox-cycling reaction with Alx that explains the decline in viability of insulin-secreting cells, leading to reduced glucokinase phosphorylating ability, diminished insulin secretory responsiveness and cell death.
Sujet(s)
Alloxane/toxicité , Homocystéine/toxicité , Cellules à insuline/effets des médicaments et des substances chimiques , Alloxane/administration et posologie , Alloxane/pharmacologie , Lignée cellulaire , Survie cellulaire/effets des médicaments et des substances chimiques , Association médicamenteuse , Évaluation préclinique de médicament , Synergie des médicaments , Glucokinase/métabolisme , Glucose/métabolisme , Homocystéine/administration et posologie , Homocystéine/pharmacologie , Humains , Insuline/métabolisme , Sécrétion d'insuline , Cellules à insuline/métabolisme , Cellules à insuline/physiologie , Oxygène/pharmacocinétique , Espèces réactives de l'oxygène/métabolisme , Espèces réactives de l'oxygène/pharmacologie , Régulation positive/effets des médicaments et des substances chimiquesRÉSUMÉ
In the wake of acquired brain insults such as status epilepticus (SE), time-dependent neuronal network alterations may occur resulting in cortical hyperexcitability and enhanced synchrony merging into chronic epilepsy. To better understand the underlying processes, we performed electrophysiological and optical imaging studies on combined hippocampal-entorhinal cortex slices. These were prepared from rats 1, 4 and 8 weeks after electrically-induced SE. Non-invasive imaging using intrinsic optical signal changes allowed detailed analysis of onset and spread patterns of seizure-like events (SLE) since coverage of the entire preparation is possible. The latency to occurrence of first SLEs after omission of Mg(2+) from the artificial cerebrospinal fluid was significantly reduced at 4 and 8 weeks after SE compared with all other groups indicating increased brain excitability. Optical imaging displayed multiregional onset and discontiguous propagation of SLEs 8 weeks after SE. Such patterns indicate neuronal hypersynchrony and are not encountered in naïve rodents in which SLEs commonly begin in the entorhinal cortex and display contiguous spread to invade adjacent regions. The electrophysiological and optical findings of the current study indicate evolving fundamental brain plasticity changes after the detrimental event predisposing to chronic epilepsy. The current results should be incorporated in any strategies aiming at prevention of chronic epilepsy.
Sujet(s)
Potentiels d'action/physiologie , Synchronisation corticale/physiologie , Hippocampe/physiopathologie , Voies nerveuses/physiopathologie , État de mal épileptique/anatomopathologie , Animaux , Maladie chronique , Modèles animaux de maladie humaine , Stimulation électrique/effets indésirables , Hippocampe/anatomopathologie , Mâle , Voies nerveuses/anatomopathologie , Techniques de culture d'organes , Rats , Rat Wistar , État de mal épileptique/physiopathologie , État de mal épileptique/prévention et contrôle , Imagerie par colorant sensible au potentiel/méthodesRÉSUMÉ
Chronically elevated concentrations of non-esterified fatty acids (NEFAs) in type 2 diabetes may be involved in ß-cell dysfunction and apoptosis. It has been shown that long-chain saturated NEFAs exhibit a strong cytotoxic effect upon insulin-producing cells, while short-chain as well as unsaturated NEFAs are well tolerated. Moreover, long-chain unsaturated NEFAs counteract the toxicity of palmitic acid. Reactive oxygen species (ROS) formation and gene expression analyses together with viability assays in different ß-cell lines showed that the G-protein-coupled receptors 40 and 120 do not mediate lipotoxicity. This is independent from the role, which these receptors, specifically GPR40, play in the potentiation of glucose-induced insulin secretion by saturated and unsaturated long-chain NEFAs. Long-chain NEFAs are not only metabolized in the mitochondria but also in peroxisomes. In contrast to mitochondrial ß-oxidation, the acyl-coenzyme A (CoA) oxidases in the peroxisomes form hydrogen peroxide and not reducing equivalents. As ß-cells almost completely lack catalase, they are exceptionally vulnerable to hydrogen peroxide generated in peroxisomes. ROS generation in the respiratory chain is less important because overexpression of catalase and superoxide dismutase in the mitochondria do not provide protection. Thus, peroxisomally generated hydrogen peroxide is the likely ROS that causes pancreatic ß-cell dysfunction and ultimately ß-cell death.
