New molecular species at redshift z = 0.89.

We present the first detections of CH3SH, C3H+, C3N, HCOOH, CH2CHCN, and H2CN in an extragalactic source. Namely the spiral arm of a galaxy located at z = 0.89 on the line of sight to the radio-loud quasar PKS 1830-211. OCS, SO2, and NH2CN were also detected, raising the total number of molecular species identified in that early time galaxy to 54, not counting isotopologues. The detections were made in absorption against the SW quasar image, at 2 kpc from the galaxy centre, over the course of a Q band spectral line survey made with the Yebes 40 m telescope (rest-frame frequencies: 58.7-93.5 GHz). We derived the rotational temperatures and column densities of those species, which are found to be subthermally excited. The molecular abundances, and in particular the large abundances of C3H+ and of several previously reported cations, are characteristic of diffuse or translucent clouds with enhanced UV radiation or strong shocks.

Medicines for Europe - 13th Pharmacovigilance Conference (January 29, 2020 - Amsterdam, the Netherlands).

This year, following the European Medicines Agency (EMA) relocation due to the Brexit process, the 13th Pharmacovigilance Conference organized by Medicines for Europe took place in Amsterdam, the Netherlands. The pharmaceutical industry is usually associated with the development and launch of new drugs for the market, but it is also committed to finding new ways of making existing drugs and processes (e.g., pharmacovigilance [PV]) more efficient and better for patients. In relation to this, a variety of topics were on the agenda at the conference, including updates on the progress of the EudraVigilance (EV) system for monitoring and analyzing potential drug-related adverse events, as well as highlights on the E.U. Network Strategy to 2025 and the EMA multi-annual work program related to big data acceptability, electronic product information (ePI) Key Principles and Roadmap for implementation, and work-sharing ongoing projects for achieving harmonization of requirements and processes. Adrian van den Hoven (Director General, Medicines for Europe) opened the conference looking towards the future, emphasizing what the current PV system needs to do in order to adapt to new landscapes. With big data, robotization, automation or globalization, there are many opportunities to streamline and become smarter on the horizon.

Direct estimation of electron density in the Orion Bar PDR from mm-wave carbon recombination lines.

CONTEXT: A significant fraction of the molecular gas in star-forming regions is irradiated by stellar UV photons. In these environments, the electron density (n e) plays a critical role in the gas dynamics, chemistry, and collisional excitation of certain molecules. AIMS: We determine n e in the prototypical strongly irradiated photodissociation region (PDR), the Orion Bar, from the detection of new millimeter-wave carbon recombination lines (mmCRLs) and existing far-IR [13Cii] hyperfine line observations. METHODS: We detect 12 mmCRLs (including α, ß, and γ transitions) observed with the IRAM 30m telescope, at ~ 25″ angular resolution, toward the H/H2 dissociation front (DF) of the Bar. We also present a mmCRL emission cut across the PDR. RESULTS: These lines trace the C+/C/CO gas transition layer. As the much lower frequency carbon radio recombination lines, mmCRLs arise from neutral PDR gas and not from ionized gas in the adjacent Hii region. This is readily seen from their narrow line profiles (Δv = 2.6 ± 0.4 km s-1) and line peak velocities (ν LSR = +10.7 ± 0.2 km s-1). Optically thin [13Cii] hyperfine lines and molecular lines - emitted close to the DF by trace species such as reactive ions CO+ and HOC+ - show the same line profiles. We use non-LTE excitation models of [13Cii] and mmCRLs and derive n e = 60 - 100 cm-3 and T e = 500 - 600 K toward the DF. CONCLUSIONS: The inferred electron densities are high, up to an order of magnitude higher than previously thought. They provide a lower limit to the gas thermal pressure at the PDR edge without using molecular tracers. We obtain P th ≥ (2 - 4)·108 cm-3 K assuming that the electron abundance is equal to or lower than the gas-phase elemental abundance of carbon. Such elevated thermal pressures leave little room for magnetic pressure support and agree with a scenario in which the PDR photoevaporates.

30th Annual Drug Information Association (DIA) Europe 2018 (April 17-19, 2018 - Basel, Switzerland).

The Drug Information Association (DIA) Europe held its annual meeting from April 17-19, 2018, in Basel, Switzerland. The key topics discussed in the 3-day meeting were related to pharmacovigilance, clinical development, patient engagement, data and data standards, preclinical development and early-phase clinical research, regulatory science, translational medicine and science, and value and access. The program was principally focused on the current opportunities and future landscape of the healthcare system as a result of the increasingly innovative technologies and effective utilization of big data. In addition, the critical need for collaboration and partnership between all the stakeholders of the healthcare system was highlighted. This report covers some of the regulatory sessions presented at the meeting in which regulators, payers, industry and patients presented their perspectives for discussion.

Chemical segregation of complex organic O-bearing species in Orion KL.

We investigate the chemical segregation of complex O-bearing species (including the largest and most complex ones detected to date in space) towards Orion KL, the closest high-mass star-forming region. The molecular line images obtained using the ALMA science verification data reveal a clear segregation of chemically related species depending on their different functional groups. We map the emission of 13CH3OH, HCOOCH3, CH3OCH3, CH2OCH2, CH3COOCH3, HCOOCH2CH3, CH3CH2OCH3, HCOOH, OHCH2CH2OH, CH3COOH, CH3CH2OH, CH3OCH2OH, OHCH2CHO, and CH3COCH3 with ~1.5″ angular resolution and provide molecular abundances of these species toward different gas components of this region. We disentangle the emission of these species in the different Orion components by carefully selecting lines free of blending and opacity effects. Possible effects in the molecular spatial distribution due to residual blendings and different excitation conditions are also addressed. We find that while species containing the C-O-C group, i.e. an ether group, exhibit their peak emission and higher abundance towards the compact ridge, the hot core south is the component where species containing a hydroxyl group (-OH) bound to a carbon atom (C-O-H) present their emission peak and higher abundance. This finding allows us to propose methoxy (CH3O-) and hydroxymethyl (-CH2OH) radicals as the major drivers of the chemistry in the compact ridge and the hot core south, respectively, as well as different evolutionary stages and prevailing physical processes in the different Orion components.

Complex organic molecules in strongly UV-irradiated gas.

We investigate the presence of complex organic molecules (COMs) in strongly UV-irradiated interstellar molecular gas. We have carried out a complete millimetre (mm) line survey using the IRAM 30 m telescope towards the edge of the Orion Bar photodissociation region (PDR), close to the H2 dissociation front, a position irradiated by a very intense far-UV (FUV) radiation field. These observations have been complemented with 8.5″ resolution maps of the H2CO JKa,Kc = 51,5 → 41,4 and C18O J = 3 → 2 emission at 0.9 mm. Despite being a harsh environment, we detect more than 250 lines from COMs and related precursors: H2CO, CH3OH, HCO, H2CCO, CH3CHO, H2CS, HCOOH, CH3CN, CH2NH, HNCO, [Formula: see text] and HC3N (in decreasing order of abundance). For each species, the large number of detected lines allowed us to accurately constrain their rotational temperatures (Trot) and column densities (N). Owing to subthermal excitation and intricate spectroscopy of some COMs (symmetric- and asymmetric-top molecules such as CH3CN and H2CO, respectively), a correct determination of N and Trot requires building rotational population diagrams of their rotational ladders separately. The inferred column densities are in the 1011 - 1013cm-2 range. We also provide accurate upper limit abundances for chemically related molecules that might have been expected, but are not conclusively detected at the edge of the PDR (HDCO, CH3O, CH3NC, CH3CCH, CH3OCH3, HCOOCH3, CH3CH2OH, CH3CH2CN, and CH2CHCN). A non-thermodynamic equilibrium excitation analysis for molecules with known collisional rate coefficients suggests that some COMs arise from different PDR layers but we cannot resolve them spatially. In particular, H2CO and CH3CN survive in the extended gas directly exposed to the strong FUV flux (Tk = 150 - 250 K and Td ≳ 60 K), whereas CH3OH only arises from denser and cooler gas clumps in the more shielded PDR interior (Tk = 40 - 50 K). The non-detection of HDCO towards the PDR edge is consistent with the minor role of pure gas-phase deuteration at very high temperatures. We find a HCO/H2CO/CH3OH ≃ 1/5/3 abundance ratio. These ratios are different from those inferred in hot cores and shocks. Taking into account the elevated gas and dust temperatures at the edge of the Bar (mostly mantle-free grains), we suggest the following scenarios for the formation of COMs: (i) hot gas-phase reactions not included in current models; (ii) warm grain-surface chemistry; or (iii) the PDR dynamics is such that COMs or precursors formed in cold icy grains deeper inside the molecular cloud desorb and advect into the PDR.

