Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression

Introduction Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients.Methods Twenty C57BL6J mice received 200 mu g of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNF alpha, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression.Results Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity.Conclusions Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker

Urinary Cytokines Reflect Renal Inflammation in Acute Tubulointerstitial Nephritis: A Multiplex Bead-Based Assay Assessment

Background: Acute tubulointerstitial nephritis (ATIN) diagnosis lays on histological assessment through a kidney biopsy, given the absence of accurate non-invasive biomarkers. The aim of this study was to evaluate the accuracy of different urinary inflammation-related cytokines for the diagnostic of ATIN and its distinction from acute tubular necrosis (ATN). Methods: We included 33 patients (ATIN (n = 21), ATN (n = 12)), and 6 healthy controls (HC). We determined the urinary levels of 10 inflammation-related cytokines using a multiplex bead-based Luminex assay at the time of biopsy and after therapy, and registered main clinical, analytical and histological data. Results: At the time of biopsy, urinary levels of I-TAC/CXCL11, CXCL10, IL-6, TNF alpha and MCP-1 were significantly higher in ATIN compared to HC. A positive correlation between the extent of the tubulointerstitial cellular infiltrates in kidney biopsies and the urinary concentration of I-TAC/CXCL11, MIG/CXCL9, CXCL10, IL17, IFN alpha, MCP1 and EGF was observed. Notably, I-TAC/CXCL11, IL-6 and MCP-1 were significantly higher in ATIN than in ATN, with I-TAC/CXCL11 as the best discriminative classifier AUC (0.77, 95% CI 0.57-0.95, p = 0.02). A combinatory model of these three urinary cytokines increased the accuracy in the distinction of ATIN/ATN compared to the individual biomarkers. The best model resulted when combining the three cytokines with blood eosinophil and urinary leukocyte counts (LR = 9.76). Follow-up samples from 11ATIN patients showed a significant decrease in I-TAC/CXCL11, MIG/CXCL9 and CXCL10 levels. Conclusions: Urinary I-TAC/CXCL11, CXCL10, IL6 and MCP-1 levels accurately distinguish patients developing ATIN from ATN and healthy individuals and may serve as novel non-invasive biomarkers in this disease

Acute tubulointerstitial nephritis induced by checkpoint inhibitors versus classical acute tubulointerstitial nephritis : are they the same disease?

The incidence of acute tubulointerstitial nephritis (ATIN) related to drugs has dramatically increased over recent years. A new subtype of ATIN, apparently different from classical drug-related ATIN, has emerged that has been related to the administration of immune checkpoint inhibitors (ICIs). We investigated these differences between ICI-related ATIN (ICI ATIN) and non-ICI-related ATIN in terms of clinical features, response to treatment with steroids and the evolution of kidney function. A total of 47 patients diagnosed with ATIN from two centres were recruited. Of these, 13 patients presented with ATIN during ICI treatment and 34 were diagnosed with ATIN attributed to other drugs. The main demographic, clinical and analytical variables such as gender, age and current medication were recorded. The type of malignancy, oncological treatment, ICI dose and presence of extrarenal immune-related adverse events were also reviewed. Renal biopsy diagnosis, time to drug withdrawal and ATIN-specific treatment, as well as laboratory data during follow-up, were also studied. Patients diagnosed with ICI ATIN presented with lower creatinine (ICI ATIN 3.8 ± 1.03 versus classical ATIN 5.98 ± 4.15 mg/dL, P = 0.007) at diagnosis and higher urinary leucocyte counts (ICI ATIN 263.2 ± 418.04 versus classical ATIN 133.55 ± 284.62, P = 0.048) compared with patients with non-ICI-related ATIN. Time from initiation of the culprit drug to ATIN diagnosis was longer in patients with ICI ATIN than in those with classical ATIN (197.07 ± 184.99 versus 114.4 ± 352.16 days, P = 0.006). In addition, during follow-up, the slope of decreasing creatinine over time was lower for ICI ATIN compared with non-ICI-related ATIN. In this study, we analysed differences between ICI ATIN and classical ATIN. We found that patients with ICI ATIN presented with a larger latency period after culprit drug initiation, milder acute kidney injury and slower creatinine amelioration compared with those with classical ATIN. These results may, in part, be ascribed to potential differences in the pathological mechanisms involved in ATIN development, suggesting that ICI and classical ATIN may be different diseases with similar renal histologies

Collapsing Glomerulonephritis in a Kidney Transplant Recipient after mRNA SARS-CoV-2 Vaccination