Sujet(s)
Cellules à insuline/métabolisme , Mitochondries/métabolisme , Espèces réactives de l'oxygène/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Acide gras libre/pharmacologie , Régulation de l'expression des gènes , Humains , Peroxyde d'hydrogène/pharmacologie , Insuline/pharmacologie , Cellules à insuline/cytologie , Mitochondries/effets des médicaments et des substances chimiques , Oxydoréduction/effets des médicaments et des substances chimiques , Récepteurs couplés aux protéines G/physiologieRÉSUMÉ
Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors-improving beta-cell resistance against immune attack-is an attractive path to pursue. The aim of this study was to investigate whether dissociation of islets to single cells prior to viral infection and reaggregation before transplantation would improve viral transduction efficacy without cytotoxicity. This procedure improved transduction efficacy with a LV-pWPT-CMV-EGFP construct from 11.2 +/- 4.1% at MOI 50 in whole islets to 80.0 +/- 2.8% at MOI 5. Viability (as measured by Hoechst/PI) and functionality (as measured by glucose challenge) remained high. After transplantation, the transfected pseudoislet aggregates remained EGFP positive for more than 90 days and the expression of EGFP colocalized primarily with the insulin-positive beta-cells. No increased vulnerability to immune attack was observed in vitro or in vivo. These data demonstrate that dispersion of islets prior to lentiviral transfection and reaggregation prior to transplantation is a highly efficient way to introduce genes of interest into islets for transplantation purposes in vitro and in vivo, but the amount of beta-cells needed for normalization of glycemia was more than eightfold higher when using dispersed cell aggregates versus unmanipulated islets. The high price to pay to reach stable and strong transgene expression in islet cells is certainly an important cell loss.
Sujet(s)
Transplantation d'ilots de Langerhans , Ilots pancréatiques/cytologie , Lentivirus/génétique , Transduction génétique , Animaux , Agrégation cellulaire/effets des médicaments et des substances chimiques , Mort cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire , Séparation cellulaire , Survie cellulaire/effets des médicaments et des substances chimiques , Cytokines/pharmacologie , Cytométrie en flux , Humains , Insuline/métabolisme , Sécrétion d'insuline , Ilots pancréatiques/effets des médicaments et des substances chimiques , Ilots pancréatiques/métabolisme , Mâle , Souris , Rats , Rat Wistar , Facteurs temps , TransgènesRÉSUMÉ
BACKGROUND: Contrast media-induced nephropathy (CIN) is an increasing cause of hospital-acquired acute kidney injury and leads to a significant increase in mortality. There is uncertainty whether the use of iso-osmolar contrast media as opposed to the use of low-osmolar contrast media would be associated with a lower incidence of CIN. Therefore, we compared the nephrotoxicity of isoosmotic contrast media iodixanol with the low-osmotic contrast media iopromid in patients receiving contrast media during coronary angiography. METHODS: In this prospective double-blind study we examined 221 patients with normal renal function who received up to 1,000 ml of contrast media during coronary angiography, and compared the effect of iodixanol and iopromid on inducing contrast media nephropathy. Patients received 800 ml fluid orally before contrast media administration and 1,000 ml saline i.v. thereafter. Creatinine clearance, serum creatinine and urine-N-acetyl-beta-D-glucosaminidase (NAG) concentration was obtained 24 h before and 48 h after contrast media administration. Decrease of 20% of the creatinine clearance, increase of 25% of serum creatinine and increase of 20% of the urine concentration of NAG was defined as CIN. RESULTS: Incidence of CIN assessed by decreased creatinine clearance was 22.2% in the iopromid group and 19.7% in the iodixanol group. CIN defined by increased serum creatinine was 6.9% in the iopromid group and 8.6% in the iodixanol group. The difference between these two groups was not significant. Subgroup analysis of the diabetic patients or the patients that received high dose of contrast media revealed no significant difference in the incidence of CIN between the two contrast media. CONCLUSION: The iso-osmolar and the low-osmolar contrast media exhibited the same incidence of CIN in our study population. If fluid administration is sufficient, the selection of either iopromid or iodixanol has no impact on the risk of developing CIN in patients with normal renal function, even when they are diabetic or receive a high dose of more than 500 ml contrast media.
