4th booster-dose SARS-CoV-2 heterologous and homologous vaccination in rheumatological patients

Objectiveto evaluate the immune response to the SARS-CoV-2 vaccines in adults with immune-mediated rheumatic diseases (IMRDs) in comparison to healthy individuals, observed 1-20 weeks following the fourth vaccine dose. Additionally, to evaluate the impact of immunosuppressive therapies, vaccination schedules, the time interval between vaccination and sample collection on the vaccine’s immune response.MethodsWe designed a longitudinal observational study conducted at the rheumatology department of Hospital de Copiapó. Neutralizing antibodies (Nabs) titers against the Wuhan and Omicron variant were analyzed between 1-20 weeks after administration of the fourth dose of the SARS-CoV-2 vaccine to 341 participants (218 IMRD patients and 123 healthy controls). 218 IMRD patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), systemic vasculitis (VS) and systemic scleroderma (SS) were analyzed.ResultsPerforming a comparison between the variants, Wuhan vs Omicron, we noticed that there were significant differences (p<0.05) in the level of the ID50, both for healthy controls and for patients with IMRDs. The humoral response of patients with IMRDs is significantly lower compared to healthy controls for the Omicron variant of SARS-CoV-2 (p = 0.0015). The humoral response of patients with IMRDs decreases significantly when the time interval between vaccination and sample collection is greater than 35 days. This difference was observed in the response, both for the Wuhan variant and for the Omicron variant.ConclusionThe IMRDs patients, the humoral response variation in the SARS-CoV-2 vaccine depends on doses and type of vaccine administered, the humoral response times and the treatment that these patients are receiving

Evidence for hypoxia-induced dysregulated cholesterol homeostasis in preeclampsia: Insights into the mechanisms from human placental cells and tissues.

Preeclampsia (PE) poses a considerable risk to the long-term cardiovascular health of both mothers and their offspring due to a hypoxic environment in the placenta leading to reduced fetal oxygen supply. Cholesterol is vital for fetal development by influencing placental function. Recent findings suggest an association between hypoxia, disturbed cholesterol homeostasis, and PE. This study investigates the influence of hypoxia on placental cholesterol homeostasis. Using primary human trophoblast cells and placentae from women with PE, various aspects of cholesterol homeostasis were examined under hypoxic and hypoxia/reoxygenation (H/R) conditions. Under hypoxia and H/R, intracellular total and non-esterified cholesterol levels were significantly increased. This coincided with an upregulation of HMG-CoA-reductase and HMG-CoA-synthase (key genes regulating cholesterol biosynthesis), and a decrease in acetyl-CoA-acetyltransferase-1 (ACAT1), which mediates cholesterol esterification. Hypoxia and H/R also increased the intracellular levels of reactive oxygen species and elevated the expression of hypoxia-inducible factor (HIF)-2α and sterol-regulatory-element-binding-protein (SREBP) transcription factors. Additionally, exposure of trophoblasts to hypoxia and H/R resulted in enhanced cholesterol efflux to maternal and fetal serum. This was accompanied by an increased expression of proteins involved in cholesterol transport such as the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette transporter G1 (ABCG1). Despite these metabolic alterations, mitogen-activated-protein-kinase (MAPK) signaling, a key regulator of cholesterol homeostasis, was largely unaffected. Our findings indicate dysregulation of cholesterol homeostasis at multiple metabolic points in both the trophoblast hypoxia model and placentae from women with PE. The increased cholesterol efflux and intracellular accumulation of non-esterified cholesterol may have critical implications for both the mother and the fetus during pregnancy, potentially contributing to an elevated cardiovascular risk later in life

Purinergic Signaling as a Regulator of Th17 Cell Plasticity

T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation

Th17_TGF-β1 cells present a regulatory phenotype.

<p>(A) IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells were sorted and then analyzed by real-time PCR for mRNA expression of several transcription factors and cytokines (n = 3). (B) IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells were sorted and then reactivated for 4 hrs with PMA plus ionomycin to assess cytokine production by CBA or (C) in the presence of PMA, ionomycin and brefeldin A to analyze GM-CSF production by FACS (n = 5). (D) Percentage of GM-CSF+ cells within IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells (n = 5). Data are presented as mean ± S.E.M. *p<0.05, **p<0.01 and ***p<0.001 determined by t-test (A) or Mann-Whitney test (B and D).</p

ATP hydrolysis by CD39 on Th17_TGF-β1 cells promotes their conversion into IL-10-producing cells.

<p>(A) IL-10 production by IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells restimulated for 3 days with anti-CD3 and anti-CD28 antibodies in the presence and absence of Tr1 polarizing cytokines (TGF-β1, IL-21 and IL-27), 50 μM ATP and 250 μM ARL67156. IL-10 production was analyzed by CBA (n = 4). (B) Th17_IL-23 cells from wild-type and P2X7R knockout mice were restimulated for 3 days with anti-CD3 and anti-CD28 antibodies and IL-10 production was analyzed by CBA (n = 3). Data are presented as mean ± S.E.M. *p<0.05; **p<0.01 determined by repeated measures analysis of variance.</p

Th17_TGF-β1 but not Th17_IL-23 cells hydrolyze ATP to adenosine in a CD39-and CD73-dependent manner and survive in the presence of high doses of ATP.