With the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies are describing cases of glomerulonephritis arising after vaccination. We present the first case of a kidney transplant patient who, after mRNA vaccination against SARS-CoV-2, developed nephrotic proteinuria and renal dysfunction, with a biopsy diagnostic of collapsing glomerulonephritis. No other triggers for this glomerulonephritis were identified. Antibodies against the spike protein were negative, but the patient developed a specific T-cell response. The close time between vaccination and the proteinuria suggests a possible determinant role of vaccination. We should be aware of nephropathies appearing after COVID-19 vaccination in kidney transplant recipients also

Effect of Bovine leukemia virus on bovine mammary epithelial cells

Bovine leukemia virus (BLV) is a retrovirus that infects cattle and is associated with an increase in secondary infections. The objective of this study was to analyze the effect of BLV infection on cell viability, apoptosis and morphology of a bovine mammary epithelial cell line (MAC-T), as well as Toll like receptors (TLR) and cytokine mRNA expression. Our findings show that BLV infection causes late syncytium formation, a decrease in cell viability, downregulation of the anti-apoptotic gene Bcl-2, and an increase in TLR9 mRNA expression. Moreover, we analyzed how this stably infected cell line respond to the exposure to Staphylococcus aureus (S. aureus), a pathogen known to cause chronic mastitis. In the presence of S. aureus, MAC-T BLV cells had decreased viability and decreased Bcl-2 and TLR2 mRNA expression. The results suggest that mammary epithelial cells infected with BLV have altered the apoptotic and immune pathways, probably affecting their response to bacteria and favoring the development of mastitis.Fil: Martinez Cuesta, Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina. Kansas State University. College of Veterinary Medicine. Department of Diagnostic Medicine and Pathobiology; Estados UnidosFil: Nieto Farías, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lendez, Pamela Anahí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Rowland, Raymond R. R.. Kansas State University. College of Veterinary Medicine. Department of Diagnostic Medicine and Pathobiology; Estados UnidosFil: Sheahan, Maureen A.. Kansas State University. College of Veterinary Medicine. Department of Diagnostic Medicine and Pathobiology; Estados UnidosFil: Cheuquepán Valenzuela, Felipe Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; ArgentinaFil: Marin, Maia Solange. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; ArgentinaFil: Dolcini, Guillermina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Ceriani, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentin

Aplicación de isótopos estables como indicadores de flujos de energía en ambientes costeros de Uruguay = Application of stable isotopes as indicators of energy fluxes in coastal environments of Uruguay

El análisis de isótopos estables en sedimentos, vegetales y animales representa una herramienta de importancia para estudios ecológicos, reconstrucciones paleoclimáticas y paleoambientales. Con base en la diferenciación isotópica entre productores primarios, esta técnica ha tenido un gran impacto en la identificación de flujos de energía entre ecosistemas terrestres y acuáticos adyacentes y en la estructura trófica. Se sintetizan aquí la nomenclatura y los principios básicos para la aplicación de isótopos estables en estudios de ambientes acuáticos. Además, se muestra su utilidad describiendo tres ejemplos recientes en ambientes costeros de Uruguay con diferentes objetivos: 1) evaluar el origen de la materia orgánica en sedimentos del Río de la Plata, 2) determinar la importancia trófica de una especie de diatomea en playas arenosas de Uruguay, y 3) evaluar la influencia de la materia orgánica antropo-génica en la Bahía de Montevideo. La composición isotópica de las fuentes de materia orgánica permitió inferir los mecanismos involucrados en la transferencia de materia orgánica en los ecosistemas costeros. En esta revisión se subrayan las ventajas de este marcador isotópico de carbono que permite discriminar fuentes de materia orgánica. Asimismo, la combinación con otros análisis complementarios como la espectrofluorometría o los biopolímeros resulta importante en investigaciones de funcionamiento ecosistémico

Caracterización fisicoquímica de una formulación alimentaria a partir de materias primas andinas

Con el propósito de disminuir las altas cifras de desnutrición y malnutrición que se presentan en Colombia y en el mundo, se ha incursionado en el mercado de  alimentos funcionales, los cuales tienen una acción benéfica sobre la salud tanto física como mental del consumidor. Por lo anterior, el objetivo de la investigación fue evaluar el contenido de componentes mayoritarios y la viscosidad de una formulación alimentaria a partir de tres materias primas andinas como la quinua, el amaranto y el sagú. En la determinación realizada mediante los métodos de análisis de la AOAC (2005) y un viscosímetro, se encontró que al desarrollar un suplemento a base de 60% de quinua, 20% de amaranto y 20% de sagú, se obtiene un 7,03% de proteína, 5,30% de grasa, 2,05% de fibra, 2,41% de ceniza, 10,45% de agua y 72,76% de carbohidratos, y un comportamiento reológico de un fluido pseudoplástico en el que su viscosidad es independiente del tiempo pero al aumentar la velocidad ésta disminuye. Consecuentemente, es posible generar una formulación alimentaria con potencial como alimento funcional, gracias a sus propiedades nutricionales, digestivas y energéticas

Conservation of the endemic dwarf carnivores of Cozumel Island, Mexico.

