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Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing.The Journal of Clinical Investigation Jul 2024The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of...
The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and Adenosine Deaminase isoform switching. We found that A-to-I editing of Antizyme Inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.
PubMed: 38954486
DOI: 10.1172/JCI180117 -
JCI Insight Jul 2024Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this...
Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.
PubMed: 38954484
DOI: 10.1172/jci.insight.171605 -
JCI Insight Jul 2024Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes...
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTβR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation. We showed that intragraft TLO are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLO in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLO or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival prolonged. Intravital microscopy of renal TLO demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLO contributes to local immune responses, leading to earlier allograft failure. TLO and the LTαβ-LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases such as autoimmunity or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.
PubMed: 38954463
DOI: 10.1172/jci.insight.177555 -
Europace : European Pacing,... Jul 2024Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute...
Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.
AIMS
Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB.
METHODS AND RESULTS
This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up.
CONCLUSION
This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.
Topics: Humans; Male; Female; Registries; Retrospective Studies; Aged; Middle Aged; Treatment Outcome; Atrioventricular Block; Catheter Ablation; Time Factors; Vagus Nerve Stimulation; Electrophysiologic Techniques, Cardiac; Syncope; Recurrence; Atrioventricular Node
PubMed: 38954426
DOI: 10.1093/europace/euae164 -
Cardiovascular Toxicology Jul 2024The studies regarding prevalence, outcomes, and predictors of prolonged corrected QT (QTc) among COVID-19 patients not on QTc-prolonging medication are not available in...
The studies regarding prevalence, outcomes, and predictors of prolonged corrected QT (QTc) among COVID-19 patients not on QTc-prolonging medication are not available in the literature. In this retrospective cohort study, the QTc of 295 hospital-admitted COVID-19 patients was analyzed and its association with in-hospital mortality was determined. The QTc was prolonged in 14.6% (43/295) of the study population. Prolonged QTc was seen in patients with older age (P = 0.018), coronary artery disease (P = 0.001), congestive heart failure (P = 0.042), elevated N-terminal-pro-B-type natriuretic peptide (NT-ProBNP) (P < 0.0001), and on remdesivir (P = 0.046). No episode of torsades de pointes arrhythmia or any arrhythmic death was observed among patients with prolonged QTc. The mortality was significantly high in patients with prolonged QTc (P = 0.003). The multivariate logistic regression analysis showed coronary artery disease (odds ratio (OR): 4.153, 95% CI 1.37-14.86; P = 0.013), and NT-ProBNP (ng/L) (OR: 1.000, 95% CI 1.000-1.000; P = 0.007) as predictors of prolonged QTc. The prolonged QTc was associated with the worst in-hospital survival (p by log-rank 0.001). A significant independent association was observed between prolonged QTc and in-hospital mortality in multivariate cox-regression analysis (adjusted hazard ratio: 3.861; (95% CI 1.719-6.523), P < 0.0001). QTc was found to be a marker of underlying comorbidities among COVID-19 patients. Prolonged QTc in hospitalized COVID-19 patients was independently associated with in-hospital mortality.
PubMed: 38954228
DOI: 10.1007/s12012-024-09886-x -
Herz Jul 2024Cardiovascular diseases are the leading cause of death worldwide. Pathophysiologically, metabolic and inflammatory processes contribute substantially to the development... (Review)
Review
Cardiovascular diseases are the leading cause of death worldwide. Pathophysiologically, metabolic and inflammatory processes contribute substantially to the development and progression of cardiovascular diseases. Over the past decade, the role of disease-propagating inflammatory processes has been strengthened and reframed, leading to trials testing anti-inflammatory drugs for the treatment of atherosclerosis and its complications. Despite these achievements, further research in both pre-clinical and clinical studies is warranted to explore new targets, to better identify responders, and to refine therapy strategies to combat inflammation in human disease. Environmental disturbances, so-called lifestyle-associated cardiovascular risk factors, greatly alter the immune system in general and leukocytes in particular, thus affecting the progression of atherosclerosis. Epidemiological studies have shown that exposure to mental stress can be closely linked to the occurrence of cardiovascular disease. Here, we describe how acute and chronic mental stress alter the immune system via neuroimmune interactions, thereby modifying vascular inflammation. In addition, we identify gaps that still need to be addressed in the future.
