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Background TNFa is a major cytokine involved in conditions such as ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Epigenetic regulation corresponds to different processes including modifications in histone proteins. These mechanisms regulate the transcription of genes coding for inflammatory cytokines such as TNFa. The acetylation of histone proteins (dependent on histone acetyl transferase-HAT-) promotes gene transcription while deacetylation (controlled by histone deacetylase) prevents this reaction. Limited data are available on HAT and HDAC activities in AS or RA. HDAC inhibitors (HDACi) are currently in development and may be of interest in modulating TNFa production in RA or AS. Objectives To determine the levels of HAT and HDAC activities in patients with AS or RA compared to healthy controls (HC) and to evaluate the ex vivo effects of HDACi (trichostatin A-TSA- and sirtinol -Sirt-) on HAT and HDAC activities and TNFa production by PBMC. Methods 21 patients with AS (New York criteria, 18 M, mean age ± SEM 44.3 ± 3.2 years, disease duration 14.1 ± 2.2 years), 52 patients with RA (ACR 1987 criteria, 16 M, mean age 56.9 ± 1.6, disease duration 11.3 ± 1.2) and 38 healthy controls (HC) (12 M, mean age: 34.6 ± 1.8) were evaluated. No patient received biologics. HAT and HDAC activities were assessed on nuclear extracts of PBMC isolated by Ficoll hypaque using a colorimetric assay (EpiQuick HAT Activity/inhibition Assay kit, and EpiQuick HDAC Activity/inhibition Assay kit, Epigentek). These activities were measured prior and after ex vivo treatment of PBMC by HDAC inhibitors. TNFa was evaluated in PBMC culture supernatants after 1 and 3 days (TNFalpha Quantikine ELISA kit, R&D Systems). Results HAT activity was decreased in patients with AS compared to HC (68.2 ± 8.1 vs 111.3 ± 15.5 ng/h/mg) (p= 0.05) while RA patients had increased HAT activity (126.8 ± 16.4 vs 111.3 ± 15.5 ng/h/mg; NS). Compared to HC, HDAC activity was decreased in both AS (p= 0.01) and RA (NS) (HC vs AS vs RA: 4778.9 ± 752 vs 1984. 6 ± 249 vs 3915.9 ± 790 pmol/min/mg). No correlation was observed between clinical disease assessment in RA or AS and HAT or HDAC activity. Ex vivo addition of TSA or Sirt to PBMC reduced HDAC activity by 51.1% in HC and by 37.7% in RA but had no effect in AS.HAT activity was not modulated by HDACi. TNFa production by PBMC was down regulated by the addition of TSA or Sirt to cell culture in HC and RA but this regulation was only obtained with Sirt in PBMC culture from patients with AS. Conclusions HAT and HDAC activities are dysregulated in AS and RA with a balance between HDAC and HAT favoring HAT activity and promoting gene transcription. Ex vivo treatment of PBMC by HDAC inhibitors may regulate HDAC activity and TNFa production especially in HC and RA but seems less effective in AS. Disclosure of Interest None Declared

Interleukin (IL)-10 is a novel cytokine produced by a variety of cells, including monocytes/macrophages, upon exposure to lipopolysaccharide (LPS). Recent observations indicate that, in turn, IL-10 exerts suppressive effects on macrophage response to LPS. Because mesangial cells are also a target for LPS, we have examined the potential role of IL-10 in the regulation of mesangial cell response to LPS. To this aim, we have studied the synthesis and the autocrine/paracrine function of IL-10 in cultured mouse mesangial cells. IL-10 mRNA expression and IL-10 protein secretion were determined by a reverse transcription polymerase chain reaction technique and a specific enzyme-linked immunosorbent assay, respectively. No IL-10 mRNA expression was detectable in unactivated cells. LPS induced IL-10 mRNA expression in a dose-dependent fashion (1 to 100 micrograms/ml). In addition, LPS induced IL-10 protein release that was both dose dependent (1 to 100 micrograms/ml) and time dependent (24 to 72 hours). We have also studied the effect of IL-10 on the production of inflammatory mediators by LPS-activated mouse mesangial cells. Whereas recombinant IL-10 inhibited the generation of tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta by 90 and 60%, respectively, it did not affect the formation of nitric oxide-derived nitrite (NO2-) and nitrate (NO3-). As shown by the use of anti-IL-10 monoclonal antibody, endogenously produced IL-10 affected the generation of TNF-alpha but neither that of IL-1 beta nor that of NO2- and NO3-. Finally, we have examined whether conditions known to also reduce the generation of TNF-alpha modified the expression of IL-10. Of all the conditions tested, only the addition of desferrioxamine and transforming growth factor-beta were found to increase IL-10 release. Together, these data demonstrate that mesangial cell-derived IL-10 has important regulatory effects on the inflammatory response of these cells to LPS because of its capacity to blunt TNF-alpha generation.