Cozumel Island, Mexico, harbours two endemic species of dwarf procyonids: the Pygmy Raccoon Procyon pygmaeus and the Dwarf Coati Nasua nelsoni. Both species are Critically Endangered, and are among the world&rsquo;s most threatened Carnivora. Here we summarise the research we have been conducting on their ecology, evolution, genetics, and conservation. We also summarise the conservation initiatives we have been undertaking and promoting in order to advance the conservation of these unique species and their habitats. This effort illustrates the importance of an interdisciplinary approach in conservation science and action in maximising effectiveness. Nevertheless, the precarious status of the species make it imperative to continue and expand the work we have carried out in Cozumel to prevent two imminent global extinctions.<br /

Plan de Gestión Parque Nacional Perito F. P. Moreno

Según la UICN, un área protegida (AP) es un espacio geográfico claramente definido, reconocido, dedicado y gestionado, mediante medios legales u otros tipos de medios eficaces, para conseguir la conservación a largo plazo de la naturaleza y de sus servicios ecosistémicos y sus valores culturales asociados (Dudley 2008). El Plan de Gestión (PG) es una herramienta importante para la adecuada gestión de las AP. Es el documento donde se definen los lineamientos técnicos y las normas generales de uso de un área de conservación. La planificación permite analizar, discutir y decidir el rumbo de las acciones para el correcto manejo o gestión del AP. Según Núñez Araya (2008), la planificación estratégica de un espacio protegido tiene como objetivo definir el futuro deseado y establecer la forma de alcanzar ese futuro, orientando la toma de decisiones para el mejor uso del espacio. Como dijo Carlos Matus (Amend et al. 2002), “o sabemos planificar o estamos obligados a la improvisación”. Por esta razón la APN ha incorporado la planificación de la gestión de las AP, recomendando lineamientos para su elaboración. En este marco se ha llevado a cabo este proceso que concluye en el presente documento.EEA Santa CruzFil: Blanco, Rocío. Administración De Parques Nacionales. Dirección Regional Patagonia Austral; Argentina.Fil: Malmierca, Laura. Administración De Parques Nacionales. Coordinación Patagonia Austral; Argentina.Fil: Mosti, Patricia. Administración De Parques Nacionales. Santa Cruz; Argentina.Fil: Valenzuela, Alejandro E.J. Administración De Parques Nacionales. Tierra del Fuego; Argentina.Fil: Aguirre, Emiliano. Parque Nacional Perito Francisco P. Moreno. Santa Cruz; ArgentinaFil: Del Castillo, Fabricio (Intendente). Parque Nacional Perito Francisco P. Moreno. Santa Cruz; Argentina.Fil: Spisso, Mariano. Parque Nacional Perito Francisco P. Moreno. Santa Cruz; Argentina.Fil: Chalukian, Silvia C. Administración de Parques Nacionales. Consultora externa; Argentina.Fil: Buria, Leonardo. Administración De Parques Nacionales. Delegación Regional Patagonia; Argentina.Fil: Caracotche, Soledad. Administración De Parques Nacionales. Delegación Regional Patagonia; Argentina.Fil: Lizárraga, Leonidas. Administración De Parques Nacionales. Dirección Regional Noroeste; Argentina.Fil: Martinez, Mariana G. Administración De Parques Nacionales. Delegación Regional Patagonia; Argentina.Fil: Mermoz, Mónica. Administración De Parques Nacionales. Delegación Regional Patagonia; Argentina.Fil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santa Cruz; Argentina.Fil: Peri, Pablo Luis. Universidad Nacional de la Patagonia Austral; Argentina.Fil: Peri, Pablo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Ronda, Gonzalo M. Consejo Nacional De Investigaciones Científicas Y Técnicas. Instituto De Estudios Andinos "Don Pablo Groeber" (IDEAN); Argentina

Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated