Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio-and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.This research was funded by FIS/FEDER funds (PI15/00298, CP14/00133, PI16/01900, PI18/01386, PI18/0133, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD- 3686 CIFRA2-CM. Salary support: ISCIII Miguel Servet to ABS and MDS-N, ISCIII Sara Borrell to JM-MM, REDinREN RD016/0009 to MF-B, and MICIU to JG-M

Altered T-cell subset distribution in the viral reservoir in HIV-1-infected individuals with extremely low proviral DNA (LoViReTs)

HIV cure strategies aim to eliminate viral reservoirs that persist despite successful antiretroviral therapy (ART). We have previously described that 9% of HIV-infected individuals who receive ART harbor low levels of provirus (LoViReTs). We selected 22 LoViReTs matched with 22 controls ART suppressed for more than 3 years with fewer than 100 and more than 100 HIV-DNA copies/10 6 CD4 + T cells, respectively. We measured HIV reservoirs in blood and host genetic factors. Fourteen LoViReTs underwent leukapheresis to analyze replication-competent virus, and HIV-DNA in CD4 + T-cell subpopulations. Additionally, we measured HIV-DNA in rectum and/or lymph node biopsies from nine of them. We found that LoViReTs harbored not only lower levels of total HIV-DNA, but also significantly lower intact HIV-DNA, cell-associated HIV-RNA, and ultrasensitive viral load than controls. The proportion of intact versus total proviruses was similar in both groups. We found no differences in the percentage of host factors. In peripheral blood, 71% of LoViReTs had undetectable replication-competent virus. Minimum levels of total HIV-DNA were found in rectal and lymph node biopsies compared with HIV-infected individuals receiving ART. The main contributors to the reservoir were short-lived transitional memory and effector memory T cells (47% and 29%, respectively), indicating an altered distribution of the HIV reservoir in the peripheral T-cell subpopulations of LoViReTs. In conclusion, LoViReTs are characterized by low levels of viral reservoir in peripheral blood and secondary lymphoid tissues, which might be explained by an altered distribution of the proviral HIV-DNA towards more short-lived memory T cells. LoViReTs can be considered exceptional candidates for future interventions aimed at curing HIV

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib

[EN] Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.SITis study is partially funded by NovartisThe authors thank Dr. João Lacerda for critical reading of the manuscript. This work was supported by grants from Novartis and the Andalusian Regional Government (P18-RT-4047, PI-0052-2018). A.R.G. and J.A.P.S. are members of CIBERONC (CB16/12/00480) and TerCel (16/0011/0035). J.V. is member of CIBERNED (CB06/05/0027). A.R.G. is funded by a Grant of the University of Seville (US-1380874) co-funded by the European Regional Development Fund (ERDF)

Breakfast habits and differences regarding abdominal obesity in a cross-sectional study in Spanish adults: The ANIBES study

Background: Previous studies have indicated that breakfast has a protective effect against obesity. The aim of this study was to describe the breakfast habits of the Spanish adult population and to assess the possible association between breakfast frequency and the presence of abdominal obesity, in a cross-sectional analysis of the ANIBES Study. Methods: A representative sample of 1655 Spanish adults (aged 39±12 y; (mean±sd)) from the ANIBES Study was investigated. The final field work was carried out from mid-September to November (three months) 2013. Collected data included a dietary data collected by a 3-days food record, and health, socioeconomic, physical activity and anthropometric (weight, height and waist circumference) data. Abdominal obesity was defined as having a waist-to-height ratio ≥0.5. The adults were also classified into three groups based on the number of days they ate breakfast (never (0/3 days), sometimes (1-2/3 days) and always (3/3 days)). Logistic regression analyses were used to evaluate the association between breakfast and abdominal obesity. Results: In total, 3.6% of adults skipped breakfast and 14.1% ate breakfast sometimes. Having always breakfast was negatively associated with abdominal obesity [OR = 0.738 (0.558–0.975) p = 0.033]. The odds of abdominal obesity after full adjustment (age, gender, and educational and activity level) were 1.5 times higher for those who skipped breakfast when compared to those who always have breakfast. By correcting the model considered for other variables, the odds among smokers decreased when they have breakfast sometimes [OR = 0.032 (0.003–0.387) p = 0.007] and always [OR = 0.023 (0.002–0.270) p = 0.003] comparing with smokers who skip breakfast. Conclusion: Breakfast frequency could be negatively associated with abdominal obesity, especially among smokers.ANIBES Study was financially supported by Coca Cola Iberia through an agreement with the Spanish Nutrition Foundation (FEN)

Volteando la tortilla. Género y maíz en la alimentación actual de México.

Ante escenarios complejos, patriarcales y desoladores que dejan ver el neoliberalismo, la globalización agroalimentaria, el calentamiento global y las contaminaciones de granos nativos por la imposición de transgénicos, nos cuestionamos si existen algunas alternativas para preservar el maíz nativo como un recurso multiestratégico (alimentario, económico, cultural, ecológico y tecnológico) tomando en cuenta las condiciones actuales de desigualdades sociales de género, etnia, clases y edad que predominan en el campo mexicano. Para responder a algunos cuestionamientos, este libro presenta algunas alternativas a través de diversas experiencias femeninas y de relaciones de género en torno al maíz y la alimentación. Todas ellas muestran que es posible construir una masa crítica para salvaguardar el maíz nativo bajo esas condiciones desoladoras, pero siempre y cuando se “voltee la tortilla”, metáfora que da pie al inicio de otra realidad humanizada y en sincronía con la naturaleza.Proyecto realizado con financiamiento Conacy

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Guía Mexicana para el Diagnóstico y el Tratamiento de la Urticaria

La urticaria es una enfermedad que padece una quinta parte de la población en algún momento de su vida. Las guías inter- nacionales recientes han propuesto unos cambios de fondo en su diagnóstico y tratamiento, por lo que había la necesidad de crear una guía nacional y multidisciplinaria, con base amplia en los gremios de especialistas y médicos de primer contacto en México. ABSTRACT Urticaria is a disease that a fifth of the population shall suffer once in a lifetime. Recent clinical guidelines have proposed some fundamental changes in the diagnosis and treatment of urticaria, making the development of a national, multidisciplinary guideline, with wide acceptability among different professional groups –both specialists and primary health care workers–, necessary in Mexico