Sujet(s)
Produits de contraste/effets indésirables , Iohexol/analogues et dérivés , Maladies du rein/induit chimiquement , Acides triiodo-benzoïques/effets indésirables , Acetylglucosaminidase/urine , Loi du khi-deux , Produits de contraste/administration et posologie , Coronarographie , Créatinine/métabolisme , Méthode en double aveugle , Femelle , Humains , Incidence , Iohexol/administration et posologie , Iohexol/effets indésirables , Mâle , Adulte d'âge moyen , Concentration osmolaire , Études prospectives , Facteurs de risque , Statistique non paramétrique , Acides triiodo-benzoïques/administration et posologieRÉSUMÉ
AIMS/HYPOTHESIS: Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. METHODS: A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. RESULTS: Exposure of RINm5F cells to IL-1beta or to a cytokine mixture (IL-1beta, TNF-alpha, IFN-gamma) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-kappaB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1beta or the cytokine mixture. In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA ( MAMA) and transport-associated protein ( TAP1/MTP), whereas the plasma membrane calcium ATPase ( PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. CONCLUSIONS/INTERPRETATION: Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.
Sujet(s)
Cytokines/immunologie , Régulation de l'expression des gènes tumoraux/immunologie , Insuline/métabolisme , Agrine/génétique , Animaux , Séquence nucléotidique , Lignée cellulaire tumorale , Amorces ADN , Sécrétion d'insuline , Insulinome , Protéines tumorales/génétique , Tumeurs du pancréas , ARN messager/génétique , RatsSujet(s)
Alloxane/toxicité , Ilots pancréatiques/effets des médicaments et des substances chimiques , Streptozocine/toxicité , Régulation de l'expression des gènes , Transporteur de glucose de type 2 , Humains , Immunité innée/effets des médicaments et des substances chimiques , Ilots pancréatiques/anatomopathologie , Ilots pancréatiques/physiologie , Transporteurs de monosaccharides/génétique , Transporteurs de monosaccharides/métabolismeRÉSUMÉ
AIMS/HYPOTHESIS: We investigated the importance of the low affinity GLUT2 glucose transporter in the diabetogenic action of alloxan in bioengineered RINm5F insulin-producing cells with different expressions of the transporter. METHODS: GLUT2 glucose transporter expressing RINm5F cells were generated through stable transfection of the rat GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: Cells expressing the GLUT2 transporter were susceptible to alloxan toxicity due to the uptake of alloxan by this specific glucose transporter isoform. The extent of the toxicity of alloxan was dependent upon the GLUT2 protein expression in the cells. The lipophilic alloxan derivative, butylalloxan, was toxic also to non-transfected control cells. Expression of the GLUT2 glucose transporter caused only a marginal increase in the toxicity of this substance. Butylalloxan, unlike alloxan itself, is not diabetogenic in vivo although, like the latter substance, it is beta-cell toxic in vitro through its ability to generate free radicals during redox cycling with glutathione. CONCLUSION/INTERPRETATION: Our results are consistent with the central importance of selective uptake of alloxan through the low affinity GLUT2 glucose transporter for the pancreatic beta-cell toxicity and diabetogenicity of this substance. Redox cycling and the subsequent generation of oxygen free radicals leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as alloxan diabetes in experimental diabetes research.
