Hyperoxia−hypoxia exposure is a proposed cause of alveolar developmental arrest in bronchopulmonary dysplasia in preterm infants, where mitochondrial reactive oxygen species and oxidative stress ...vulnerability are increased. The aryl hydrocarbon receptor (AhR) is one of the main activators of the antioxidant enzyme system that protects tissues and systems from damage. The present study aimed to determine if the activation of the AhR signaling pathway by prenatal administration of indole-3-carbinol (I3C) protects rat pups from hyperoxia–hypoxia-induced lung injury. To assess the activation of protein-encoding genes related to the AhR signaling pathway (Cyp1a1, Cyp1b1, Ugt1a6, Nqo1, and Gsta1), pup lungs were excised at 0, 24, and 72 h after birth, and mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction assays (RT-qPCR). An adapted Ratner's method was used in rats to evaluate radial alveolar counts (RACs) and the degree of fibrosis. The results reveal that the relative expression of AhR-related genes in rat pups of prenatally I3C-treated dams was significantly different from that of untreated dams. The RAC was significantly lower in the hyperoxia–hypoxia group (4.0 ± 1.0) than that in the unexposed control group (8.0 ± 2.0; P < 0.01). When rat pups of prenatally I3C-treated dams were exposed to hyperoxia–hypoxia, an RAC recovery was observed, and the fibrosis index was similar to that of the unexposed control group. A cytokine antibody array revealed an increase in the NF-κB signaling cascade in I3C-treated pups, suggesting that the pathway could regulate the inflammatory process under the stimulus of this compound. In conclusion, the present study demonstrates that I3C prenatal treatment activates AhR-responsive genes in pup’s lungs and hence attenuates lung damage caused by hyperoxia–hypoxia exposure in newborns.
The factors that predispose an individual to a higher risk of death from COVID-19 are poorly understood. The goal of the study was to identify factors associated with risk of death among patients ...with COVID-19. This is a retrospective cohort study of people with laboratory-confirmed SARS-CoV-2 infection from February to May 22, 2020. Data retrieved for this study included patient sociodemographic data, baseline comorbidities, baseline treatments, other background data on care provided in hospital or primary care settings, and vital status. Main outcome was deaths until June 29, 2020. In the multivariable model based on nursing home residents, predictors of mortality were being male, older than 80 years, admitted to a hospital for COVID-19, and having cardiovascular disease, kidney disease or dementia while taking anticoagulants or lipid-lowering drugs at baseline was protective. The AUC was 0.754 for the risk score based on this model and 0.717 in the validation subsample. Predictors of death among people from the general population were being male and/or older than 60 years, having been hospitalized in the month before admission for COVID-19, being admitted to a hospital for COVID-19, having cardiovascular disease, dementia, respiratory disease, liver disease, diabetes with organ damage, or cancer while being on anticoagulants was protective. The AUC was 0.941 for this model’s risk score and 0.938 in the validation subsample. Our risk scores could help physicians identify high-risk groups and establish preventive measures and better follow-up for patients at high risk of dying.
ClinicalTrials.gov Identifier
: NCT04463706
BACKGROUND:The presence of epicardial connections (ECs) between pulmonary veins (PVs) and other anatomic structures may hinder PV isolation. In this study, we analyzed their prevalence, location, ...associated factors, and clinical implications.
METHODS:Five hundred thirty-four consecutive patients with atrial fibrillation undergoing radiofrequency ablation were included. We considered that an EC was present if(1) the first pass around the PV antrum did not produce PV isolation and (2) subsequent atrial activation during PV pacing showed that the earliest site was located away from the ablation line and later activation sites were observed near the ablation line. Clinical and electrophysiological variables were collected from all patients. Patients were followed during 12.9±9.4 months, and any documented atrial tachyarrhythmia after the 3-month blanking period was classified as a recurrence.
RESULTS:Out of the 534 patients included, 72 (13.5%) were found to have 81 ECs. There was a significant association between the presence of ECs and structural heart disease (15.3% in patients without ECs versus 36.5% in patient with ECs; P<0.001) and patent foramen ovale (4.6% versus 13.5%; P=0.002). The presence of a left common trunk was significantly associated with the absence of ECs (29.6% in patients without ECs versus 16.2% in patients with ECs; P=0.014). Patients with ECs had lower acute success in PV isolation compared with patients without ECs (99.1% versus 86.1%; P<0.001). After adjusting for age, sex, type of atrial fibrillation, left atrium area, hypertension, structural heart disease, presence of left common trunk, patent foramen ovale, and time for atrial fibrillation diagnosis to the ablation, we found a significantly higher risk of atrial tachyarrhythmia recurrences in patients with ECs compared with patients without ECs (hazard ratio, 1.7 95% CI, 1.1–2.9; P=0.04).