PubMed: 38954012
DOI: 10.1007/s00059-024-05254-1 -
Clinical Neuroradiology Jul 2024We conducted a matched-control analysis to compare the outcomes of large vessel occlusion (LVO) patients treated with mechanical thrombectomy (MT) plus Intra-arterial...
AIM
We conducted a matched-control analysis to compare the outcomes of large vessel occlusion (LVO) patients treated with mechanical thrombectomy (MT) plus Intra-arterial thrombolysis (IAT) versus those treated with MT alone.
METHODS
The subjects of this study were chosen from ANGEL-ACT registry. All patients who received MT were identified and categorized into two groups: "MT + IAT" and "MT," based on whether or not they received additional intra-arterial medication IAT during the MT procedure. After being subjected to 1:1 propensity score matching, the outcome measures, including modified Rankin Scale (mRS) score at 90 days, successful recanalization at the final angiogram, symptomatic intracranial hemorrhage (sICH) within 36 h, and death within 90 days, were compared.
RESULTS
The study encompassed a total of 1607 patients, with 641 individuals assigned to the MT + IAT group and 966 to the MT group. After applying propensity score matching, a total of 524 pairs were identified for comparison. The results indicated that there were no significant differences between the two groups with regard to the modified Rankin Scale (mRS) score (median: 3 vs. 3 points; P = 0.83), successful recanalization (89.9 vs. 88.9%; P = 0.62), sICH (8.3 vs. 8.7%; P = 0.79), and death (15.5 vs. 16.4%; P = 0.70).
CONCLUSIONS
IAT during MT does not confer an elevated risk of sICH or mortality. Furthermore, the combination of MT and IAT may produce comparable functional outcomes in comparison to MT alone, when treating acute LVO patients.
PubMed: 38953962
DOI: 10.1007/s00062-024-01431-1 -
Pediatric Cardiology Jul 2024Plasma exchange is an effective treatment for Kawasaki disease (KD), suggesting that plasma from patients with KD bears its causative agents. The aim of this study was...
Plasma exchange is an effective treatment for Kawasaki disease (KD), suggesting that plasma from patients with KD bears its causative agents. The aim of this study was to use mass spectrometry to identify candidate agents in patient sera. Serum samples were obtained from 17 KD patients. In six patients, samples were collected in each of three phases: the acute phase prior to acetylsalicylic acid (ASA) and intravenous immunoglobulin administration (Phase A1), the remission phase with ASA (Phase A2), and the remission phase without any medication (Phase A3). Sera from the remaining 11 patients were collected during Phases A1 and A2. The study also included two age- and gender-matched control groups, one with eight afebrile children and one with eight febrile children diagnosed with infectious disease. Patients in Phase A1 and febrile controls did not differ in body temperature, white blood cell counts, or C-reactive protein levels. Mass spectrometry analysis revealed that the intensity levels of m/z 9416, identified as apolipoprotein CIII (Apo CIII), were lower in Phase A1 samples compared with samples from patients in Phases A2 and A3, and from febrile controls (all comparisons, p < 0.01). Serum Apo CIII levels were also lower in Phase A1 samples compared with samples from Phase A2 patients and afebrile controls (both p < 0.01), but samples from patients in Phase A2 did not differ significantly from those of the afebrile controls (p = 0.55). This study demonstrated that serum Apo CIII level was decreased in the acute phase of KD.
PubMed: 38953952
DOI: 10.1007/s00246-024-03546-1 -
Journal of Clinical Research in... Jul 2024Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the...