The production and the effects of tumor necrosis factor alpha (TNF alpha) have been studied in isolated glomeruli and cultured glomerular cells from animal or human origin. Glomeruli from rats injected with E. coli lipopolysaccharide (LPS) and glomeruli exposed to LPS in vitro release TNF alpha into the medium. The glomerular cells responsible for TNF alpha synthesis are mesangial cells. Production of TNF alpha is controlled by other locally produced mediators. Prostaglandin E2 and interleukin-10 are inhibitory. Hydroxyl radicals stimulate the transformation of the transmembrane form of TNF alpha into its soluble form which is secreted into the medium. TNF alpha acts on its producing cells and on the neighbouring cells. It induces contraction of mesangial cells, increases the synthesis of a variety of local mediators including prostaglandins, platelet-activating factor and chemotactic agents, particularly interleukin-8. Synthesis of this cytokine implies activation of tyrosine kinase and of transcription factors, essentially NFkB. Taken together, these results suggest that TNF alpha plays a marked role in the development of glomerular injury and incite us to search for treatments inhibiting its synthesis and its effects.

Inflammatory diseases of the renal glomerulus and tubulointerstitium are characterized by destructive and restorative processes. These alterations are mediated by soluble molecules, including cytokines that instruct target cells to alter their proliferation, differentiation phenotype, secretion and migration. One of these cytokines is tumor necrosis factor-alpha (TNF alpha). Its expression within the glomerulus has been observed in both resident cells and infiltrating monocytes/macrophages in response to cell stimulation with chemicals, immune complexes, bacterial lipopolysaccharides, and advanced glycosylation end products. Its release can be amplified by deposits of terminal complement proteins (C5b-9) or formation of platelet-activating factor and reactive oxygen species, and, on the contrary, blunted by that of prostaglandins or anti-inflammatory interleukin (IL)-6 and IL-10. The roles of TNF alpha in the pathogenesis of glomerular diseases include reduction of blood flow and filtration rate, alteration of the barrier function of capillary wall, formation of capillary thrombi and infiltration of the structure by blood-borne cells. Expression of TNF alpha has been observed in tubulointerstitium as well, mainly in proximal tubular epithelial cells. In vitro, this expression can be amplified by IL-1 and, inversely, suppressed by immunosuppressive drugs. Roles of TNF alpha in tubulointerstitium remain largely undefined, but may include infiltration of the interstitium by inflammatory cells and alteration in tubular transport of fluid and electrolytes. Extensive study will be necessary to further elucidate intracellular signals induced by TNF alpha binding to target cells within the kidney and thus to establish possibilities of therapeutic intervention.

Infiltrating macrophages elicit tumor-destructive reactions by releasing cytolytic factors including tumor necrosis factor alpha (TNF-alpha). Because platelets represent another major component of the cell infiltrate in tumors, we examined whether they could affect TNF alpha-induced cell death. Exposure of L-929 fibrosarcoma cells to human platelets reduced TNF alpha-induced cytotoxicity and cytolysis, as determined by 51Cr release assay and DNA fragmentation assay. This inhibitory effect, which depended on the concentration of platelets (0.1 to 10 x 10(6)/0.1 ml), was as high as 50%. The decrease in responsiveness to TNF-alpha reflected neither a degradation of TNF-alpha nor an inability of L-929 cells to bind TNF-alpha. Indeed, even though Scatchard analysis indicated the presence of 100 to 150 125I-TNF-alpha binding sites/platelet with a kd of 3.8 to 6.4 nM, addition of platelets up to 5 x 10(6)/0.1 ml did not compete with 125I-TNF-alpha binding to L-929 cells. Furthermore, addition of platelets 1 or 2 hours after that of TNF-alpha was still protective suggesting that platelets rather promoted hyporesponsiveness of L-929 cells to a postbinding effect of TNF-alpha Platelet-induced reduction of TNF-alpha response could be reproduced with supernatant fluids from platelets incubated at 37 degrees C for 24 hours. The platelet-derived factor responsible for this effect was found to be a lipid of low molecular weight with high affinity for albumin and charcoal. A role for 12(S) hydroxyeicosatetraenoic acid is proposed because this metabolite reduced TNF-alpha-induced cytolysis in a dose-dependent manner, whereas other platelet-derived lipids including thromboxane A2 and platelet activating factor were inactive. These observations indicate that the role of associated platelets has to be considered when analyzing the cytotoxic and cytolytic activity of macrophage-derived TNF-alpha on tumor cells.