Trans-cis molecular photoswitching in interstellar Space.

As many organic molecules, formic acid (HCOOH) has two conformers (trans and cis). The energy barrier to internal conversion from trans to cis is much higher than the thermal energy available in molecular clouds. Thus, only the most stable conformer (trans) is expected to exist in detectable amounts. We report the first interstellar detection of cis-HCOOH. Its presence in ultraviolet (UV) irradiated gas exclusively (the Orion Bar photodissociation region), with a low trans-to-cis abundance ratio of 2.8 ± 1.0, supports a photoswitching mechanism: a given conformer absorbs a stellar photon that radiatively excites the molecule to electronic states above the interconversion barrier. Subsequent fluorescent decay leaves the molecule in a different conformer form. This mechanism, which we specifically study with ab initio quantum calculations, was not considered in Space before but likely induces structural changes of a variety of interstellar molecules submitted to UV radiation.

VELOCITY-RESOLVED [C ii] EMISSION AND [C ii]/FIR MAPPING ALONG ORION WITH HERSCHEL.

We present the first ~7.5'×11.5' velocity-resolved (~0.2 km s-1) map of the [C ii] 158 µm line toward the Orion molecular cloud 1 (OMC 1) taken with the Herschel/HIFI instrument. In combination with far-infrared (FIR) photometric images and velocity-resolved maps of the H41α hydrogen recombination and CO J=2-1 lines, this data set provides an unprecedented view of the intricate small-scale kinematics of the ionized/PDR/molecular gas interfaces and of the radiative feedback from massive stars. The main contribution to the [C ii] luminosity (~85 %) is from the extended, FUV-illuminated face of the cloud (G0>500, nH>5×103 cm-3) and from dense PDRs (G≳104, nH≳105 cm-3) at the interface between OMC 1 and the H ii region surrounding the Trapezium cluster. Around ~15 % of the [C ii] emission arises from a different gas component without CO counterpart. The [C ii] excitation, PDR gas turbulence, line opacity (from [13C ii]) and role of the geometry of the illuminating stars with respect to the cloud are investigated. We construct maps of the L[C ii]/LFIR and LFIR/MGas ratios and show that L[C ii]/LFIR decreases from the extended cloud component (~10-2-10-3) to the more opaque star-forming cores (~10-3-10-4). The lowest values are reminiscent of the "[C ii] deficit" seen in local ultra-luminous IR galaxies hosting vigorous star formation. Spatial correlation analysis shows that the decreasing L[C ii]/LFIR ratio correlates better with the column density of dust through the molecular cloud than with LFIR/MGas. We conclude that the [C ii] emitting column relative to the total dust column along each line of sight is responsible for the observed L[C ii]/LFIR variations through the cloud.

[Characteristics of immigrant women and their neonates]. / Características de las mujeres inmigrantes y de sus hijos recién nacidos.

