Mammalian embryogenesis is a complex process controlled by transcription factors that regulate the balance between pluripotency and differentiation. Transcription factor aryl hydrocarbon receptor ...(AhR) regulates OCT4/POU5F1 and NANOG, both essential controllers of pluripotency, stemness and early embryo development. Molecular mechanisms controlling OCT4/POU5F1 and NANOG during embryogenesis remain unidentified. We show that AhR regulates pluripotency factors and maintains the metabolic activity required for proper embryo differentiation. AhR-lacking embryos (AhR−/−) showed a pluripotent phenotype characterized by a delayed expression of trophectoderm differentiation markers. Accordingly, central pluripotency factors OCT4/POU5F1 and NANOG were overexpressed in AhR−/− embryos at initial developmental stages. An altered intracellular localization of these factors was observed in the absence of AhR and, importantly, Oct4 had an opposite expression pattern with respect to AhR from the two-cell stage to blastocyst, suggesting a negative regulation of OCT4/POU5F by AhR. We propose that AhR is a regulator of pluripotency and differentiation in early mouse embryogenesis.
•AhR regulates pluripotency factors OCT4 and NANOG during early embryo differentiation•AhR lacking embryos (AhR−/−) show a pluripotent phenotype•Pluripotent phenotype of AhR−/− embryos show enhanced glycolytic metabolism
In this article, Fernández-Salguero and colleagues show that transcription factor AhR regulates pluripotency factors and maintains the metabolic activity required for proper embryo differentiation. AhR-lacking embryos (AhR−/−) showed a pluripotent phenotype characterized by a delayed expression of trophectoderm differentiation markers. Accordingly, central pluripotency factors were overexpressed in AhR−/− embryos at initial developmental stages.
Ultra-processed food (UPF) consumption during gestation may lead to increased oxidative stress (OS) and could affect pregnancy outcomes. This study aims to evaluate the association of UPF consumption ...during pregnancy with circulating levels of OS markers. Diet was assessed (average of three assessments) in 119 pregnant women enrolled in the OBESO perinatal cohort (Mexico), obtaining quantitative data and the percentage of energy that UPFs (NOVA) contributed to the total diet. Sociodemographic, clinical (pregestational body-mass index and gestational weight gain) and lifestyle data were collected. Maternal circulating levels of OS markers (malondialdehyde (MDA), protein carbonylation (PC), and total antioxidant capacity (TAC)) were determined at the third trimester of pregnancy. Adjusted linear regression models were performed to analyze the association between UPFs and OS markers. UPFs represented 27.99% of the total energy intake. Women with a lower UPF consumption (<75 percentile°) presented a higher intake of fiber, ω-3, ω-6, and a lower ω-6/3 ratio. Linear regression models showed that UPFs were inversely associated with TAC and MDA. Fiber intake was associated with PC. UPF intake during pregnancy may result in an increase in oxidative stress. When providing nutrition care, limiting or avoiding UPFs may be an intervention strategy that could promote a better antioxidant capacity in the body.
Transcription factor aryl hydrocarbon receptor (AHR) has emerged as one of the main regulators involved both in different homeostatic cell functions and tumor progression. Being a member of the ...family of basic-helix-loop-helix (bHLH) transcriptional regulators, this intracellular receptor has become a key member in differentiation, pluripotency, chromatin dynamics and cell reprogramming processes, with plenty of new targets identified in the last decade. Besides this role in tissue homeostasis, one enthralling feature of AHR is its capacity of acting as an oncogene or tumor suppressor depending on the specific organ, tissue and cell type. Together with its well-known modulation of cell adhesion and migration in a cell-type specific manner in epithelial-mesenchymal transition (EMT), this duality has also contributed to the arise of its clinical interest, highlighting a new potential as therapeutic tool, diagnosis and prognosis marker. Therefore, a deregulation of AHR-controlled pathways may have a causal role in contributing to physiological and homeostatic failures, tumor progression and dissemination. With that firmly in mind, this review will address the remarkable capability of AHR to exert a different function influenced by the phenotype of the target cell and its potential consequences.
Abstract
Background and Aims
Longer survival in renal transplantation means an increase in the number of patients who return to dialysis after graft loss. There is little literature about the ...management of immunosupression(IS) in these patients and the complications derived from its maintenance and its withdrawal/reduction.
Method
We conducted a retrospective study involving a cohort of patients who returned to dialysis after graft failure at Doce de Octubre Hospital from 2015 to 2022. We analyzed baseline characteristics, IS withdrawal scheme, and the complications derived in the 27 months following the restart of dialysis.