The role of tumor necrosis factor alpha in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically--by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli--and biochemically--by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor alpha significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor alpha was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction10%) was analyzed. Tumor necrosis factor alpha also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

In this review the authors describe the physiopathological mechanisms responsible for inflammatory lesions in primary glomerulonephritis. Primary glomerular nephropathies can be reproduced experimentally: models have been set up for non-proliferative kidney diseases such as minimal change disease or membranous glomerulopathies, and for proliferative kidney diseases such as Berger's disease. Studies performed with these models have resulted in the identification of inflammatory mechanisms creating glomerular lesions which may be acute (proteinuria) or progressive (glomerular sclerosis). These mechanisms include activation of resident cells, notably mesangial cells, and recruitment of circulating cells such as neutrophils, monocytes/macrophages and platelets. These cells participate in the local inflammatory reaction by releasing soluble mediators including biologically active lipids, such as eicosanoids, reactive oxygen and nitrogen derivatives, proteases, cytokines and vasoactive polypeptides. The importance of these mediators has been deduced from the fact that they are produced locally in excess, their introduction produces lesions and, above all, their suppression by inhibitory or antagonistic pharmacological agents reduces the severity of the lesions. Several observations have shown that the development of all the lesions can be prevented simply by blocking the activity of only one of these mediators. It is therefore possible to consider replacing the conventional glucocorticoid treatment, which has multiple pharmacological actions, by a more specific treatment directed against a single mediator.

TNF alpha is generated in inflammatory lesions of the glomerulus. Both resident mesangial cells and infiltrating macrophages contribute to this generation, when exposed to bacterial lipopolysaccharide and immune complexes, respectively. TNF alpha has multiple actions on glomerular cells and on distant target cells that appear to promote in turn either amplification or limitation of TNF alpha release and TNF alpha binding. For instance, there is in vitro evidence that locally generated reactive oxygen metabolites: 1) cause increased release of TNF alpha into the extracellular space by accelerating the cleavage of its cell-associated precursor, and 2) reduce the expression of both cell-associated and soluble TNF alpha receptors. Thus it might be expected that reactive oxygen metabolites released at the site of glomerular inflammation limit autocrine, juxtacrine and paracrine effects of TNF alpha and simultaneously increase its widespread release into the circulation.

Compressively strained germanium-on-insulator (c-GeOI) substrates with a definitely reduced defect density are expected to yield superior hole mobilities together with low off-state currents in p-type metal oxide semiconductor field effect transistors (MOSFETs). In order to fabricate c-GeOI wafers, we started with double-side polished Si(0 0 1) substrates and grew, by reduced pressure-chemical vapour deposition, Si0.15Ge0.85 virtual substrates (VS) on the front side. The wafer curvature was compensated thanks to the deposition of a thick Ge layer on the backside. We then grew, after a chemical mechanical polishing, various thickness (37–148 nm) Ge layers. They stayed smooth (root-mean-square roughness

We have studied the structural properties of tensily strained Si (t-Si) layers grown by reduced pressure–chemical vapor deposition on top of SiGe(100), (110), and (111) virtual substrates (VSs). Chemical mechanical planarization has been used beforehand to eliminate the as-grown surface crosshatch on all orientations and reduce by 10 up to 100 times the surface roughness. A definite surface roughening has occurred after the epitaxy of t-Si on (110) and (111). For the lowest Ge contents investigated, top Si(100) and (110) layers are locally “defect-free” whereas numerous {111} stacking faults are present in the t-Si(111) layers. For higher Ge content SiGe VS, a degradation of the crystallographic quality of (110) and (111) t-Si layers has been evidenced, with the presence of dislocations, stacking faults, and twins. Quantification of the strain level in the t-Si layers has been carried out using visible and near-UV Raman spectroscopy. The Ge contents in the VS determined by Raman spectroscopy were very clo...