BACKGROUND: Immigrant status is frequently assumed to constitute a health risk because migration is inevitably associated with a period of significant adjustment and stress. OBJECTIVE: To compare the social characteristics and perinatal outcomes of mothers who deliver in a third level hospital in Spain according to their socioeconomic level of the country of origin. METHODS: From December 2000 to March 2001, women who delivered were selected according to the socioeconomic status of their birth country. All women from low and middle income countries (immigrant mothers) and a sample (1:2) of those from high income countries (mainly Spanish-born mothers) completed a questionnaire on antenatal care, demographic and social characteristics, and country of birth and were followed-up to monitor neonatal clinical features. RESULTS: During the three months of the study, 203/1352 (15 %, CI 13.2-17.1) of the delivering mothers were immigrants. Most were from Central and South America (56 %, CI 49-62). Prenatal care was appropriate in most of the women (in 92.1 % of immigrant mothers and in 96.8 % of Spanish mothers, p 5 0.01). The proportions of premature births, low birth weight and very-low birth weight showed no statistically significant differences between immigrant and Spanish mothers (15 vs. 10.6, 6.4 vs. 9.4, and 2.1 vs. 1.5, respectively, p > 0.05 in all comparisons). Perinatal complications, including an Apgar score < or = 6, and the need for admission to the neonatal unit or to the intensive or intermediate care units, were not more frequent in the newborns of immigrant mothers. Immigrant women had less social or family support after delivery and maternity leave was much less frequent (62 % vs. 90 %, p < 0.001). CONCLUSIONS: Most of the immigrant women had healthy pregnancies and healthy birth outcomes. Perinatal complications do not seem to be more frequent among immigrant women. Differences were found in social support. To improve the health of these children, social support to immigrant women and their children should be intensified.

Características de las mujeres inmigrantes y de sus hijos recién nacidos / Characteristics of immigrant women and their neonates

Antecedentes: Se suele considerar la condición de inmigrante como un riesgo para la salud que se asocia con un período de ajuste y de estrés. Objetivo: Comparar las características sociales y la evolución perinatal de las mujeres que paren en un hospital de tercer nivel en España en función del nivel socioeconómico del país de origen. Métodos: De diciembre de 2000 a marzo de 2001, se seleccionó a las mujeres en el momento de parir en función del nivel socioeconómico del país de origen. Todas las mujeres procedentes de países de escasos recursos económicos (aquí denominadas también mujeres inmigrantes), y una muestra (1:2) de las que no procedían de esos países (principalmente España), cumplimentaron un cuestionario sobre atención prenatal, características demográficas y sociales, país de origen, y fueron seguidas para valorar la evolución clínica neonatal. Resultados: Durante los 3 meses del estudio, 203/1.352 (15 por ciento; intervalo de confianza (IC) del 95 por ciento, 13,2-17,1) de las mujeres que parieron eran inmigrantes. La mayoría procedían de países de Centro y Sudamérica (56 por ciento; IC 95 por ciento, 49-62). El embarazo se controló en la mayoría de los casos, 92,1 por ciento de las mujeres inmigrantes y 96,8 por ciento de las españolas, p=0,01. Las proporciones de parto prematuro, bajo peso y muy bajo peso no difirieron entre las dos categorías de madres y fueron respectivamente, en las mujeres inmigrantes y en las españolas, 15 por ciento frente a 10,6 por ciento, 6,4 por ciento frente a 9,4 por ciento y 2,1 por ciento frente a 1,5 por ciento, (en todos los casos p > 0,05). Las complicaciones perinatales, Apgar 6, ingreso en la unidad neonatal, ingreso en cuidados intensivos e intermedios, no fueron más frecuentes en los hijos de madres inmigrantes. Las mujeres inmigrantes tuvieron menos apoyo social y familiar y son muchas menos las que disfrutan de baja laboral por maternidad (62 por ciento frente a 90 por ciento, p < 0,001). Conclusiones: La mayoría de las mujeres inmigrantes tienen embarazos y recién nacidos sanos. Las complicaciones perinatales no parecen más frecuentes en los hijos de mujeres inmigrantes. Las diferencias que se observan se refieren más al apoyo social. Para mejorar la salud de estos niños, se debería intensificar el apoyo social a las mujeres inmigrantes y a sus hijos (AU)

Mujeres inmigrantes: características del control prenatal y del parto / Female immigrants: characteristics of antenatal care and delivery