Sujet(s)
Alloxane/toxicité , Glucose/pharmacologie , Ilots pancréatiques/anatomopathologie , Transporteurs de monosaccharides/génétique , Transporteurs de monosaccharides/métabolisme , 3-O-méthylglucose/pharmacologie , Alloxane/analogues et dérivés , Alloxane/antagonistes et inhibiteurs , Animaux , Cellules cultivées , Régulation de l'expression des gènes/physiologie , Transporteur de glucose de type 2 , Ilots pancréatiques/effets des médicaments et des substances chimiques , Ilots pancréatiques/métabolisme , Cinétique , Microsomes/métabolisme , Rats , Protéines recombinantes/métabolismeRÉSUMÉ
AIMS/HYPOTHESIS: We describe a new Type I (insulin-dependent) diabetes mellitus rat model (LEW.1AR1/Ztm-iddm) which arose through a spontaneous mutation in a congenic Lewis rat strain with a defined MHC haplotype (RT1.Aa B/Du Cu). METHODS: The development of diabetes was characterised using biochemical, immunological and morphological methods. RESULTS: Diabetes appeared in the rats with an incidence of 20 % without major sex preference at 58+/-2 days. The disease was characterised by hyperglycaemia, glycosuria, ketonuria and polyuria. In peripheral blood, the proportion of T lymphocytes was in the normal range expressing the RT6.1 differentiation antigen. Islets were heavily infiltrated with B and T lymphocytes, macrophages and NK cells with beta cells rapidly destroyed through apoptosis in areas of insulitis. CONCLUSION/INTERPRETATION: This Type I diabetic rat develops a spontaneous insulin-dependent autoimmune diabetes through beta cell apoptosis. It could prove to be a valuable new animal model for clarifying the mechanisms involved in the development of autoimmune diabetes.
Sujet(s)
Maladies auto-immunes , Diabète de type 1/génétique , Diabète de type 1/immunologie , Modèles animaux de maladie humaine , Animaux , Apoptose , Lymphocytes B/anatomopathologie , Glycémie/analyse , Diabète de type 1/métabolisme , Glycosurie , Hyperglycémie , Insuline/sang , Ilots pancréatiques/immunologie , Ilots pancréatiques/anatomopathologie , Corps cétoniques/urine , Cellules tueuses naturelles/anatomopathologie , Macrophages/anatomopathologie , Mâle , Microscopie électronique , Polyurie , Rats , Rats de lignée LEW , Souches mutantes de rat , Lymphocytes T/anatomopathologieRÉSUMÉ
AIMS: To investigate a correlation of the platelet activation marker CD62 and secretion of the growth factor PDGF from platelets in coronary patients under therapy with the GPIIb/IIIa-inhibitor abciximab. METHODS: Flow cytometric assessment of fibrinogen binding (GPIIb/IIIa-binding site) and CD62 expression, as well as PDGF release of human platelets (immunoassay) and platelet aggregation with 20 microM ADP and 2 microg ml(-1) collagen were evaluated in nine patients with stable coronary artery disease. Patients were undergoing elective balloon angioplasty and were treated with aspirin (100 mg day(-1)), heparin (ACT < 220 s) and abciximab (bolus and infusion over 12 h). Blood samples were obtained before initiation of abciximab therapy (under aspirin and heparin) (I), 3 h after angioplasty under abciximab (II) and 12 h after termination of abciximab infusion (III). RESULTS: Compared with sample I before abciximab therapy, fibrinogen binding was reduced to 37% (+/- 34 s.d., P < 0.05) (II) and 55% (+/- 40 s.d., P < 0.05) (III). Reduced fibrinogen binding also led to a significant reduction of the aggregation response to ADP (down to 37% +/- 20) and collagen (down to 0%). Mean fluorescence intensity of CD62-expression was 78 units (+/- 20 s.d.) (I), 72 units (+/- 14 s.d.) (II) and 64 units (+/- 12 s.d., P < 0.05) (III). PDGF release from isolated, washed platelets was 99 (+/- 33 s.d.) ng/10(9) platelets at (I), 82 (+/- 31 s.d.) ng/10(9) platelets and 96 (+/- 30 s.d.) ng/10(9) platelets. CONCLUSIONS: The results indicate that despite a strong reduction of GPIIb/IIIa-binding and platelet aggregation, CD62 as a marker of platelet secretion and the secretion product PDGF were only slightly reduced under abciximab treatment. No direct correlation between CD62 expression and PDGF release could be demonstrated.
