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This technical note complements a published lining evaluation for a canal in Egypt. Concrete and geomembrane linings are compared regarding leakage control and cost. Published data on leakage with concrete and geomembrane linings are reviewed, and analyses show that the predicted leakage rate is significantly lower with a geomembrane lining than with a concrete lining. The findings presented herein on leakage control and cost are significantly different from the findings of the published lining evaluation.

This study provides a preliminary approximate quantification of the difference in seam reliability between fusion seams and extrusion seams of high-density polyethylene (HDPE) geomembranes based on leaks that exist at the end of installation. The two different seaming methods as well as seam testing methods are discussed. The reliability of the two seaming methods is compared using the number of leaks associated with extrusion seams versus fusion seams, which were found using electrical leak location surveys performed on a sampling of large geomembrane-lined facilities.

ABSTRACT: This paper shows that two physical characteristics of geosynthetic drains can be significantly affected by the flow boundaries: the specific surface area and the average flow path diameter. These two physical characteristics are important, because they have a significant influence on the hydraulic characteristics of geosynthetic drains. A theoretical analysis leads to a quantification of the effect of smooth and rigid flow boundaries on the specific surface area and the average flow path diameter. Numerical calculations performed using the equations proposed in this paper show that the effect of these flow boundaries is negligible in cases where the geosynthetic drain consists of a needle-punched nonwoven geotextile. In contrast, the effect of smooth and rigid flow boundaries on geonet drains is usually significant. The fact that even boundaries that are smooth and rigid have a significant influence on the measured hydraulic transmissivity of geonets supports the usual recommendation that, to measure a representative geonet transmissivity in the laboratory, flow boundaries that are representative of the field conditions must be used. For the sake of comparison, the methodology is also applied to granular drains. It is shown that the effect of flow boundaries is generally negligible in the case of granular (sand and gravel) drains. More generally, it is shown that the effect of flow boundaries that are smooth and rigid is negligible when the drain thickness is at least 20 times the size of the solid constituents of the drainage material, such as the diameter of the granular particles, or the diameter of geotextile fibers and geonet ribs.

This paper presents equations for calculating the rate of liquid flow through defects in the geomembrane component of a composite liner. The considered defects have a uniform width and have a length that is finite or infinite. Two types of defects are considered: narrow defects such as tears, cuts and defective seams, and wide defects, such as damaged wrinkles. As a first step, the paper presents a new expression for a previously published equation for the rate of liquid flow through an infinitely long defect in the geomembrane component of a composite liner. This new expression is significantly simpler than the original equation. The new expression is then combined with empirical equations for the rate of liquid flow through a circular defect in the geomembrane component of a composite liner to obtain equations for the rate of liquid flow through a defect of finite length in the geomembrane component of a composite liner. The rate of flow through defects of finite length comprises two components: flow that takes place over the length of the defect and flow that takes place at the two ends of the defect. A parametric study shows that, in most cases, a large fraction of the flow takes place at the ends of defects of finite length. Therefore, it is generally not recommended to do a two-dimensional calculation, thereby neglecting flow at the ends of the defect. Examples of use of the proposed equations are presented.

This paper presents state-of-the-art examples to show that, in a wide variety of cases, the behavior of geosynthetics can be quantified using theoretical analyses. Seven examples are reviewed: geotextile filter retention, geotextile filter clogging, geomembrane stress–strain behavior, geomembrane strain concentrations, geomembrane stress cracking pattern, geomembrane wrinkles, and geosynthetic resistance to differential settlement. The selected examples are such that the important behavioral aspect is not the behavior of the structure in which the geosynthetic is incorporated, but the behavior of the geosynthetic itself. In each case, the phenomenon or problem is described, the theoretical analysis is presented, and the results are discussed. An important message conveyed by this paper is that the solution of engineering problems can only result from rational analyses, not from common sense. Note: This paper is an updated version of a paper initially published as a Special Lecture in the proceedings of the Fifth International Conference on Geotextiles Geomembranes and Related Products, held in Singapore in 1994.

A theoretically based design method for the thickness of the base course of unpaved roads is developed in this paper, which considers distribution of stress, strength of base course material, interlock between geosynthetic and base course material, and geosynthetic stiffness in addition to the conditions considered in earlier methods: traffic volume, wheel loads, tire pressure, subgrade strength, rut depth, and influence of the presence of a reinforcing geosynthetic (geotextile or geogrid) on the failure mode of the unpaved road or area. In this method, the required base course thickness for a reinforced unpaved road is calculated using a unique equation, whereas more than one equation was needed with earlier methods. This design method was developed for geogrid-reinforced unpaved roads. However, it can be used for geotextile-reinforced unpaved roads and for unreinforced roads with appropriate values of relevant parameters. The calibration of this design method using data from field wheel load tests and laboratory cyclic plate loading tests on unreinforced and reinforced base courses is presented in the companion paper by the authors.