Inversion mode n-channel MOSFETs have been built on (6H) silicon carbide (SiC) substrates, with thermal oxide as the gate insulator, and with channel lengths ranging from 1 to 25 mu m. Drain leakage currents lower than 0.04 pA/ mu m channel width have been experimentally obtained at temperatures up to 400 degrees C and V/sub d/=5 V.

Because infiltration of mononuclear cells and fibroblast proliferation are associated in chronic inflammatory lesions, we tested the hypothesis that leukotrienes (LT), a product of activated mononuclear cells, may modulate fibroblast growth. Proliferation of cultured human skin fibroblasts was estimated by [3H]thymidine incorporation and cell count at increasing concentrations (0.1 nM to 0.1 microM) of LTC4 or LTD4. LTC4 and LTD4 stimulated cell growth in a dose-dependent manner only in the presence of 50 microM indomethacin. Under similar conditions, LTE4 but not LTB4 (0.1 microM) was active. Both asynchronous, growing cells and synchronous, quiescent cells were sensitive to LT when prostaglandin (PG) synthesis was suppressed by indomethacin. Other blockers of cyclooxygenase such as ibuprofen and aspirin exhibited identical permissive activity, and the effect of indomethacin was totally abolished by addition of PGE2. LTC4 modified neither [3H]arachidonic acid release from prelabeled fibroblasts nor PGE2 production by fibroblasts. These results demonstrate that the sulfidopeptide LT stimulate fibroblast proliferation only when the endogenous synthesis of PG is blocked, but they do not enhance the synthesis of PG in their target cells showing no evidence for a negative feed-back loop. Nevertheless, it seems likely that the initiation and development of the fibrotic process in the different tissues depends in part on the local balance between PG and LT productions.

The weight, total phosphorus content, and phosphorus content as a percentage of fresh weight was determined for oocytes in different positions in the ovarioles in the same female of Bombyx mori L. The weight and total phosphorus content increase up to the fifteenth oocyte, whereas phosphorus expressed as a percentage of fresh weight remains nearly constant although it may vary by about 15 per cent in neighbouring oocytes.

The infection of a lepidopteran with small quantities ofBacillus thuringiensisBerl. (oligo-infection) slows down the lipid storage but does not affect water and nitrogen contents. The similary of action of this treatment with that of total starvation is less striking than the comparison of glycogen contents.

This is a report of a round table organized during the second meeting of Clinical Pharmacology held in Giens (France) in September 1985. At the beginning of the meeting, the clinical aspects of drug-induced nephrotoxicity were reviewed. Thus we tried to precise the real interest of the studies of proteinuria, urinary cytology, enzymuria and fractional clearances of lithium or magnesium. The most interesting part of our discussions was to know the point of view of men working in drugs companies when a renal abnormality is found during a clinical trial of a drug and when previous experimental studies did not find any renal adverse effects of the drug. It was suggested in a such situation to do particular studies. Methods generally used to study renal physiology as autoradiography micropuncture, microinjection had to be performed to localize the action of the drug along the nephron. It was also discussed of the use of isolated perfused kidney as a tool in drug disposition and the use of renal cells culture. A better understanding of the mechanisms of direct renal toxicity of drugs was obtained from the results of experimental models. It is not so easy, at the present time, to know the mechanisms of immunological drug-induced nephrotoxicity. It seems necessary to develop new experimental models. The results obtained in animals with Cl2Hg or D. Penicillamine or gold salts afford to suspect some mechanisms for these types of nephropathies. This aspect of drug induced nephropathy is more complex because there is a large interindividual variation in susceptibility to these drugs.

Treatment by procyanidolic oligomers can significantly decrease the proteinuria indiced in the Rat by intravenous injection of anti glomerular basement membranes antibodies. Immunohistological analysis shows that procyanidolic oligomers do not interfere with the mechanisms of immunopathological injury involved in this model (antibody binding to glomerular basement membrane, complement activation, glomerular influx of polymorphonuclear leucocytes). Their protective effect may be due to an increased resistance of the glomerular capillary to the inflammatory mediators released by neutrophils.

Human polymorphonuclear (PMN) leucocytes bind synthetic [3H]-labelled leukotriene C4 ([3H]LTC4) with rapid saturation and reversibility of approximately 90%, by a 700-fold higher concentration of non-radioactive LTC4. [3H]LTC4 is recognized specifically by 10,778 +/- 6260 (mean +/- SD) sites per PMN leucocyte that exhibit a KD of 34.3 +/- 1.7 nM. The specificity of the LTC4 receptors is supported by the competitive inhibition of binding of [3H]LTC4 by LTC4, LTC4-sulphone, LTD4, and LTE4 with relative potencies of approximately 100:20:3:1. The four-fold higher level of specific binding of [3H]LTC4 by sonicates than by intact PMN leucocytes is attributable to intracellular receptors. Of the total number of receptors recovered in sonicates of PMN leucocytes, one-third are associated with membranes and the other two-thirds with lysosomal granules. The affinity of the membrane receptors for LTC4 is indistinguishable from that of receptors on intact PMN leucocytes, whereas the affinity of granule receptors is significantly higher. The characteristics of the receptors are consistent with a role in mediating uptake and metabolism of LTC4 by PMN leucocytes.

The C6-sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) evoked increases in the cytosolic concentration of intracellular calcium ([Ca+2]i) in dimethylsulfoxide-differentiated HL-60 cells, as assessed by the fluorescence of quin-2. The increases in [Ca+2]i reached a peak within 15-90 s, attained 50% of the maximum level at 1.2 nM LTD4 and 60 nM LTC4, were greater in maximal magnitude for LTD4 than LTC4, and subsided in 5-7 min. Flow cytometric evaluation of the LTD4-induced increases in [Ca+2]i, reflected in increases in the fluorescence of intracellular indo-1, revealed that a mean of 77% of differentiated HL-60 cells responded, as contrasted with lesser increases in only 50% of undifferentiated HL-60 cells. The capacity of pretreatment of HL-60 cells with LTD4 to prevent subsequent responses of [Ca+2]i to LTC4 and LTD4, and the finding that the serine-borate inhibitor of conversion of LTC4 to LTD4 suppressed concurrently both LTC4-induced rises in [Ca+2]i and increases in adherence to Sephadex G-25 indicated that the responses of HL-60 cells to LTC4 required conversion to LTD4. That pertussis toxin and a chemical antagonist of LTD4 reduced the [Ca+2]i response suggested a dependence on LTD4 receptors. The LTD4-induced increases in [Ca+2]i were dependent on extracellular calcium and diminished by lanthanum, but not affected by nifedipine nor associated with changes in membrane potential, as measured with the fluorescent probe 3,3'-dipentyloxacarbocyanine. Thus, the increase in [Ca+2]i in HL-60 cells, which is coupled to an increase in adherence, appears to involve LTD4 receptor-specific and voltage-independent calcium channels in the plasma membrane.

PGE2 production in the presence of mercuric chloride was measured by specific radioimmunoassay in isolated whole glomeruli and in cultured glomerular cells. Under basal conditions, mercuric chloride at 10 micrograms.ml-1 caused a twofold stimulation of PGE2 in isolated whole glomeruli, and at 1 to 10 micrograms.ml-1 it caused a more marked increase of PGE2 (eight times the control value) in mesangial or epithelial glomerular cells. An excess of arachidonic acid, however, blunted the stimulatory effects of mercury. Furthermore, the effect of mercuric chloride on PGE2 production was only observed with intact preparations but not with cell homogenates. Mercury inhibited cyclooxygenase activity in purified glomerular microsomes. It also inhibited phospholipase activity in purified glomerular cell membranes, whereas it stimulated phospholipase activity in intact cells. These results demonstrate that mercury modifies PGE2 synthesis via multiple mechanisms. Stimulation occurring at low doses of mercury can be attributed to the indirect activation of phospholipase. We suggest that mercuric chloride suppresses the inhibitory effect of lipomodulin on this enzyme.

To assess the role of gallium-67 (67Ga) scintigraphy in the diagnosis of glomerular diseases, we performed the following technique in 39 patients with glomerulonephritis (GN) who underwent simultaneous Ga scan and histologic examination. 72 hours after IV injection of Ga citrate (2 mCi), isotopic kidney activity (normally undetectable) was compared to the activity of the liver and quantified as follows: less than (1+), equal to (2+) or greater than (3+) that of the liver. Renal biopsy was performed at the same time to evaluate the type of the GN and to quantify interstitial cellular infiltration. Proteinuria, serum albumin and creatinine were measured. There was a significant correlation between the level of 67Ga kidney activity and the degree of proteinuria and hypoalbuminemia. On the contrary, no correlation was found between isotopic activity and the degree of renal failure or the degree of interstitial cellular infiltration. Increased kidney 67Ga activity did not appear characteristic of a specific histologic type of GN. Increased glomerular permeability may alter renal uptake of Ga; therefore 67Ga scanning does not appear to contribute significantly to the diagnosis and the follow-up of either primary or secondary GN.

Eighteen patients with Hodgkin's disease received chemotherapy and 40 Gy mantle-field irradiation. Radiation-induced lung injuries were studied 5 times during one year for each patient by chest x-ray, CT examination of the thorax and pulmonary function tests. Homogeneous and inhomogeneous densities developed within the radiations ports. They were more often and more easily detected by CT than by chest x-ray (39% vs 11% at the end of the irradiation). CT changes suggested that homogeneous lung density increase and lung nodules corresponded to the radiation pneumonitis phase, also that linear aspects and/or lung condensation aspects corresponded to irradiation-induced lung fibrosis. The displacement of the vessels and the fissures were seen more precisely by CT than by chest x-ray. There was a highly significant correlation between the number of modified areas and the increase in the coefficient of retraction (p less than 0.001).

Eighteen patients with mediastinal Hodgkin's disease treated with chemotherapy first, then irradiation were investigated during 1 year by means of 5 CT and radiological examinations of the chest. Four months after irradiation pericardial thickening was detected in 60 p. cent of the patients. The authors underline the high frequency, early occurrence and usually spontaneous resolution of radiation-related pericarditis without clinical or radiological signs.

Glycogen reserves are entirely consumed during total starvation of Bombyx mori L. larvae. While the storage of glycogen is lowering and the dietary supply of carbohydrates stopped, the amount of trehalose also decreases but less rapidly than this of glycogen. Relative homeostasis is maintained but only for the ten first hours of inanition. Quantitative evaluation of blood trehalose, which is preformed more rapidly than glycogen analysis, might be used as an efficient test to characterized some physiopathological states.

Reactive oxygen species (ROS) are formed by incomplete reduction of molecular oxygen. They include superoxide anion (O2-.), hydrogen peroxide (H2O2), hydroxyl radical (OH.), and singlet oxygen (1O2). ROS may induce different types of cell injury, particularly lipid peroxidation and membrane damage. ROS have been shown to play an essential role in the mechanisms of experimental models of several renal diseases: ischemic acute renal failure, renal graft rejection, acute glomerulonephritis, and toxic renal diseases. They are produced by the renal cells and also by the inflammatory bone marrow-derived cells invading the renal tissue. ROS, regardless of their origin, may degrade the glomerular basement membrane and alter the glomerular and tubular cell functions. Particularly, they produce an increase in cyclic AMP synthesis and prostaglandin production in the glomeruli. Recent studies have shown that the glomerular mesangial cells themselves generated ROS on stimulation by phagocytosis of foreign particles or exposure to the complement membrane attack complex or platelet-activating factor. Production of ROS is in narrow relationship with the metabolism of arachidonic acid. Conversion of this fatty acid via the lipoxygenase pathway is associated with an increase of ROS, whereas its transformation into prostaglandins via the cyclooxygenase pathway results in the opposite effect. Production of ROS in activated mesangial cells can be inhibited by glucocorticoids via a receptor-mediated mechanism. The fact that some of these characteristics are different in leukocytes suggests the possibility in the future of the more specific pharmacological control of the inflammatory process in the glomerular mesangium.

Summary form only given. The trend for size reduction in portable electronics is driving the integration of passive components onto silicon substrates. Several teams have demonstrated the feasibility of using thin film magnetics for low power conversion. However, the power density achieved are typically of the order of 1 W/cm/sup 2/. Design and fabrication techniques for achieving high power density and high efficiency components have been presented by Brunet et al (16/sup th/ APEC Conf., p.1189-97 (2001)). This paper presents the electrical performance of fabricated E-core micro-transformers and the use of these thin film components in a DC-DC converter.