Sujet(s)
Angioplastie coronaire par ballonnet/méthodes , Anticorps monoclonaux/usage thérapeutique , Plaquettes/métabolisme , Maladie coronarienne/sang , Fragments Fab d'immunoglobuline/usage thérapeutique , Sélectine P/sang , Facteur de croissance dérivé des plaquettes/métabolisme , Abciximab , Anticorps monoclonaux/administration et posologie , Maladie coronarienne/traitement médicamenteux , Humains , Fragments Fab d'immunoglobuline/administration et posologie , Techniques in vitro , Injections veineuses , Mâle , Adulte d'âge moyen , Sélectine P/immunologie , Agrégation plaquettaire/effets des médicaments et des substances chimiques , Antiagrégants plaquettaires/sang , Antiagrégants plaquettaires/pharmacologie , Complexe glycoprotéique IIb-IIIa de la membrane plaquettaire/antagonistes et inhibiteurs , Complexe glycoprotéique IIb-IIIa de la membrane plaquettaire/métabolisme , Facteurs tempsRÉSUMÉ
Aims Platelets play a central role in the restenosis process by inducing neointimal proliferation after coronary interventions. Glycoprotein IIb/IIIa Pl(A2)polymorphism has been associated with the occurrence of acute coronary syndromes and increased restenosis rates. Statins have been shown to exert potent antiproliferative, antiinflammatory and antithrombotic properties, thereby potentially interfering with the major processes of in-stent restenosis. Therefore, we sought to find out whether statin therapy interferes with restenosis and clinical outcome at 6 months following successful coronary stent implantation in the presence or absence of the Pl(A2)allele. Methods and Results Six hundred and fifty consecutive patients were followed for 6 months after coronary stent insertion. Carriers of the Pl(A2)allele demonstrated a significantly increased restenosis rate, which was abrogated by statin therapy (50.9% vs 28.6%, P=0.01). Moreover, statin therapy was associated with a significant reduction (28.2% vs 49.3%, P<0.01) in the occurrence of major adverse coronary events (myocardial infarction, cardiac death, target vessel revascularization) in the 6 months after the intervention in patients with the Pl(A2)allele. Conclusion Statin therapy reduces increased stent restenosis rates and improves clinical outcome following coronary stent implantation in patients bearing the Pl(A2)allele, suggesting that statins interfere with the functional consequence of a genetically determined platelet-mediated risk factor associated with Pl(A2)polymorphism.
Sujet(s)
Anticholestérolémiants/usage thérapeutique , Occlusion du greffon vasculaire/prévention et contrôle , Complexe glycoprotéique IIb-IIIa de la membrane plaquettaire/génétique , Polymorphisme de nucléotide simple , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Allèles , Coronarographie , Femelle , Humains , Mâle , Adulte d'âge moyen , Facteurs de risque , EndoprothèsesRÉSUMÉ
Development of coronary artery aneurysms is one typical complication of Kawasaki disease and can cause coronary artery disease even in early childhood. Information about course and outcome in adults is rare. Here, we present a 49-year-old man with serious three-vessel coronary artery disease and giant coronary artery aneurysms following suspected Kawasaki disease.
Sujet(s)
Pontage aortocoronarien , Maladie coronarienne/étiologie , Maladie coronarienne/chirurgie , Maladie de Kawasaki/complications , Anévrysme coronarien/étiologie , Humains , Mâle , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: Stent implantation in lesions of degenerated aortocoronary vein grafts is associated with a high risk of periprocedural thrombus embolization and in-stent restenosis. METHODS AND RESULTS: In a multicenter study, we followed up 109 consecutive patients (mean age 66+/-8 years, 12% female) who received polytetrafluoroethylene (PTFE) membrane-covered stents for 125 de novo stenoses in vein grafts 11+/-5 years after bypass surgery. Stent deployment was successful in all but 1 patient; 1 patient suffered from subacute stent thrombosis. Six-month cardiac mortality was 7% (8 patients), 3 patients (3%) underwent repeat bypass surgery, and 9 patients (8%) required target-lesion PTCA. Repeat angiography revealed vessel occlusions in 9% and in-stent restenosis in 8% of patients by the end of follow-up. CONCLUSIONS: Membrane-covered stents appear to be a safe and efficient treatment strategy associated with a low incidence of restenosis and target-vessel revascularization. Compared with previous studies, the investigated device is not associated with an increase in mortality or late vessel occlusions.
Sujet(s)
Pontage aortocoronarien , Occlusion du greffon vasculaire/thérapie , Endoprothèses , Sujet âgé , Études de cohortes , Coronarographie , Femelle , Études de suivi , Occlusion du greffon vasculaire/épidémiologie , Humains , Mâle , Membrane artificielle , Polytétrafluoroéthylène/métabolismeRÉSUMÉ
The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation.