Toll-like receptors in acute kidney injury

Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological conditionThe authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI20/00375, PI20/00487), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Spanish Ministry of Science and Innovation (RTI2018-099114-B-100, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C

Nrf2 Plays a Protective Role Against Intravascular Hemolysis-Mediated Acute Kidney Injury

Massive intravascular hemolysis is associated with acute kidney injury (AKI). Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a central role in the defense against oxidative stress by activating the expression of antioxidant proteins. We investigated the role of Nrf2 in intravascular hemolysis and whether Nrf2 activation protected against hemoglobin (Hb)/heme-mediated renal damage in vivo and in vitro. We observed renal Nrf2 activation in human hemolysis and in an experimental model of intravascular hemolysis promoted by phenylhydrazine intraperitoneal injection. In wild-type mice, Hb/heme released from intravascular hemolysis promoted AKI, resulting in decreased renal function, enhanced expression of tubular injury markers (KIM-1 and NGAL), oxidative and endoplasmic reticulum stress (ER), and cell death. These features were more severe in Nrf2-deficient mice, which showed decreased expression of Nrf2-related antioxidant enzymes, including heme oxygenase 1 (HO-1) and ferritin. Nrf2 activation with sulforaphane protected against Hb toxicity in mice and cultured tubular epithelial cells, ameliorating renal function and kidney injury and reducing cell stress and death. Nrf2 genotype or sulforaphane treatment did not influence the severity of hemolysis. In conclusion, our study identifies Nrf2 as a key molecule involved in protection against renal damage associated with hemolysis and opens novel therapeutic approaches to prevent renal damage in patients with severe hemolytic crisis. These findings provide new insights into novel aspects of Hb-mediated renal toxicity and may have important therapeutic implications for intravascular hemolysis-related diseases.Supported by FIS/FEDER CP14/00008, CP16/00014, CP16/00017, PI15/00448, PI16/00735, PI16/02057, PI17/00130, PI17/01495, PI17/01700, ISCIII-RETIC REDinREN RD012/0021, RD016/0009 FEDER funds, Spanish Ministry of Economy and Competitiveness (RYC-2017-22369), Sociedad Española de Nefrología, Fundacion Renal Iñigo Álvarez de Toledo (FRIAT), Comunidad de Madrid CIFRA2 B2017/BMD-3686 and BMD-3827, Fundacion La Caixa, CaixaImpulse program CI17-00048, and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM).S

Clinical experience with integrase inhibitors in HIV-2-infected individuals in Spain.

Background: HIV-2 is a neglected virus despite estimates of 1–2 million people being infected worldwide. The virus is naturally resistant to some antiretrovirals used to treat HIV-1 and therapeutic options are limited for patients with HIV-2. Methods: In this retrospective observational study, we analysed all HIV-2-infected individuals treated with inte- grase strand transfer inhibitors (INSTIs) recorded in the Spanish HIV-2 cohort. Demographics, treatment modal- ities, laboratory values, quantitative HIV-2 RNA and CD4 counts as well as drug resistance were analysed. Results: From a total of 354 HIV-2-infected patients recruited by the Spanish HIV-2 cohort as of December 2017, INSTIs had been given to 44, in 18 as first-line therapy and in 26 after failing other antiretroviral regimens. After a median follow-up of 13 months of INSTI-based therapy, undetectable viraemia for HIV-2 was achieved in 89% of treatment-naive and in 65.4% of treatment-experienced patients. In parallel, CD4 gains were 82 and 126cells/mm3, respectively. Treatment failure occurred in 15 patients, 2 being treatment-naive and 13 treatment-experienced. INSTI resistance changes were recognized in 12 patients: N155H (5), Q148H/R (3), Y143C/G (3) and R263K (1). Conclusions: Combinations based on INSTIs are effective and safe treatment options for HIV-2-infected individ- uals. However, resistance mutations to INSTIs are selected frequently in failing patients, reducing the already limited treatment options

HTLV-1 infection in solid organ transplant donors and recipients in Spain

HTLV-1 infection is a neglected disease, despite infecting 10-15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopathy

Investigation of the splitting of quark and gluon jets

The splitting processes in identified quark and gluon jets are investigated using longitudinal and transverse observables. The jets are selected from symmetric three-jet events measured in Z decays with the Delphi detector in 1991-1994. Gluon jets are identified using heavy quark anti-tagging. Scaling violations in identified gluon jets are observed for the first time. The scale energy dependence of the gluon fragmentation function is found to be about two times larger than for the corresponding quark jets, consistent with the QCD expectation TeX . The primary splitting of gluons and quarks into subjets agrees with fragmentation models and, for specific regions of the jet resolution TeX , with NLLA calculations. The maximum of the ratio of the primary subjet splittings in quark and gluon jets is TeX . Due to non-perturbative effects, the data are below the expectation at small TeX . The transition from the perturbative to the non-perturbative domain appears at smaller TeX for quark jets than for gluon jets. Combined with the observed behaviour of the higher rank splittings, this explains the relatively small multiplicity ratio between gluon and quark jets

Search for scalar fermions and long-lived scalar leptons at centre-of-mass energies of 130 GeV to 172 GeV

Data taken by DELPHI during the 1995 and 1996 LEP runs have been used to search for the supersymmetric partners of electron, muon and tau leptons and of top and bottom quarks. The observations are in agreement with standard model predictions. Limits are set on sfermion masses. Searches for long lived scalar leptons from low scale supersymmetry breaking models exclude stau masses below 55~GeV/c$^2$ at the 95\% confidence level, irrespective of the gravitino mass

Measurements of the leptonic branching fractions of the τ\tau

Data collected with the DELPHI detector from 1993 to 1995 combined with previous DELPHI results for data from 1991 and 1992 yield the branching fractions B({\tau \rightarrow \mbox{\rm e} \nu \bar{\nu}}) = (17.877 \pm 0.109_{stat} \pm 0.110_{sys} )\% and $B({\tau \rightarrow \mu \nu \bar{\nu}}) = (17.325 \pm 0.095_{stat} \pm 0.077_{sys} )\%$

Magnetic Field Modulation of Chirooptical Effects in Magnetoplasmonic Structures

In this work we analyse the magnetic field effects on the chirooptical properties of magnetoplasmonic chiral structures. The structures consist of two-dimensional arrays of Au gammadions in which thin layers of Co have been inserted. Due to the magnetic properties of the Au/Co interface the structures have perpendicular magnetic anisotropy which favours magnetic saturation along the surface normal, allowing magnetic field modulation of the chirooptical response with moderate magnetic fields. These structures have two main resonances. The resonance at 850 nm has a larger chirooptical response than the resonance at 650 nm, which, on the other hand, exhibits a larger magnetic field modulation of its chirooptical response. This dissimilar behaviour is due to the different physical origin of the chirooptical and magneto-optical responses. Whereas the chirooptical effects are due to the geometry of the structures, the magneto-optical response is related to the intensity of the electromagnetic field in the magnetic (Co) layers. We also show that the optical chirality can be modulated by the applied magnetic field, which suggests that magnetoplasmonic chiral structures could be used to develop new strategies for chirooptical sensing.Funding from Spanish Ministry of Economy and Competitiveness through grants “FUNCOAT” CONSOLIDER CSD2008–00023, and MAPS MAT2011–29194-C02–01, and from Comunidad de Madrid through grants “NANOBIOMAGNET” S2009/MAT-1726 and “MICROSERES-CM” S2009/TIC-1476 is acknowledged.Peer Reviewe

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