Objetivos: Comparar las características sociodemográficas, el control de la gestación y el parto en mujeres procedentes de países de escasos recursos económicos (denominadas inmigrantes en el presente trabajo) y en las que no lo son (principalmente españolas).Métodos: Entre diciembre de 2000 y marzo de 2001 se incluyó en el estudio a todas las mujeres inmigrantes y a una muestra representativa (1:2) de las mujeres no inmigrantes que dieron a luz en un hospital de Madrid.Resultados: Durante el período de estudio, 203/1.352 (15 por ciento; intervalo de confianza [IC] del 95 por ciento, 13,2-17,1) de las mujeres que parieron fueron inmigrantes; el 56 por ciento (IC del 95 por ciento, 49-62) procedía de Centro y Sudamérica. La mayoría tuvo un embarazo y un parto sin complicaciones. El número mediano de visitas de control de embarazo fue de 8 (intervalo intercuartil [IQ], 6-9) para las inmigrantes y 9 (IQ, 8-10) para las españolas; la proporción de cesáreas fue, respectivamente, del 17,3 por ciento (IC del 95 por ciento, 12,5-23,3) y el 16,3 por ciento (IC del 95 por ciento, 12,9-20,2).Conclusiones: Las mujeres procedentes de países de escasos recursos económicos que acuden a parir a un hospital de tercer nivel de Madrid tienen un seguimiento de la gestación adecuado y no presentan mayor riesgo de complicaciones durante el embarazo y el parto, contrariamente a lo que suele ser la percepción generalizada. Las diferencias encontradas son principalmente de características sociales. Estos resultados pueden no ser extrapolables a otros centros, ya que la población de mujeres inmigrantes y españolas que se atiende en los distintos centros sanitarios puede ser muy diferente (AU)

Protective effects of lazaroid U74389G on intestinal graft after heterotopic small bowel transplantation in rats.

BACKGROUND: Experimental studies have shown that 21-aminosteroids (21-A) are powerful inhibitors of superoxide-mediated iron-dependent lipid peroxidation. This study was aimed at determining how far the blocking effect of one of these substances (lazaroid U74389G) on lipid peroxidation protects intestinal grafts morphologically and biologically in a heterotopic transplant model (SBT) in rats. ANIMALS AND METHODS: Heterotopic LEW were performed using Ringer lactate (4 degrees C) as preservation solution. In Group 1 (n = 7) the donor and recipient animals received 3 and 6 mg/kg of the 21-A U74389G, respectively. Group 2 (n = 7) received the same doses of the vehicle of the drug. Sham group underwent only a laparotomy. Bacterial translocation (BT) was determined in mesenteric lymph nodes (MLN), liver (L), and spleen (S) 60 min after reperfusion. Tissue myeloperoxidase (MPO), malondialdehyde (MDA), and percentage conversion xanthine dehydrogenase/xanthine oxidase (XD/XO) were also determined in the ileal graft. Histological damage was graded according to Park's classification. RESULTS: Tissue MDA (nmol/mg prot) was significantly lower in Group 1 (0.53 +/- 0.09) than in Group 2 (3.66 +/- 1, P < 0.05) and showed levels similar to those of the sham-operated group (0.40 +/- 0.05). Injury grades were also significantly different in both study groups (Group 1, 0-1; Group 2, 2-3, P < 0.05). BT (log CFU/g tissue) in Group 1 were MLN, 0; L, 0.36; and S, 0. In Group 2, MLN, 1.07; L, 0.81; and S, 1.49 (P < 0.05 in MLN). Increase in MPO activity (U/g prot) in comparison with sham-operated animals was similar in the two study groups (Group 1, 1.49 +/- 0.58; Group 2, 1.22 +/- 0.46; Sham, 0.34 +/- 0.37 (P < 0.05 1,2 vs sham). Conversion of XD to XO was unaffected by the supplementation of the drug. CONCLUSION: 21A U74389G inhibits lipid peroxidation, protects intestinal graft, and reduces BT after heterotopic SBT in rats.

Cytokines and Fas regulate apoptosis in murine renal interstitial fibroblasts.