Investigating the Middle Triassic volcanic and volcaniclastic rocks in the External Dinarides (Croatia and Bosnia and Herzegovina) an undeveloped rift system has been determined. This rift system was formed as a back-arc extension in the north-western edge of Palaeotethys Ocean (Stampfli & Borel, 2002 ; Schmidt et al., 2008). Geochemical data (whole rock REE and trace element composition and EMP analysis on pyroxene and feldspar crystals and crystaloclasts of different volcanic and volcaniclastic facies) indicates calc-alkaline magma composition, characteristic for subduction zones and contamination by the crustal material. Therefore we interpret the development of Middle Triassic rift in the Dinarides as a back-arc rift area that was strongly influenced by the subduction of the Palaeotethys toward north that stared in Early Permian and lasted throughout the whole Triassic. The geotectonic history of this part of Tethys is described as follows: In the Upper Permian and Early Triassic the Dinarides were located in the western Palaeotethys. According to the palinspastic reconstructions (Haas et al., 1995 ; Scotese, 2002 ; Stampfli & Borel, 2002 ; Schmidt et al., 2008 ; Stampfli et al., 2013) this Palaeotethyan area represented a shallow bay resembling a vast epicontinental sea, in the Dinarides, interpreted as a broad epeiric ramp (Aljinović et al., 2015). In the southern part of this ocean rifting started in the Permian between the Cimmerian block and the southwest coast of Pangea. This rift system (Neotethys) advanced to the north and finally formed the Tethyan Ocean in the Jurassic. From afore mentioned palaeogeographic reconstructions it is notable that the subduction of Pelaeotethys persisted throughout the Triassic. This subduction process could have influenced the magma formation in the Middle Triassic. The former subduction, which caused the formation of Pangea could have also left the imprint on the Middle Triassic magma composition (Crisci et al., 1984). Palinspastic reconstructions place the area of the External Dinarides, and surrounding areas in the vicinity of earlier Gondwana and Laurasia suture line, the similar direction of the newly formed Tethyan rift. This caused the subduction of the Gondwana crustal material, and its partial melting that had great influence on the Middle Triassic magma in the western Tethys. Except the primary rifting direction there were additional extensional/rift systems in the continental part of Pangea. There were three recorded back-arc rift zones in the Middle Triassic: Meliata and Meliac Oceans, and the rift system directed across the Dinaridic and Alpine area. The area of the External Dinarides was bordered by the opening of the Tethyan Ocean from the southwest and opening of the Meliata and Meliac Oceans in the north. The External Dinaridic aborted rifting direction did not evolve because of these two compressive movements that forced its closure.

Upper Permian and lowermost Triassic strata of the Masore section in western Slovenia have been restudied by means of bio- and lithostratigraphy. The section is mainly characterized by a carbonate succession of the Bellerophon Formation deposited in a shallow ramp environment that was located in the western part of the Palaeo-Tethys. Four types of microfacies have been differentiated in the Bellerophon Formation and microfacies indicate deposition on the well inhabited inner ramp and the reworking of primary biomicrites in the vicinity of small biostromes. Deposition of the bioclast-rich Bellerophon Formation abruptly ceased and was overlain by fossil-poor microbial deposits of the Permian-Triassic boundary (PTB) transition marked by laminated microbialites – stromatolites. The microbial facies was deposited in the mid-part of an unrimmed ramp around a fair-weather wave break. The conodont elements recovered enabled the recognition of the Hindeoduspraeparvus Zone (Late Changhsingian) in the Bellerophon Formation. Gondolellids are documented in the PTB transitional interval with microbial microfacies, whereas the Isarcicellaisarcica Zone (EarlyGriesbachian) is recognized in the tectonically separated Werfen Formation just above the microbial deposit of the section. The conodont faunas are characterized by dominant Hindeodus-Isarcicella populations indicating restricted marine environments. The PTB transitional interval beds are marked also by the presence of Clarkinasuggesting a good communication with the open sea, possibly in a deeper part of an extensive ramp.The recovery of gondolellid elements from the PTB interval of Slovenia has significant global correlation potential. Foraminifers from the Upper Permian Bellerophon Formation are abundant, diverse, and consist of species characteristic for the Upper Permian, of many regions of the Palaeo-Tethys. Foraminifers from the PTB transitional interval are very scarce and represented by the agglutinated species Ammodiscuskalhori and Hyperamminadeformis, with rare representatives of the Late Permian calcareous genera Geinitzina, Tristix and Globivalvulina, probably holdover taxa trying to survive in a stressful environment after the mass extinction of calcareous foraminifers.