Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

RGS1 Modulates Autophagic and Metabolic Programs and Is a Critical Mediator of Human Regulatory T Cell Function.

Regulatory T cells (Tregs) are critical mediators of immune tolerance and play a diametric role in cancer and autoimmunity. Tumor-infiltrating Tregs are often associated with poor prognosis in solid tumors because their enrichment in the tumor microenvironment contributes to immunosuppression. Conversely, dysregulation in the Treg compartment can disrupt self-tolerance, leading to autoimmunity. In the present study, we describe what is, to our knowledge, a novel regulator of Tregs, the GTPase activator regulator of G protein 1 (RGS1), demonstrating that RGS1-deficient human Tregs show downregulation of Treg-associated genes and are less immunosuppressive. These RGS1-deficient Tregs exhibit perturbations to the FOXP3-c-MYC transcriptional axis and downstream metabolic and autophagy programs by shifting their energy demands toward glycolysis and rendering them less autophagic. Taken together, RGS1 may serve as an apical node of Treg function by regulating the FOXP3-c-MYC transcriptional axis, thereby providing a therapeutic rationale for targeting RGS1 for treatment of cancer and autoimmune diseases.

Cellular mechanisms and effects of IL-4 receptor blockade in experimental conjunctivitis evoked by skin inflammation.

Ocular surface diseases, including conjunctivitis, are recognized as common comorbidities in atopic dermatitis (AD) and occur at an increased frequency in patients with AD treated with biologics targeting IL-4 receptor α (IL-4Rα) or IL-13. However, the inflammatory mechanisms underlying this pathology are unknown. Here, we developed a potentially novel mouse model of skin inflammation-evoked conjunctivitis and showed that it is dependent on CD4+ T cells and basophils. Blockade of IL-4Rα partially attenuated conjunctivitis development, downregulated basophil activation, and led to a reduction in expression of genes related to type 2 cytokine responses. Together, these data suggest that an IL-4Rα/basophil axis plays a role in the development of murine allergic conjunctivitis. Interestingly, we found a significant augmentation of a number of genes that encode tear proteins and enzymes in anti-IL-4Rα-treated mice, and it may underlie the partial efficacy in this model and may represent candidate mediators of the increased frequency of conjunctivitis following dupilumab in patients with AD.

[Impact of delayed renal function in the renal graft receptor survival from cadaver donor]. / Impacto de la función renal retardada en la sobrevida del injerto renal de donador de cadáver.

OBJECTIVE: to determine the risk factors that lead to delayed graft function (DGF) on long-term renal transplant survival (LTRTS). METHODS: we studied 58 patients who received cadaver transplant. DGF was defined as failure to decrease creatinine plasmatic levels spontaneously during the first postoperative week, requiring at least one dialysis treatment during the first postoperative week or urinary volume < 1 L/24 hr by 2 consecutive days in the first postoperative week. RESULTS: by the Kaplan-Meier and Log rank test, we observed that the DGF > 15 days is associated with a reduction in the LTRTS (Log rank = 4.15, p = 0.042). The logistic regression analysis suggested that cold ischemia time > 12 hr (adjusted OR = 7.99, 95 % CI = 2.36-27.04, p = 0.001) and dialysis of the recipients > 3 years (adjusted OR = 1.67, 95 CI = 1.14-3.47, p = 0.032), were associated with DGF of the renal graft. CONCLUSIONS: this results suggest that DGF > 15 days is associated with a reduction in a LTRTS graft and it supports the presence of risk factors that reduce the graft survival: cold ischemia time > 12 hr and a dialysis time > 3 years for the recipients.

Suicidio en un Hospital Psiquiátrico Privado: estudio de 21 casos observados en 20 años (1968-1987) / Suicide in a Private Psiquiatric Hospital: study of 21 cases observed during 20 years (1968-1987)

Se hace el estudio retrospectivo de 5188 pacientes jóvenes (40.1 años) y crónicos (16.3 años de enfermedad), atendidos como hospitalizados en el curso de 20 años y diagnosticados de acuerdo a la ICD-9. Se analiza las peculiaridades demográficas y psiquiátricas del conjunto y de cada grupo patológico, encontrándose semejanzas y disparidades con estudios similares foráneos, pues la carencia de ellos en nuestro medio no permite otras comparaciones. Por último, se comentan algunas situaciones en las que el médico puede tener responsabilidad por negligencia