CONCLUSIONS:ECs between PVs and other adjacent structures are frequent in patient with atrial fibrillation (prevalence13.5%). Structural heart disease and a patent foramen ovale are strongly associated with the presence of ECs. ECs reduce the acute and chronic success of PV isolation.
System dynamics is a powerful tool that allows modeling of complex and highly networked systems such as those found in the human immune system. We have developed a model that reproduces how the ...exposure of human monocytes to lipopolysaccharides (LPSs) induces an inflammatory state characterized by high production of tumor necrosis factor alpha (TNFα), which is rapidly modulated to enter into a tolerant state, known as endotoxin tolerance (ET). The model contains two subsystems with a total of six states, seven flows, two auxiliary variables, and 14 parameters that interact through six differential and nine algebraic equations. The parameters were estimated and optimized to obtain a model that fits the experimental data obtained from human monocytes treated with various LPS doses. In contrast to publications on other animal models, stimulation of human monocytes with super-low-dose LPSs did not alter the response to a second LPSs challenge, neither inducing ET, nor enhancing the inflammatory response. Moreover, the model confirms the low production of TNFα and increased levels of C-C motif ligand 2 when monocytes exhibit a tolerant state similar to that of patients with sepsis. At present, the model can help us better understand the ET response and might offer new insights on sepsis diagnostics and prognosis by examining the monocyte response to endotoxins in patients with sepsis.
IgA Nephropathy in Elderly Patients Sevillano, Angel M; Diaz, Monserrat; Caravaca-Fontán, Fernando ...
Clinical journal of the American Society of Nephrology,
08/2019, Letnik:
14, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group.
In ...this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy.
We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (
value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome.
The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.
Experimental autoimmune encephalomyelitis (EAE), the most common model for multiple sclerosis, is characterized by inflammatory cell infiltration into the central nervous system and demyelination. ...Previous studies have demonstrated that administration of some polyphenols may reduce the neurological alterations of EAE. In this work, we show that ellagic acid, a polyphenolic compound, is beneficial in EAE, most likely through stimulation of ceramide biosynthesis within the brain. EAE was induced in Lewis rats by injection of guinea-pig spinal cord tissue along with Freund's complete adjuvant containing Mycobacterium tuberculosis. Clinical signs first appeared at day 8 post-immunization and reached a peak within 3 days, coincident with reduction of myelin basic protein (MBP) in the cortex. Sphingolipids, the other major components of myelin, also decreased at the acute phase of EAE, both in the cerebral cortex and in the spinal cord. In rats receiving ellagic acid in the drinking water from 2 days before immunization, the onset of the disease was delayed and clinical signs were reduced. This amelioration of clinical signs was accompanied by sustained levels of both MBP and sphingolipid in the cortex, without apparent changes in infiltration of inflammatory CD3+ T-cells, microglial activation, or weight loss, which together suggest a neuroprotective effect of ellagic acid. Finally, in glioma and oligodendroglioma cells we demonstrate that urolithins, the ellagic acid metabolites that circulate in plasma, stimulate the synthesis of ceramide. Together these data suggest that ellagic acid consumption protects against demyelination in rats with induced EAE, likely by a mechanism involving sphingolipid synthesis.
•Ellagic acid administration to EAE-induced rats delays clinical signs of the disease.•Ellagic acid prevents the loss of MBP and sphingolipids from the brain of EAE rats.•Urolithins stimulate ceramide synthesis in glioma C6 and oligodendroglioma HOG cells.•Regular ellagic acid consumption may exert neuroprotective actions.
The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the ...activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of Onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in Onconephrology consultations.
A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not ...yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population.
Multicenter, retrospective cohort study.
111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN).
Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score.
Time to kidney failure.
Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines.
The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient ICC=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure.
Only a subset of the kidney biopsies was centrally reviewed. Residual confounding.
We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.
Display omitted
PDF