OBJECTIVE
Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the risk of fracture. The importance of diagnosis and treatment during childhood and adolescence is due to its long-term negative effects. In this study, our objectives were to determine the diagnostic findings, treatment efficacy, and follow-up characteristics of childhood with secondary osteoporosis.
METHODS
61 patients diagnosed with secondary osteoporosis between January 2000 and January 2021 were included in the study. The research is a cross-sectional and descriptive study. Study participants had to be under 18 years of age when the primary underlying disease was diagnosed and received treatment for secondary osteoporosis. Patient data were collected from patient files. Patient data were obtained from patient files in hospitals and were interpreted through the IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, NY, USA).
RESULTS
61 patients (28 women/33 men) were evaluated. The most common underlying primary diseases in patients with secondary osteoporosis were inflammatory diseases (57.7%), neuromuscular diseases (26.2%), immunodeficiency (13.1%), acute lymphoblastic leukemia (8.2%), metabolic diseases (8.2%), and solid organ transplantation. (8.2%), bone marrow transplantation (6.6%) and epilepsy (6.6%). The average chronological age when secondary osteoporosis was diagnosed was 11.89±4.88 years. They were evaluated for osteoporosis 6.39±5.13 years after the onset of the underlying primary chronic diseases. 78.7% of the patients had one or more chronic drug use. Systemic steroid use was 59%, chemotherapeutics 23%, immunomodulatory drugs 19.7%, antiepileptic drugs 8.2%, inhaled steroids 4.9%, IVIG 1.6%, and antituberculosis drugs 1.6%. Additionally, 1.6% of the patients were using testosterone as replacement, 3.3% L-Thyroxine, 1.6% estrogen, and 1.6% growth hormone. Bone pain was detected in 49.2% of the patients. All patients had vertebral fractures before treatment. Bisphosphonate treatment was given to 45 patients with secondary osteoporosis. There was a statistically significant increase in mean bone mineral density (BMD) and bone mineral content values six months after treatment, (p<0.001). There was a significant increase in BMD Z-score values for chronological and height age (p<0.001). The patients' BMD values increased on average by 31.15% with treatment. Following bisphosphonate treatment, there was a significant reduction in both fracture number and bone pain in patients (p<0.01). When patients who received and did not receive steroid treatment were compared, both groups received similar benefits from bisphosphonate treatment.
CONCLUSION
Secondary osteoporosis is a condition that is influenced by many factors, such as the primary disease causing osteoporosis, chronic medication use, especially steroids. If left untreated, osteoporosis leads to important diseases such as bone pain, bone fractures, immobilization, and reduced linear growth of bone. When used to treat childhood secondary osteoporosis, Bisphosphonates significantly improve BMD and reduce fracture risk.
PubMed: 38953735
DOI: 10.4274/jcrpe.galenos.2024.2024-4-4 -
Nanoscale Jul 2024Living drugs offer a new frontier in medicine, paving the way for personalized and potentially curative treatments. A customized living drug generally requires...
Living drugs offer a new frontier in medicine, paving the way for personalized and potentially curative treatments. A customized living drug generally requires specialized technologies for highly effective and selective delivery to lesion locations. In this study, we explored an interfacial engineering method for living drugs by wrapping them with a "stealth coating", achieving "ON/OFF" switching of the communications between probiotics and the gastrointesinal (GI) tract. This maximized the bioactivity of living drugs following oral administration to exempt acidic insults and then significantly improved the retention through the gastrointestinal tract. With the notable ability to improve oral availability, the interfacial-engineered living drugs represent remarkable effects for enhanced oral delivery and treatment efficacy in the dextran sulfate sodium (DSS)-induced acute colitis model. We believe that this work has the potential to revolutionize medicine by precisely targeting and increasing curative activity in the future of disease treatment.
PubMed: 38953700
DOI: 10.1039/d4nr01927j