Results
A total of 50 patients were enrolled in the study: 58% male, 86% hypertensive, 30% diabetic and 52% with heart disease. The median age at transplant was 41.5 (33.7-53.2). 70% of donations were in brain death, 18% asystole and 10% alive. The duration of the graft was 8.5 years (5,14), 96% of patients developed anti-HLA antibodies and 40% suffered active rejection. Upon restarting dialysis, all the patients were receiving IS: 84% calcineurin inhibitors (CNI) (tacrolimus, cyclosporine), 58% antimetabolites (mycophenolate, azathioprine), and 10% mTOR inhibitors (everolimus). Haemodialysis was performed in 70% of patients through central venous catheterization in 68.6%. The median time to stop IS was 10 months (6,19). Between the first and the third month, imTOR 0(0.4) and antimetabolite 1(0.3) were finalized. Discontinuance of CNI and steroids was at 2 months (1,8) and 8 months (3,15.7) respectively. As complications derived of IS, 64% of patients developed serious infection and 12% were diagnosticated of neoplasms. On the other hand, eighteen patients presented immunological intolerance to the graft, 100% requiring an increase of steroids, 72.2% percutaneous embolization and finally 50% require a transplantectomy. The rate of immunological intolerance, embolization and transplantectomy was higher in patients with withdrawal IS during the first year. Patients on haemodialysis (HD) had higher rate of graft intolerance compared to peritoneal dialysis (PD) (40.5% vs 23%), attributable to early suspension of IS (62% before the first year), but similar rate of infection (61.5%PD, 64.8%HD). At 27 months (14.5,44.2) of follow-up after returning dialysis, 64% of patients remained on dialysis (30% on waiting list for a second kidney transplantation), 28% were retransplanted, and 8% were died.
Conclusion
Most of transplant recipients returned to haemodialysis through a venous catheter. Withdrawal of immunosuppression was performed on a median of 10 months, faster in mTOR and antimetabolites, and more progressive in CNI and steroids. Stop IS before the first year is more common in haemodialysis group and it is associated with a higher rate of graft intolerance. Finally we want to highlight the significant percentage of embolizations in our hospital, that let us avoid a 12.2% of the transplantectomies.
Acute leukemia is the most common type of cancer in pediatric patients. This type of cancer accounts for a third of all childhood cancer cases. More than half of pediatric acute leukemia patients ...show signs and symptoms such as hepatomegaly, splenomegaly, pallor, fever and bruising at the time of diagnosis. In early stages of acute lymphoblastic leukemia (ALL), nephromegaly and other renal manifestations such as high blood pressure (HBP) and renal failure are uncommon, although renal infiltration and nephromegaly are common in advanced-stage pediatric patients. This is a retrospective case review with a critical appraisal of the existing evidence from the literature. We present a clinical case of a child with HBP associated with bilateral nephromegaly which resolved after chemotherapy treatment. This patient presented with HBP that required pharmacological treatment, likely owing to nephromegaly. All HBP secondary causes were rejected. Nephromegaly was resolved after chemotherapy treatment, and antihypertensive medication was discontinued. Nephromegaly and HBP are rare manifestations of ALL debut in pediatrics. The present case report illustrates this unusual combination and Suggests clinicians to consider malignancy as its causal factor, especially if the symptoms are accompanied by other suggestive extrarenal manifestations.
The indiscriminate use of naproxen as an anti-inflammatory has been the leading cause of pollution in sewage effluents. Conversely, titanium dioxide is one of the most promising photocatalyst for the ...degradation of pollutants. Ti-La mixed oxides containing 0, 1, 3, 5, and 10 wt.% of lanthanum were synthetized by sol-gel and tested as photocatalysts in the degradation of naproxen (NPX). The materials were further characterized by X-ray diffraction (XRD), nitrogen physisorption (BET), scanning electron microscopy (SEM), UV-Vis and Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The XRD patterns resembled that of anatase titania. The Eg values, determined from the UV-Vis spectra, vary from 2.07 to 3.2 eV corresponded to pure titania. The photocatalytic activity of these materials showed a degradation of naproxen from 93.6 to 99.8 wt.% after 4 h under UV irradiation.
Coronavirus disease 2019 (COVID-19) is a highly variable condition. Validated tools to assist in the early detection of patients at high risk of mortality can help guide medical decisions.
We sought ...to validate externally, as well as in patients from the second pandemic wave in Europe, our previously developed mortality prediction model for hospitalized COVID-19 patients.
Three validation cohorts were generated: 2 external with 185 and 730 patients from the first wave and 1 internal with 119 patients from the second wave. The probability of death was calculated for all subjects using our prediction model, which includes peripheral blood oxygen saturation/fraction of inspired oxygen ratio, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, IL-6, and age. Discrimination and calibration were evaluated in the validation cohorts. The prediction model was updated by reestimating individual risk factor effects in the overall cohort (N = 1477).
The mortality prediction model showed good performance in the external validation cohorts 1 and 2, and in the second wave validation cohort 3 (area under the receiver-operating characteristic curve, 0.94, 0.86, and 0.86, respectively), with excellent calibration (calibration slope, 0.86, 0.94, and 0.79; intercept, 0.05, 0.03, and 0.10, respectively). The updated model accurately predicted mortality in the overall cohort (area under the receiver-operating characteristic curve, 0.91), which included patients from both the first and second COVID-19 waves. The updated model was also useful to predict fatal outcome in patients without respiratory distress at the time of evaluation.
This is the first COVID-19 mortality prediction model validated in patients from the first and second pandemic waves. The COR+12 online calculator is freely available to facilitate its implementation (https://utrero-rico.shinyapps.io/COR12_Score/).
Abstract
Background and Aims
Post-transplant lymphoproliferative disorders (PTLD) are one of the most common malignancies in kidney transplant (KT) recipients. Immunosuppressive therapy and Epstein ...Barr Virus (EBV) play a main role in their pathogenesis.
Method
In this study we retrospectively analyze the characteristics, clinical evolution and treatments of a group of KT recipients performed between 1986 and 2020 in a single center.
Results
We included 31 patients (64.5% males). Polycystic kidney disease was the most frequent cause of renal failure. Before KT a 6.5% of the patients presented another malignancy, 10% were EBV seronegative and one received immunosuppressive therapy secondary to his primary disease.
Mean age at KT was 43±12 years. 68% of the KT came from brain-dead donors. The most frequent immunosuppressive regime consisted in tacrolimus, mycophenolic acid and prednisone (61.3%). Basiliximab and Timoglobulin were used in the same proportion for the induction therapy (22.6%). Before PTLD appearance the immunosuppressive therapy was reduced in the 54.8% of the recipients. 13% of them presented acute allograft rejection.
The majority of PTLD were diagnosticated between 2016 and 2020. Median time to develop PTLD was 13 years. 54.3% of the patients presented with extranodal involvement. Although all the patients positivized EBV serology, 60% of them had undetectable EBV viral load.
The main therapeutical strategy after PTLD consisted in a reduction of the immunosuppressive therapy. In this way, 28.6% of the recipients was treated with monotherapy with a calcineurin inhibitors and 21.5% with monotherapy with a mTOR inhibitor. In other hand 16.7% received a combination of tacrolimus with a mTOR inhibitor. Rejections were not observed in our group and all the patients presented a preserved kidney function at the end of follow up. Four recipients died because of PTLD. The remaining 27 presented a complete response or stabilization of the disease.
Conclusion
Most of the PTLD were detected between 2016-2020. The time from transplantation to PTLD appearance was long, being EBV viral load negative in the majority of the cases. Graft survival after chemotherapy and reduction of immunosuppressive therapy was excellent, with a low risk of rejection and a good prognosis for hematologic disease. It is possible that a reduction in immunosuppression in selected patients could prevent the development of PTLD.
Thyroid autoimmunity (TAI) has been associated with a significantly increased risk of miscarriage in women with recurrent pregnancy loss (RPL). The aim of this study was to determine the prevalence ...of TAI in women with RPL and compare the clinical characteristics of positive and negative TAI women.
This is a retrospective cross-sectional study; 203 women with RPL were included. Thyroid profile, anti-thyroid peroxidase (TPO-Ab), and anti-thyroglobulin (TG-Ab) antibodies were measured in all participants. Clinical characteristics and causes of RPL were compared between positive and negative TAI.
Prevalence of TAI was 14.8%; prevalence of positive TPO-Ab and TG-Ab was 12.3% and 4.9%, respectively. Women with TAI had significantly higher concentrations of thyrotropin (TSH) compared to women without TAI (4.8 ± 3.8 versus 3.1 ± 1.1,
= 0.001). There was no significant difference in age, the number of gestations, miscarriages, state of antiphospholipid antibodies (aPL), or causes of RPL between women that were TAI-positive versus TAI-negative. Prevalence of positive TAI by cause of RPL was: endocrine 7/25 (28%), genetic 1/5 (20%), autoimmune 1/5 (20%), anatomic 8/55 (14.5%), and unexplained cause 13/112 (11.6%).
The prevalence of TAI in women with RPL is 14.8%. Women with an endocrine cause have the highest prevalence of TAI.
We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke ...Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020.
We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time: daytime (8:00 am-8:59 pm) and nighttime (9:00 pm-7:59 am). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated.
We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio acOR, 1.620 95% CI, 1.020-2.551); no significant difference between trial groups was present during daytime (acOR, 0.890 95% CI, 0.680-1.163;
=0.014). Influence of nighttime on the treatment effect was only evident in patients with large vessel occlusion(daytime, acOR 0.766 95% CI, 0.548-1.072; nighttime, acOR, 1.785 95% CI, 1.024-3.112 ;
<0.01); no heterogeneity was observed for other stroke subtypes (
>0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers.
Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome.
URL: https://www.
gov; Unique identifier: NCT02795962.
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