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Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome.
Jeunemaitre, X, Mousseaux, E, Frank, M, Adham, S, Pitocco, F, Billon, C, Ben Yakhlef, M, El Hachmi, M, Bura-Rivière, A, Lapébie, FX, et al
Circulation. 2025;(10):686-695
Abstract
BACKGROUND Vascular Ehlers-Danlos syndrome is a rare genetic disorder characterized by defective type III collagen and a high risk of arterial morbidity and mortality. Several cardiovascular drugs are used for treatment, including celiprolol, but no controlled trial in this condition has been conducted to date. We hypothesized the benefit of the addition of an angiotensin II receptor blocker. METHODS A multicenter, randomized, placebo-controlled trial was conducted to assess the efficacy and safety of the angiotensin II receptor blocker irbesartan in adults with vascular Ehlers-Danlos syndrome on stable background celiprolol therapy. Patients were randomized 1:1 to receive irbesartan (150 mg/day titrated to 300 mg/day) or placebo for 2 years. The composite primary outcome was defined as any vascular Ehlers-Danlos syndrome-related fatal or nonfatal arterial event or any new or worsening arterial lesions detected by systematic head-to-pelvis computed tomography angiography or peripheral arterial duplex ultrasound at different time points, using a time-to-first-event analysis. RESULTS Twenty-nine participants (62% female; 40.3±11.3 years of age) were randomized to irbesartan, and 28 (64% female; 40.7±11.0 years of age) were randomized to placebo. The composite primary outcome occurred in 8 of 29 patients (27.6%) receiving irbesartan versus 15 of 28 patients (53.6%) receiving placebo (hazard ratio, 0.42 [95% CI, 0.17, 0.99]; P<0.05). The risk of recurrent symptomatic or nonsymptomatic arterial events was lower with irbesartan than with placebo (risk ratio, 0.37 [95% CI, 0.19, 0.68]; P=0.002). A reduction of progression of arterial lesions was observed at all sites. Irbesartan significantly reduced systolic blood pressure compared with placebo (baseline-adjusted difference of 5.4 mm Hg [P<0.001]), but no relation was observed with the reduction of the primary composite outcome. Eleven episodes of irbesartan-related hypotension were recorded, leading to a downtitration in 4 patients. CONCLUSIONS Compared with placebo, irbesartan reduced the risk of severe symptomatic and asymptomatic arterial events in patients with vascular Ehlers-Danlos syndrome on background celiprolol therapy. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT02597361.
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A Narrative Review on the Neurocognitive Profiles in Eating Disorders and Higher Weight Individuals: Insights for Targeted Interventions.
Krug, I, Dang, AB, Lu, E, Ooi, WL, Portingale, J, Miles, S
Nutrients. 2024;(24)
Abstract
Background/Objectives: Recent research has increasingly explored the cognitive processes underlying eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), other specified feeding or eating disorders (OSFEDs), and individuals with higher weight (HW). This critical narrative review focuses on neurocognitive findings derived from mainly experimental tasks to provide a detailed understanding of cognitive functioning across these groups. Where experimental data are lacking, we draw on self-report measures and neuroimaging findings to offer supplementary insights. Method: A search of major databases that prioritized meta-analyses and recent publications (last 10 years) was conducted. Using comprehensive search terms related to EDs, HW, and neurocognition, eligible studies focused on human neurocognitive outcomes (e.g., cognitive flexibility, attentional bias, etc.) published in English were selected. Results: We found that some neurocognitive characteristics, such as cognitive rigidity, impulsivity, emotion processing difficulties, and dysregulated reward processing, appear transdiagnostic, spanning multiple ED subtypes and HW populations. We also revealed neurocognitive features specific to ED subtypes and HW. For instance, individuals with AN demonstrate an enhanced focus on detail, and BN and BED are characterized by a pronounced attentional bias toward food-related stimuli. In individuals with HW, cognitive processes underpin behaviours associated with overeating and weight gain. Conclusions: These findings highlight the critical importance of understanding both the unique and shared neurocognitive patterns across ED subtypes and HW populations. By identifying transdiagnostic factors, such as cognitive rigidity and reward processing, alongside ED subtype/HW-specific vulnerabilities, researchers and clinicians can develop more nuanced, evidence-based interventions that address the core mechanisms driving disordered eating behaviours.
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Identification of an Allele-Specific Transcription Factor Binding Interaction that May Regulate PLA2G2A Gene Expression.
Hara, A, Lu, E, Johnstone, L, Wei, M, Sun, S, Hallmark, B, Watkins, JC, Zhang, HH, Yao, G, Chilton, FH
Bioinformatics and biology insights. 2024;:11779322241261427
Abstract
The secreted phospholipase A2 (sPLA2) isoform, sPLA2-IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA2-IIA. The work in the manuscript leveraged 4 publicly available datasets to investigate the mechanism by which rs11573156 influences sPLA2-IIA levels via bioinformatics and modeling analysis. Through genotype-tissue expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA2-IIA, PLA2G2A. SNP2TFBS was used to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified eQTL SNPs. Subsequently, candidate TF-SNP interactions were cross-referenced with the ChIP-seq results in matched tissues from ENCODE. SP1-rs11573156 emerged as the significant TF-SNP pair in the liver. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was likely affected by tissue SP1 protein levels. Using an ordinary differential equation based on Michaelis-Menten kinetic assumptions, we modeled the dependence of PLA2G2A transcription on SP1 protein levels, incorporating the SNP influence. Collectively, our analysis strongly suggests that the difference in the binding dynamics of SP1 to different rs11573156 alleles may underlie the allele-specific PLA2G2A expression in different tissues, a mechanistic model that awaits future direct experimental validation. This mechanism likely contributes to the variation in circulating sPLA2-IIA protein levels in the human population, with implications for a wide range of human diseases.
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Secondary Stroke Risk Reduction in Black Adults: a Systematic Review.
Cao, C, Jain, N, Lu, E, Sajatovic, M, Still, CH
Journal of racial and ethnic health disparities. 2023;(1):306-318
Abstract
OBJECTIVE To address the fact that Black adults (BAs) experience significantly greater stroke burden than the general population, we conducted a systematic literature review which described evidence-based interventions targeting secondary stroke risk reduction in BAs. DATA SOURCE Publications were selected from PubMed, Ovid, Cochrane, and Web of Science databases. We included peer-reviewed, longitudinal, English-language studies performed in the USA which reported results for BAs separately and had adult participants who had experienced stroke-related events. RESULTS Six of the 7 studies employed behavioral interventions which promoted education on stroke risk factors, problem-solving skills, and healthy-coping strategies. These studies demonstrated improvements in one or more biologic outcomes including cholesterol control and systolic blood pressure. CONCLUSIONS Existing interventions on secondary stroke risk reduction approaches are effective in reducing secondary stroke risk among BAs, especially in individuals with poorly controlled blood pressure at baseline. However, additional research is needed because the current approaches may limit generalizability.
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The Role of Mitochondria-Targeting miRNAs in Intracerebral Hemorrhage.
Gareev, I, Beylerli, O, Liang, Y, Lu, E, Ilyasova, T, Sufianov, A, Sufianova, G, Shi, H, Ahmad, A, Yang, G
Current neuropharmacology. 2023;(5):1065-1080
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Abstract
Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, most often occurring between the ages of 45 and 60. Arterial hypertension (AH) is most often the cause of ICH, followed by atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication and vitamin deficiencies. Cerebral hemorrhage can occur by diapedesis or as a result of a ruptured vessel. AH is difficult to treat, requires surgery and can lead to disability or death. One of the important directions in the study of the pathogenesis of ICH is mitochondrial dysfunction and its regulation. The key role of mitochondrial dysfunction in AH and atherosclerosis, as well as in the development of brain damage after hemorrhage, has been acknowledged. MicroRNAs (miRNAs) are a class of non-coding RNAs (about 18-22 nucleotides) that regulate a variety of biological processes including cell differentiation, proliferation, apoptosis, etc., primarily through gene repression. There is growing evidence to support dysregulated miRNAs in various cardiovascular diseases, including ICH. Further, the realization of miRNAs within mitochondrial compartment has challenged the traditional knowledge of signaling pathways involved in the regulatory network of cardiovascular diseases. However, the role of miRNAs in mitochondrial dysfunction for ICH is still under-appreciated, with comparatively much lesser studies and investigations reported, than those in other cardiovascular diseases. In this review, we summarize the up-to-date findings on the published role miRNAs in mitochondrial function for ICH, and the potential use of miRNAs in clinical settings, such as potential therapeutic targets and non-invasive diagnostic/prognostic biomarker tools.
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Opioid Management in CKD.
Lu, E, Schell, JO, Koncicki, HM
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(5):786-795
Abstract
Patients with chronic kidney disease (CKD) experience a high pain and symptom burden. Concurrently, opioid prescription and use in patients with CKD continues to increase, leading to concern for opioid-related risks. Nephrologists increasingly face challenging clinical situations requiring further evaluation and treatment of pain, for which opioid use may be indicated. However, nephrologists are not commonly trained in pain management and may find it difficult to compile the necessary information and tools to effectively assess and treat potentially multidimensional pain. In these situations, they may benefit from using an evidence-based stepwise approach proposed in this article. We address current approaches to opioid use for pain management in CKD and offer a stepwise approach to individualized opioid assessment, focusing on kidney-specific concerns. This includes thorough evaluation of the pain experience, opioid use history, and treatment goals. We subsequently discuss considerations when initiating opioid therapy, strategies to reduce opioid-related risks, and recommended best practices for opioid stewardship in CKD. Using this sequential approach to opioid management, nephrologists can thereby gain a broad overview of key patient considerations, the foundation for understanding implications of opioid use, and a patient-tailored plan for opioid therapy.