In some applications of geosynthetic clay liners (GCLs), the bentonite layer component of the GCL is encapsulated between two geomembranes. One of the benefits of this configuration is to decrease the risk of shear strength decrease due to bentonite hydration. The liner thus formed is typically used to contain a liquid, such as water or leachate. If there is a defect in the upper geomembrane, some of the liquid initially contained above the upper geomembrane migrates into the bentonite. Similarly, if there is a defect in the lower geomembrane, some of the liquid initially contained in the soil underlying the lower geomembrane migrates into the bentonite. The liquid that has migrated into the bentonite then migrates laterally in the bentonite between the two geomembranes. The analyses presented in this paper provide analytical solutions for the one-dimensional and axisymmetrical cases. In each of the two cases, two types of analytical solution are provided: an equation that gives the time required for the hydration front to reach a certain distance from the geomembrane defect, and an equation that gives the rate of liquid migration through the defect. It appears that the time required for the hydration front to reach a relatively small distance (e.g. a few meters) is very long (i.e. of the order of decades). Therefore a very long time is required for the development of a large hydrated area that could significantly impact shear strength. Also, a very long time is required for liquid migrating through a defect in the upper geomembrane to reach a defect in the lower geomembrane, thereby creating a leakage path from the medium overlying the upper geomembrane to the medium underlying the lower geomembrane. The analyses also show that the rate of liquid migration through the upper geomembrane defect is very small compared with the rate of leakage through the same defect in the geomembrane component of a typical composite liner where the soil component is clay or a GCL. The results of these analyses demonstrate the effectiveness of a liner that consists of a layer of bentonite encapsulated between two geomembranes, and provide a method to quantify this effectiveness.

Hydrated bentonite has a low shear strength, which may adversely impact the stability of structures incorporating geosynthetic clay liners (GCLs). Accordingly, in a growing number of GCL applications, the configuration is such that the bentonite layer is encapsulated between two geomembranes in order to reduce the potential for bentonite hydration. This paper considers an encapsulated bentonite layer formed using GM-GCL panels (i.e. panels consisting of a bentonite layer adhered to a carrier geomembrane). The panels are joined by overlapping at the edges and are overlain by a welded geomembrane. Water can migrate from the underlying soil into the bentonite of the overlaps, flow in the bentonite, and migrate laterally in the bentonite between the two geomembranes. Water is driven from the soil to the bentonite by a head difference that results in great part from the suction at the hydration front. This paper presents an analytical method to evaluate the extent of the hydrated area of the bentonite layer as a function of: time, the initial and hydrated moisture content of the bentonite, the hydraulic conductivity of the bentonite, the overlap width, the distance between overlaps, and the head difference. It is important to know the hydrated area for stability calculations. Numerical applications show that, for typical values of the parameters, it takes many decades to hydrate a significant fraction of the bentonite layer area. The analyses presented in this paper also show that, for typical landfill applications, the hydrated area due to leakage through defects in the upper geomembrane is negligible with respect to the hydrated area resulting from water migrating through the overlaps, assuming that the upper geomembrane is installed using good construction quality assurance practices. Uncertainties associated with the methodology presented herein are discussed, and guidance is provided on evaluation of the shear strength of the encapsulated bentonite layer as a function of the shear strength of the unhydrated bentonite, the shear strength of the hydrated bentonite, and the hydrated area.

FOREWORD: Every four years, an International Conference on Geosynthetics provides an opportunity to bring together, from all over the world, a variety of people involved in this field. Thus, in September 2002, 1200 participants attended the 7th International Conference on Geosynthetics held in Nice, France. Among several innovative features, this conference included ‘special sessions’ on key subjects selected by the conference Scientific Committee. For each special session, two session leaders, known for their expertise on the subject, were invited to plan the session several months before the conference, and, in particular, to select topics for discussion. The special session on ‘Geomembranes in landfills’ was especially significant, as it was organized with the cooperation of Geosynthetics International. This cooperation between a conference and a technical journal was proposed by the conference Scientific Committee as an original experiment aimed at promoting the diffiusion of valuable technical information. The following paper reports in great detail the discussion that took place at the special session on ‘Geomembranes in landfills’. We must say that this special session, with more than 200 attendees, and the resulting paper fully matched our highest expectations thanks to the leadership provided during the session by J. P. Giroud and N. Touze-Foltz, and their careful editing of the discussion transcript. We should also acknowledge the contribution of the fifteen attendees who took part in the discussion and agreed to review the edited transcript. It is no secret that discussion transcripts require extensive editing prior to publication. The two session leaders should be commended for producing an edited version that remains very lively and retains the favour of heated debates between researchers and practitioners. The readers will also appreciate that the paper reports the discussion of the three important topics selected by the session leaders in a well-organized manner. Based on the reported discussion, it is clear that there are significant discrepancies between the state of the art and the state of practice, as well as discrepancies between the states of practice in different countries. The paper that follows is a first step towards a reduction of these discrepancies and will, therefore, benefit practitioners in many countries. Certainly, one of the most interesting features of the discussion at the special session on ‘Geomembranes in landfills’ is the active participation of practitioners, whereas too often at international conferences practitioners essentially listen to researchers. It would have been a great loss had this discussion not been reported, as is unfortunately the case of most discussions at most conferences. Therefore, the readers of this paper will certainly agree with us that this experiment of cooperation with a technical journal should be repeated at future International Conferences on Geosynthetics. by J. P. Gourc, H. Girard and P. Delmas *

Flow in porous media, such as geosynthetic and granular drains, is often nonlaminar. Nonlaminar flow can vary in character from semiturbulent to turbulent, depending upon the flow velocity, which is related to the hydraulic gradient. An exponent on the hydraulic gradient is used in the relationship among the hydraulic gradient, the apparent flow velocity, and the saturated hydraulic conductivity or transmissivity to quantify the degree of turbulence of the flow in porous media. Numerical values of this exponent are established for both granular and geosynthetic drains based on an analysis of published and unpublished experimental data. It appears that for typical hydraulic gradients encountered in practice, the degree of turbulence for flow in granular drains depends essentially on the particle size, with flow through sand drainage layers being laminar and flow through gravel drainage layers being nonlaminar. In geosynthetic drains, the degree of turbulence depends on the applied compressive stres...

This paper investigates the impact of the following five assumptions on the accuracy of Newmark seismic deformation analysis applied to geosynthetic cover systems: (i) the potential failure mass is noncompliant; (ii) the dynamic response of the potential failure mass is uncoupled from displacement (slip); (iii) permanent displacements accumulate in only one direction; (iv) vertical ground motions do not influence permanent displacement; and (v) the yield acceleration is constant. Information presented in the literature indicates the impact of the assumption of a noncompliant failure mass and the assumption of a seismic response uncoupled from displacement is insignificant for typical geosynthetic cover systems. The results of computer analyses indicate that the effects of two-way sliding and vertical ground motions can, in most practical cases, be neglected. However, the assumption of a constant yield acceleration, when based on residual (or la rge displacement) shear strength, may result in calculated displacements that are significantly larger than those calculated using a yield acceleration that degrades with accumulated displacement from a peak value to a residual, or large displacement, value. Overall, results of this investigation indicate that conventional Newmark analyses based upon residual shear strength yield conservative results when applied to geosynthetic cover systems.

A model is described of acute inflammation in the pleural cavity of rats using calcium pyrophosphate as the irritant. This model would seem to simulate the pseudogout syndrome. It has been shown to be acute in onset, dominated by polymorphonuclear cells, complement independent. The advantage of the model is that volume of exudate, numbers and types of cells may be quantitated. Prostaglandins and cyclic AMP have been measured in the migrating cells. The significance of these findings has been discussed.

Cetirizine was first described as a specific anti-H1 molecule displaying potent antiallergic activity. It was later found that its pharmacological properties extended to cellular actions as on eosinophil recruitment at inflammatory sites in allergic patients. Monocytes and macrophages participate in allergic mechanisms, particularly through high affinity H1 and H2 membrane receptors and generation of pro- and anti-inflammatory agents; among them histamine-induced factors, IL-1 and prostanoids are of importance. The aim of this work was to investigate the effect exerted by various concentrations of cetirizine (0.1-10 micrograms/ml) applied in vitro to human monocytes and peritoneal rat macrophages cultured for 24 h. Peritoneal macrophages were collected either from normal or experimentally inflamed rats. Human monocytes, isolated from peripheral blood, were studied either in a resting state or after stimulation by LPS from Escherichia coli (1 and 10 micrograms/ml). Cetirizine (10 micrograms/ml) significantly enhanced IL-1 release by human monocytes stimulated by a weak LPS concentration (1 microgram/ml) but could not modify the maximal increase of IL-1 release induced by 10 micrograms/ml of LPS. It did not exert any effect on resting cells. Cetirizine (0.1-10 micrograms/ml) enhanced PGE2 release by resting human monocytes. Concentrations of 1 and 10 micrograms/ml enhanced PGE2 release by LPS-stimulated monocytes, and by healthy and inflamed rat macrophages. This effect was concentration-dependent. Our findings point to an anti-inflammatory action of cetirizine via PGE2 release and histamine H2 interactions. Cetirizine did not directly modify IL-1 generation by resting monocytes but the IL-1 production observed after LPS stimulation could promote the mechanisms by which PGE2 is released.

Among the multiple biological activities of nitric oxide (NO) an immunoregulatory role consisting of the mediation of macrophage suppressive activity, has recently been evidenced. In the present work, we investigated whether NO was implicated in immunosuppression following burn injury. Thermal injury affecting 20-25% of the total body surface area in Wistar rats, provoked a biphasic depression of spleen cell proliferative responses to phytohemagglutinin (PHA) and concanavalin A (Con A). We show that these responses are fully restored on day 4 after burn and only by 55% on day 10 when spleen cells were stimulated in the presence of NG-monomethyl-L-arginine (NMMA), a potent inhibitor of the macrophage inducible NO synthase. Nitrite content in culture supernatant, as an indicator of NO release (in the absence of NMMA), was significantly augmented in Con A-stimulated spleen cells from burned rats as compared to normal spleen cells. These results show for the first time that NO is implicated, at least in part, in an immunosuppression state which is not linked to an infectious disease.

International audience; This paper presents empirical equations for the evaluation of advective flow rates through composite liners, i.e. liners comprising a geomembrane and a low-permeability soil layer. The advective flow is due to defects in the geomembrane and depends on contact conditions between the geomembrane and the soil layer. Three types of defects (circular defects, defects of infinite length, and damaged wrinkles) and three types of contact conditions (excellent, good, and poor) are considered. The methodology for developing the empirical equations consists of selecting a mathematical expression for the empirical equations and selecting values for the unknowns of the empirical equations such that flow rates calculated using the empirical equations are as close as possible to flow rates rigorously calculated using existing analytical solutions. This was achieved by conducting numerical calculations for more than 120,000 cases defined by a wide range of values of the parameters (contact conditions, defect type and size, soil layer thickness and hydraulic conductivity, and hydraulic head). As the empirical equations are much simpler than the analytical solutions, they provide design engineers with a practical tool for evaluating flow rates through composite liners.

The antibacterial activity of ofloxacin was evaluated in urine over a period of 96 h after oral administration for 5 days of 200 mg twice a day in 12 healthy female volunteers. Bacteriostatic and bactericidal activity of urines were studied for five strains of enterobacterias recovered from urinary infections: two strains of Escherichia Coli Nal-S and Nal-R, two strains of Proteus mirabilis Nal-S and Nal-R, and one strain of Klebsiella pneumoniae Nal-S. Mean urinary concentrations of ofloxacin were very high during the first 12 h following last intake. They were still above 7 mg/l till the 48th hour and above 1.6 mg/l till the 72nd hour. Bactericidal activity of urine was present for 72 h in respect of four strains studied at that time; urine was not bactericidal as regards E. coli Nal-R. After 5 days of oral treatment with ofloxacin (200 mg b.i.d.), urine retains a bactericidal activity for at least 72 h against bacterial strains of urinary tract infections.

The explosive growth in cytokines has been followed by many attempts to bring them into clinical use. Immediate applications are already recognized in cancer and infectious diseases. Future applications are foreseeable in inflammatory and auto-immune diseases. The use of accurate and sensitive methods for cytokine measurements in body fluids is an absolute prerequisite to define the pharmacological effect of parenterally administered recombinant cytokines. Enzyme-linked immunosorbent assay (ELISA) has become the most convenient method but there is an urgent need for a real standardization of this technique. Moreover, ELISA may be susceptible to cross-reactivity due to the high percentage of amino-acid homology between the various cytokines. The pharmacokinetic profile of recombinant cytokines may be influenced by endogenous production, receptor binding effect, receptor antagonists and soluble receptors. Cytokines elicit an immunogenic response and anticytokine antibodies should be monitored. Serum half-life of elimination is about 4 h after subcutaneous administration. In contrast with conventional drugs, pharmacokinetic data do not provide useful information for the design of a clinical protocol, and the rational choice of the unit dose and dosing schedule should be based on biological considerations. In vitro studies on the duration of receptor occupancy required for effector augmentation provide one of the bases for the choice of therapeutic protocol. Recombinant cytokines share biological activities and synergize with or antagonize one another so that it is difficult to evaluate their effects in clinical studies. Thus, pharmacological results do not always correlate with therapeutic effect. There is no direct relationship between dose and activity. One must determine the optimum biological dose (OBD), which is the minimal dose resulting in a significant augmentation of effector cell activity correlating with the therapeutic response. Surrogate markers may help to assess the clinical response such as 2',5'-oligo(A) synthetase or neopterin following interferon administration. Cytokines' adverse effects are difficult to foresee in the human because studies in rodents and dogs cannot fully predict them because of their species specificity. New relevant animal models are needed such as transgenic animals and parallel animal models. Pro-inflammatory cytokines inhibit cytochrome P-450 and have the potential to cause drug-cytokine interactions.

The pharmokinetics of drugs used to treat lung disease in pregnant women undergo changes due to the physiological variations induced by pregnancy. Dosage must therefore be adapted; increased doses are often required for the treatment of severe lung infections. Most drugs used for lung disease have a teratogenic potential and thus carry a risk for the fetus. Drugs used for asthma usually present little risk for the fetus. Administration by inhalation is particularly well adapted as it limits systemic diffusion. Excessively high doses can however lead to neonatal toxicity. Penicillins, cephalosporins and erythromycin have been shown to be well tolerated and are the choice antibiotics. Aminoglycosides require careful monitoring due to the risk of renal and auditory toxicity. Fluoroquinolones, sulfamides and tetracyclines should be avoided. Available data on recent compounds such as the new macrolides (azithromycin, clarithromycin) are too limited for recommending their use during pregnancy. In case of resistant tuberculosis, it is sometimes necessary to prescribe a second choice anti-tuberculosis drug with known or suspected fetal toxicity.

Accurate assessment of pain is the key to appropriate analgesia. This necessitates not only an understanding of the organic component, but also a comprehension of the role played by the mental, social and spiritual dimensions in the individual patient's suffering. It implies that the entire care team must be involved in pain management. The nature of a patient's pain is one predictor of the response to treatment. It is mainly characterized by its location, intensity, extent, timing and type (excessive nociception, neurogenic, or mixed), the circumstances in which it appears, and any accompanying signs. The choice of analgesic for treating pain due to excessive nociception was greatly facilitated by the introduction of the WHO three-step approach. Better knowledge of the pharmacological and pharmacokinetic properties of the different analgesics has contributed to increase their efficacy and tolerability. Certain types of pain of neurogenic origin respond poorly to both opiate and non opiate analgesics. They can be treated with other drugs whose mechanisms of action in pain relief are not fully understood. They include the following; antidepressants (amitriptyline, nortriptyline, desipramine and doxepine); anticonvulsants (carbamazepine, phenytoin, valporic acid and clonazepam); antiarrhythmic agents (lidocaine, mexiletine, flecainide and tocainide). The unwanted effects of these different treatments, together with psychological disturbances induced by the underlying disease, can call for the use of antiemetics, laxatives, spasmolytics, glucocorticoids and psychotropic agents (anxiolytics, neuroleptics and antidepressants). Finally, in many cases, better pain relief is obtained by combining drug-based therapy with other interventions such as radiation therapy, neurosurgery, and psychological/behavioral approaches. All these means must be chosen and used according to each individual patient's needs. Pain must be considered as a disease that can and must be eliminated or at least attenuated.

Intestinal toxicity exerted by indomethacin was compared to that induced by copper-indomethacinate, free or associated to zwitterionic phospholipids. A single high dose of indomethacin (15 or 20 mg/kg), copper-indomethacinate (15 or 20 mg/kg), or copper-indomethacinate liposomes or nanocapsules (15 mg/kg) was orally administered. Then 24 hr later jejunoileal tissue was taken for macroscopic observation, ex vivo nitrite production, and determination of myeloperoxydase and iNOS activities. Antiinflammatory activity of the drugs was investigated using the carrageenan-induced paw edema model. Indomethacin induced penetrating ulcerations of the intestine that were maximal at hour 24. Copper-indomethacinate induced significantly less ulceration than indomethacin with no significant difference in MPO and iNOS activities. The injurious action of indomethacin on the small intestine was further reduced when copper-indomethacinate was administered as the phospholipid-associated state while similar anti-inflammatory action was observed on rat paw edema. The antiulcerogen effect of copper-indomethacinate seems to be linked to its free radical scavenging effect without any modification of nitric oxide release.

We analysed changes in choline (CHO) and phosphorylcholine (PCHO) content of stimulated human polymorphonuclear leukocytes (PMNs) by a chemiluminescence assay to further examine the relative contributions of phospholipase D (PLD) and PLC to phosphatidylcholine (PC) breakdown. PLD activation was also analysed by measuring tritiated phosphatidic acid (PA) and diglycerides (GDs) in PMNs labelled with tritiated alkyl-lyso PC. Stimulation of PMNs with formyl-methionyl-leucyl-phenylalanine fMLP; 0.1 microM induced a weak elevation of mass choline (+25% of basal level) that was strongly potentiated in PMNs primed with cytochalasin B (+350% relative to the control value of 657+/-53 pmol/10(7) cells). CHO production was rapid and transient, peaking within 1 min, and ran parallel to that of tritiated PA. Thereafter, the amount of tritiated PA declined strongly (40% of maximum by 3 min), whereas the elevated choline content induced by fMLP plateaued for at least 5 min. Phorbol myristate acetate (PMA) sustained the formation of CHO for as long as 20 min, which correlated with that of [3H]PA in a time- and concentration-dependent manner. PCHO content of resting PMN leukocytes (1560 +/- 56 pmol/10(7) cells) was not modified after stimulation of PMNs with fMLP or PMA for at least 10 min, which argues against breakdown of phosphatidylcholine by PLC. For longer treatment (10-20 min), fMLP stimulated a significant enhancement of PCHO level, which occurred concomitantly with a decrease in CHO level, suggesting that choline kinase rather than PLC may be activated. Unlike fMLP, PMA stimulated a fall in PCHO between 10 and 15 min after PMN stimulation, pointing to different regulatory mechanisms of PCHO level. These data indicate that DG formation from PC in PMNs is mediated by PLD but not by PLC and show that chemiluminescence measurement of choline is a reliable index of PLD activation.

1. The toxic effects of nonsteroidal anti-inflammatory drugs for the lower gastrointestinal tract share certain features with inflammatory processes, suggesting that the release of inflammation cytokines such as TNF-alpha may damage the intestine. 2. Rats received a s.c. injection of indomethacin. Then, jejunum-ileum was taken up for the quantification of ulcerations, production of TNF-alpha, nitrites and PGE2 ex vivo and activity of calcium-independent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential effectors of TNF-alpha. 3. Jejunum-ileum from rats having received indomethacin (10 mg kg(-1)) produced TNF-alpha ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase. 4. Similar intestinal ulcerations and upregulation of TNF-alpha were obtained with flurbiprofen (30 mg kg(-1)), chemically unrelated to indomethacin. 5. TNF-alpha production was proportional to the indomethacin dose (from 3-20 mg kg(-1)) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration. 6. Pretreatment of rats with RO 20-1724, a type-IV phosphodiesterase inhibitor which inhibits TNF-alpha synthesis, substantially reduced jejunum-ileum ulcerations, TNF-alpha and nitrite production and tissue enzyme activities. 7. These findings provide evidence that TNF-alpha is increased in indomethacin-induced intestinal ulcerations and support suggestions that TNF-alpha is involved at an early stage of nonsteroidal anti-inflammatory drug toxicity for the small intestine.

Rats transgenic for HLA-B27 and human beta 2-microglobulin develop a spontaneous, multisystem, inflammatory disease that resembles human B27-associated disease and that involves the gut mucosa. This model predominantly affects the colon and is characterized by an extensive infiltration of the mucosa by inflammatory cells, largely composed of mononuclear cells. In addition, an increased plasma level of nitric oxide (NO)-derived metabolites was described in this model. Deficiency in the anti-inflammatory cytokine, interleukin-10 (IL-10), leads to the development of colitis in IL-10 knockout mice, suggesting that IL-10 plays a major role in the control of gut inflammation. The objectives of this work were to study the mechanisms of the inflammatory bowel disease (IBD) in HLA-B27 rats and to determine the effects of treatment with IL-10. The 33-3 line of HLA-B27 recombinant rats with established disease was treated in two consecutive experiments with murine recombinant IL-10 for five weeks. Assessment of the effect of this treatment was performed, based on clinical, histological and biological (myeloperoxidase and inducible NO synthase activities; tumor necrosis factor-alpha, interferon-delta, CD3, iNOS and beta-actin mRNA expression. In 33-3 rats with established disease, mesenteric lymph nodes were hyperplastic, and colonic cellularity and MPO and iNOS activities in the colonic mucosa were increased without any detectable effects of IL-10 administration. IFN-gamma and iNOS mRNA were only detected in the colon of transgenic rats. Despite a lack of effect on disease expression, IL-10 strikingly reduced the level of IFN-gamma mRNA in gut mucosa. Up-regulation of IFN-gamma mRNA suggests that the IBD of HLA-B27 rats is mediated by T-helper 1 lymphocytes. Sustained administration of IL-10, in HLA-B27 rats with established disease, efficiently inhibited IFN-gamma mRNA expression but did not influence disease expression: these results indicate that IFN-gamma may exert a critical role at an earlier stage of the disease rather in the maintenance of the lesions.

The purpose of this study was to investigate circulating polymorphonuclear leucocyte (PMNL) oxidative metabolism and lipid peroxidation in patients with adult respiratory distress syndrome (ARDS) who were treated with low- frequency, positive-pressure ventilation with extracorporeal carbon dioxide removal.

At physiological and pharmacological doses, adenosine protects tissues against a varieties of injuries: ischemia-reperfusion, convulsions, inflammation.... We tested the hypothesis that the antiinflammatory properties of adenosine occur via a down-regulation of TNF. Agonists of adenosine receptors (ARA) and agents potentiating endogenous adenosine (APA) were evaluated for their effects on TNF production by endotoxin-stimulated human monocytes. Additionally, one of the most potent agonists, R-phenylisopropyladenosine (R-PIA), was tested on two experimental models of acute phase response, endotoxin shock and carrageenan-induced plantar oedema. Several ARA and APA inhibited monocyte TNF production in a concentration-dependent manner. R-PIA and other ARA were active at micromolar concentrations. The property is pharmacologically relevant since rats receiving a lethal dose of endotoxins were protected by R-PIA and endotoxin-induced serum TNF levels were abolished by a pretreatment with R-PIA. Inhibitory effects on serum TNF production were obtained with similar doses of dexamethasone sodium phosphate and one hundred-fold higher doses of pentoxifylline. R-PIA was also found active on carrageenan-induced oedema. The anti-oedematous properties of R-PIA were associated with a marked reduction of locally-produced TNF and were also observed after the administration of dexamethasone, pentoxifylline and a neutralizing anti-TNF antibody. Our results indicate that adenosine is a potent inhibitor of TNF production induced by different stimuli. This property could lead to therapeutic applications in inflammatory diseases and other in which TNF is known to play a pathogenic or aggravating role. Comparison between ARA and APA in terms of tolerance and efficacy merits further attention.

Dexamethasone (sodium phosphate), pentoxifylline, fusidic acid (sodium salt), pentamidine (isethionate) and R -phenylisopropyladenosine (R-PIA) were tested for their anti-tumor necrosis factor (TNF) activities in an endotoxin-induced shock rat model. All the drugs reduced serum TNF concentrations in a dose-dependent manner, whereas their effects on serum interleukin-6 levels differed. Doses that reduced TNF levels by 50% were 0.012 mg/kg for dexamethasone, 0.06 mg/kg for R-PIA, 0.24 mg/kg for pentamidine, 6.5 mg/kg for fusidic acid and 15 mg/kg for pentoxifylline. Administration of the drugs to rats before intraplantar injection of carrageenan reduced paw edema by 50–70%. Injection of a monoclonal anti-TNF antibody reproduced the inhibitory effect. Moreover, the time course of tissue-associated TNF following carrageenan injection was compatible with mediation fo edema by TNF. Results obtained for this acute, non-immunological inflammatory reaction strongly suggest that the model is TNF-dependent. Our results reinforce the idea that TNF is a crucial target in the therapeutics of inflammatory reactions. These drugs, which are able to cross cell barriers, might have clinical applications in localized and/or chronic diseases in which TNF is involved.

In the circulation, human polymorphonuclear leukocytes (PMN) are exposed to various factors, such as lipoproteins, which could alter their metabolic and functional characteristics. In this work, the effects of low-density lipoproteins (LDL) on PMN oxidative metabolism and migration were studied in vitro. LDL stimulated PMN superoxide generation. This effect lasted for 15-20 min and was concentration-dependent. Staurosporine, a potent inhibitor of protein kinase C, did not suppress this stimulating effect. The chemotactic response of PMN to formyl-methionyl-leucyl-phenylalanine and C5a was inhibited by LDL and this effect was conserved after trypsination of LDL. LDL from normolipidemic subjects were more potent than LDL from hypertriglyceridemic subjects for both effects. LDL had no effect on superoxide generation by opsonized zymosan-stimulated PMN. These data showed that PMN responses may be modified by environmental conditions such as the presence of lipoproteins.