<p>IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells were sorted and cultured for 1 hr with 10 μM ATP in the presence of 50 μM ARL67156 or 50 μM APCP. Supernatants were then analyzed by HPLC to assess (A and B) ATP and (C and D) AMP hydrolysis (n = 5). (E) Representative FACS analysis of Th17 cell survival (Annexin V-/PI-) in the presence of graded doses of ATP. (F) Percentage of Th17 cell survival in the presence of ATP (n = 3). (G) IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells were sorted and then analyzed by real-time PCR to assess mRNA encoding P2X7 receptor (n = 4). Data are presented as mean ± S.E.M. *p<0.05 and **p<0.01 determined by Mann-Whitney test (B and D), two-way analysis of variance (F) or t-test (G).</p

Th17_TGF-β1 cells are less colitogenic than Th17_IL-23 cells and produce IL-10 and IFN-γ <i>in vivo</i>.

<p>1.3x10⁶ IL-17-GFP+ Th17_TGF-β1 and Th17_IL-23 cells were transferred to Rag1^-/- mice. (A) The weight of mice was measured over the course of 6 weeks after adoptive transfer of Th17 cells (n = 5–8 mice per group). (B) Colon length was measured 6 weeks following transfer of Th17 cells (n = 5). (C) Clinical score was calculated based on weight loss and colon length 6 weeks after adoptive transfer of Th17 cells (n = 5). (D) Colonic histopathology. H&E and alcian blue staining, original magnification 20X. Scale bar 100 μm (E) To determine intestinal cytokine production, intestinal tissues of Th17 recipient mice were cultured for 24 hs at 37°C and 5% CO₂ and production of several cytokines was analyzed by CBA (n = 6). (F and G) Representative FACS analysis of IL-17, IL-10 and IFN-γ production by Th17_TGF-β1 and Th17_IL-23 cells 6 weeks after adoptive transfer to Rag1^-/- mice. Data are presented as mean ± S.E.M. *p<0,05, **p<0,01 and ***p<0,001 comparing Th17_TGF-β1 and Th17_IL-23; ᵜᵜp<0,01 comparing PBS and Th17_TGF-β1; ^¤¤¤p<0,001 comparing PBS and Th17_IL-23 determined by two-way analysis of variance (A). *p<0,05 determined by Kruskal-Wallis test (B,C and E).</p

Geografía de la Salud sin fronteras, desde Iberoamérica

Este libro de Geografía sin fronteras, desde Iberoamérica, reúne trabajos de especialistas en materia de Geografía de la salud de países de Iberoamérica, con diversidad de enfoques y métodos, que permitirá al lector tener una visión del estado actual de esta rama holística e integral de la geografía y la importancia que tiene en la solución de problemas que aquejan nuestra sociedad. El libro se estructura en tres partes: la primera aborda aspectos epistemológicos, teórico conceptuales; en la segunda se presentan las aplicaciones de los SIG y aspectos metodológicos para abordar la salud púbica; y en la tercera se presentan estudios de caso. En la primera parte se aborda la epistemología de la Geografía de la salud: retos y convergencias; geografía y salud: integración de conocimientos y prácticas, como un modo de mirar hacia el mundo a partir de la geografía. Se desarrolla la dimensión local de lo cotidiano de la salud en el territorio; se abordan los procesos de urbanización y resultados en salud; se presenta el tema de la planeación estratégica, un nuevo pensamiento hacia la construcción de ciudades saludables; se abordan reflexiones sobre el estado del arte en la gestión municipal del riesgo de desastres en México. El último tema de esta primera parte del libro es sobre “La geografía médica de Jesús Galindo y Villa”, en el que se analizan los elementos que permitieron construir una cartografía desde la perspectiva de la Geografía de la Salud. La segunda parte del libro incluye aplicaciones de los SIG y metodologías. El primer trabajo es la metodología de evaluación multicriterio en el análisis espacial de la salud, cuyo objetivo es brindar elementos para el apoyo a la toma de decisiones que apunten a lograr una mejora en la calidad de vida de la población. Otra temática es la aplicación de las geo-tecnologías en la geografía de la salud, como los sistemas de información geográfica (SIG), los cuales se ha incrementado su uso en el campo de la salud en los últimos años. Las aplicaciones son muy diversas pueden utilizarse para trazar la ruta más efectiva que seguirá una ambulancia, para ubicar los servicios médicos de una ciudad, así como para analizar patrones de distribución de una determinada enfermedad. Se aborda el tema de tendencias y escenario para el 2020 de la diabetes mellitus en el Estado de México con el propósito es incentivar la iniciativa de políticas públicas que incidan en la disminución de esta enfermedad e impulsar estilos de vida más saludables, principalmente en municipios más vulnerables. La tercera parte del libro son estudios de caso de latitudes diferentes: de Puerto Rico, de México y de Chile, en los que se desarrollan las temáticas de riesgos naturales, vulnerabilidad, contaminación en ciudades, estilos de vida, espacios verdes y análisis espacial estadístico y comparativo de la práctica agroecológica. Exhortamos al lector a leer este valioso documento que le permitirá contar con bases teórico conceptuales, conocer algunas aplicaciones y tener una visión del potencial de la geografía de la salud. Agradecemos los valiosos aportes de los colegas participantes en esta obra, como una de las pocas en esta temática en idioma español y portugués, que sin duda seguirá fortaleciendo esta rama de la geografía. También agradecemos a las autoridades de la Facultad de Geografía de la Universidad Autónoma del Estado de México y de la Coordinación para la Innovación y la Aplicación de la Ciencia y la Tecnología de la Universidad Autónoma de San Luis Potosí, por el valioso apoyo brindado para la publicación de este libro