Renal fibrosis is characterized by an increased number of fibroblasts and excessive deposition of extracellular matrix. Apoptotic cell death is a physiological mechanism to limit cell numbers, and an insufficient rate of death may contribute to fibroblast accumulation. However, little is known about the regulation of renal fibroblast survival. The authors have studied the interaction of cytokines and the Fas receptor in the regulation of apoptosis of renal fibroblasts and have observed that murine renal fibroblasts express Fas and the Fas ligand. Tumor necrosis factor alpha (TNFalpha) and agonistic anti-Fas antibodies induce apoptosis of renal fibroblasts in a time- and dose-dependent manner. Serum contains survival factors for renal fibroblasts. Both serum deprivation and TNFalpha increase the sensitivity to Fas-induced death and the expression of fas mRNA and Fas receptor. By contrast, insulin-like growth factor-1 decreases apoptosis induced by both serum deprivation and Fas activation and partially prevents the increase in Fas receptor expression induced by serum deprivation. Murine renal fibroblasts express constitutively both fas ligand mRNA and cell-surface Fas ligand, but the authors could not demonstrate a role for Fas ligand in the autocrine regulation of fibroblast survival. These data suggest that Fas and other cytokines cooperate to regulate renal fibroblast apoptosis. Modulation of the Fas death-signaling pathway in renal fibroblasts could represent a new therapeutic target for renal fibrosis.

Agonistic anti-Fas antibodies induce glomerular cell apoptosis in mice in vivo.

Recent studies suggest that apoptotic cell death regulates the cell complement in glomerular diseases. However, little is-known about the factors that promote glomerular cell apoptosis. Activation of the Fas receptor by the Fas ligand or agonistic antibodies triggers apoptosis in some cell types that express Fas. Cultured human mesangial cell are among the cells that undergo apoptosis upon Fas activation, but it is unclear whether mesangial cells are sensitive to death induced by Fas in vivo. We have now explored the role of Fas in experimental glomerular injury. Murine mesangial cells in culture express fas and undergo apoptosis when stimulated with the Jo2 agonistic anti-Fas mAb. A fas mRNA transcript is present in normal murine kidney and freshly isolated glomeruli. Balb-c mice developed hematuria and proteinuria within 24 hours of the intraperitoneal injection of 10 micrograms Jo2 anti-Fas mAb. In addition to liver cell apoptosis, glomerular cell apoptosis and mesangial cell depletion were evident in the kidney at three hours and more pronounced at 24 hours. Glomerular and liver injury were not prevented by decomplementation. These data suggest that Fas activation in vivo by specific antibodies induces glomerular and mesangial cell apoptosis in mice.

Effect of oral supplementation of ornithine-alpha-ketoglutarate on the intestinal barrier after orthotopic small bowel transplantation.

The aim of this study was to analyze the possible protective effects of a glutamine and arginine precursor (ornithine-alpha-ketoglutarate [OKG]) on the mucosa of a transplanted intestine when administered with either a defined formula oral diet (DFD) or a standard chow. Isogenic male Lewis rats (250 g) were submitted to a laparotomy (groups 1 and 2) or to an orthotopic small bowel transplantation (SBT; groups 3-6). Groups 1, 3, and 5 received a DFD 14 days after surgery. Groups 2, 4, and 6 received standard chow. In addition, groups 5 and 6 received a daily oral supplementation of 1.4 g/kg of OKG. Weight changes and food intake were recorded daily. At the end of the study, bacterial translocation (BT) was measured in mesenteric lymph nodes, liver, and spleen. The protein/DNA index was also determined in intestinal mucosa. SBT induced BT in all transplanted groups, especially in those fed DFD. Addition of OKG (groups 5 and 6) significantly reduced BT in comparison with groups 3 and 4 and improved the protein/DNA index as well as weight gain. It is concluded that OKG supplementation protects the intestinal barrier after SBT, and that this effect is more marked when it is added to a standard chow.

Expression of leucocyte chemoattractants by interstitial renal fibroblasts: up-regulation by drugs associated with interstitial fibrosis.

Interstitial inflammation is a strong predictor of long-term renal damage. The potential role of renal interstitial fibroblasts in recruitment of inflammatory leucocytes into the interstitium is unclear. We have thus studied the mRNA expression of several leucocyte chemotactic factors by rat renal interstitial fibroblasts and its modulation by cytokines. In addition, the effects of two unrelated drugs associated with the development of interstitial fibrosis, namely puromycin aminonucleoside (PAN) and cyclosporin A (CsA), were also studied. Rat renal interstitial fibroblasts showed constitutive mRNA expression for the chemokines monocyte chemoattractant protein 1 (MCP-1) and interferon-inducible protein 10 (IP-10). In addition, these cells also exhibited constitutive mRNA expression for cyclophilin B, an immunophilin recently found to have leucocyte chemoattractant properties. The inflammatory cytokine tumour necrosis factor-alpha up-regulated IP-10 and MCP-1 mRNA expression (10- and four-fold, respectively), but had no effect on cyclophilin B mRNA levels. IP-10 and MCP-1 produced about a four-fold increase in MCP-1 and cyclophilin B mRNA expression, but did not affect IP-10 mRNA. PAN caused an augmentation in IP-10, MCP-1 and cyclophilin B mRNA levels (12-, 9.5, and two-fold, respectively), while CsA increased only cyclophilin B mRNA in a dose-dependent manner. In conclusion, rat renal interstitial fibroblasts express mRNA for chemotactic factors and this expression is up-regulated by inflammatory cytokines, PAN and CsA. The present findings suggest that renal interstitial fibroblasts may play an active role in the recruitment of inflammatory leucocytes into the interstitium.

Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia.

Fas ligand (FasL) and Fas belong to a recently described family of cytokines and receptors with similarities to tumor necrosis factor (TNF) and its receptors. Upon engagement by specific antibodies or by FasL, Fas transduces a signal for apoptosis in permissive cells. Although apoptosis occurs during renal development and following injury to mature cells, the factors responsible for programmed renal cell death are uncertain. We have studied Fas expression by renal cells in vitro and during endotoxemia in mice. Several renal cell types, including glomerular mesangial cells and tubular epithelial cells express a Fas transcript in culture. Lipopolysaccharides (LPS), interleukin-1 beta, interferon-gamma (IFN-gamma), and TNF-alpha increase the levels of Fas mRNA in cultured mesangial and tubular cells. TNF-alpha and LPS raise the level of Fas mRNA in a time- and dose-dependent manner with Fas receptor expression peaking after 72 h of exposure to LPS. Anti-Fas antibodies can induce the death of cultured mesangial cells. This cell death shows the characteristic changes of apoptosis, including DNA fragmentation and pyknotic changes of the nucleus. Increases in Fas by LPS, TNF-alpha, and IFN-gamma enhance the killing induced by the anti-Fas antibody. FasL is also expressed by cultured renal cells, and TNF-alpha treatment of mesangial cells increases its expression. In vivo, Fas mRNA is present at low level in normal kidney. LPS increases the levels of Fas mRNA and protein in kidney and produces evidence of apoptosis along nephrons. These data suggest that transcripts encoding natural FasL and Fas are induced by LPS and may play a role in endotoxemia-induced acute renal failure and organ dysfunction.

Anti-Fas antibodies induce cytolysis and apoptosis in cultured human mesangial cells.

Death of renal cells often occurs during the acute and resolution phases of some forms of glomerulonephritis. The apoptotic Fas protein belongs to a recently described family of cytokine receptors with similarities to tumor necrosis factor (TNF) receptors, and may contribute to the necrobiology of renal cells. Fas transduces a signal for apoptosis in sensitive cells after binding by specific antibodies or following contact with natural Fas ligand. We have studied Fas in cultured human mesangial cells. Cytoflurography demonstrated Fas expression on the surface of human mesangial cells that was increased by stimulation with interferon gamma (IFN gamma). Agonistic anti-human Fas antibodies were cytotoxic to these cells. Cytotoxicity was time- and dose-dependent, and was modulated by pre-stimulation of the mesangial cells with IFN gamma and/or by co-treatment with actinomycin-D. Mesangial cell death following exposure to anti-Fas antibodies has features consistent with apoptosis, such as internucleosomal DNA fragmentation, nuclear shrinkage and condensation, and decreased DNA content. These data suggest that Fas and its ligand could play a mechanistic role in human glomerular cell injury.