The concentration and concanavalin A (ConA)-dependent microheterogeneity of serum and urinary alpha 1-acid glycoprotein (AGP) were studied in patients with various degrees of renal impairment and compared with healthy control values. Serum concentrations of AGP were significantly higher in hemodialyzed and uremic patients than in the control subjects (1.54 +/- 0.42 g/l, p < 0.05, and 1.20 +/- 0.40 g/l, p < 0.05, respectively, versus 0.83 +/- 0.17 g/l). There was a similar increase in serum alpha 1-protease inhibitor and haptoglobin concentrations in the uremic patients (r = 0.87 and r = 0.70; p < 0.001). Urinary concentrations of AGP were also significantly higher in the hemodialyzed and uremic patients than in the control subjects, despite wide variability in the patients (20 +/- 14 mg/24 h, p < 0.05, and 126 +/- 160 mg/24 h, p < 0.05, respectively, versus 3 +/- 1 mg/24 h). AGP clearance was significantly higher in the uremic patients than in the hemodialyzed patients (p < 0.01) and the control subjects (p < 0.01). The proportions of strongly ConA-reactive AGP fractions were higher in the serum of the hemodialyzed (18.6 +/- 5.2%; p < 0.05) and uremic patients (18.1 +/- 5.3%; p < 0.05) than in the control subjects (14.5 +/- 2.5%). There was a similar difference in the urine samples (26.7 +/- 8.2%, p < 0.01; 20.1 +/- 6.2%, p < 0.01, respectively, versus 10.3 +/- 4.8%), with also a significant difference between the hemodialyzed and uremic patients (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Elastase-alpha 1 proteinase inhibitor (E alpha 1PI) concentrations were assessed in gingival crevicular fluids and evaluated in relation to the clinical signs of periodontal disease. 7 gingivitis patients (group G), 38 patients with adult periodontitis and clinically stable lesions (group AP), 21 patients with rapidly progressive periodontitis and clinically stable lesions (group RPP) and 11 patients with either adult periodontitis or rapidly progressive periodontitis and clinically progressive lesions (group Pr) were studied. 6 healthy subjects served as the control group (group H). Significantly differences were observed in the E alpha 1PI concentration between the healthy, gingivitis, clinically stable periodontitis and clinically progressive periodontitis group. In the control group, no E alpha 1PI was detected. Groups G, AP and RPP showed mean E alpha 1PI concentrations of 10.95 +/- 4.96 micrograms/ml, 35.55 +/- 18.64 micrograms/ml and 38.56 +/- 20.89 micrograms/ml, respectively. In these groups, high enzyme levels were correlated with clinical signs of inflammation. The highest E alpha 1PI levels were observed in the clinically progressive lesions. However, they were not necessarily associated with bleeding on probing or clinical evidence of inflammation. These data suggest that a significant increase in crevicular E alpha 1PI levels may be an early manifestation of a progressive or potentially progressive periodontal lesion.

An impairment of polymorphonuclear leukocyte (PMN) functions has been described following burn trauma. It was thus of interest to investigate the effect of RU 41740, an agent known to stimulate these cells, on rat PMN functions after burn injury. In the present study the responsiveness to classical stimuli of PMN from untreated burned rats was approximately 40% lower than healthy control values. In vitro treatment with RU 41740 increased oxidative metabolism of PMNs from burned and healthy rats. The effect was dose-related but was most striking in the case of PMNs from healthy rats. Significant differences were obtained with concentrations higher than 1 micrograms/ml for healthy rats but only 10 micrograms/ml for burned rats. In vivo treatment with RU 41740 also led to an enhancement of PMN oxidative metabolism on both burned and healthy rats. The maximal effective dose was 10 mg/kg/day in both cases. In contrast, 25 and 50 mg/kg/day doses inhibited PMN oxidative metabolism.

alpha 2-Macroglobulin (alpha 2M) was purified both from the serum of male rats developing an acute turpentine-induced inflammatory reaction where its concentration is greatly increased (3-4 mg/ml) and from the serum of healthy males where it is present at low levels (15-30 micrograms/ml). A three-step purification procedure involving gel filtration, anion exchange chromatography on DEAE cellulose and negative immunoaffinity was used. A pure native alpha 2M, as assessed by biochemical and immunological tests, was obtained. This alpha 2M differed from other subforms in terms of its electric charge and its complement-inhibiting activity in a complement-dependent immune haemolysis test. Moreover, this inhibitory activity was not affected by complexing with trypsin or modification by interaction with methylamine showing that this newly described property is not linked to the well known antiproteinase function of alpha 2M.

A non-immunological acute inflammatory reaction, induced in rats by intrapleural injection of calcium pyrophosphate microcrystals, decreased natural killer activity of lung intracapillary leucocytes (LICL), and, to a lesser extent, of spleen cells. NK activity was significantly depressed as early as 2 h after pleurisy induction, maximally suppressed at 72 h (when the inflammation had resolved) and returned to near-normal values by day 10. This decrease in NK activity was demonstrated using YAC-I lymphoma cells and syngeneic fibrohistiocytoma (P77) cells, as targets. The inhibition of NK activity of LICL was accompanied by an impaired destruction of P77 tumour cells injected i.v. 3 days after the onset of pleurisy. This was shown by an increase in the number of radiolabelled tumour cells surviving in the lungs at 24 h and of tumour nodules developed in lung parenchyma at 3 weeks. Suppression of NK activity was not due to a decrease in the proportion of large granular lymphocytes (LGL) in the LICL population. Suppressor macrophages may be involved, at least in part, since a partial restoration of LICL cytotoxicity was obtained after depletion of plastic-adherent cells. The effect of inflammation was reproduced in normal rats by injecting inflammatory serum or PGE2, suggesting a possible role of circulating mediators.

Various acute inflammatory reactions modify effector and immunoregulatory functions of neutrophils, macrophages and lymphocytes locally as well as at distance from the inflammatory focus. Non-specific defenses are augmented concomitantly. These phenomena have been related to low molecular weight peptides called phlogokines. These findings may contribute to a better knowledge of the inflammatory process, while phlogokines may be of potential therapeutic value.