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Frontiers in Nutrition 2024Cardiovascular disease (CVD) is the leading cause of death in women, with increased risk following menopause. Dietary intake of beetroot juice and other plant-based...
Seven-day dietary nitrate supplementation clinically significantly improves basal macrovascular function in postmenopausal women: a randomized, placebo-controlled, double-blind, crossover clinical trial.
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death in women, with increased risk following menopause. Dietary intake of beetroot juice and other plant-based nitrate-rich foods is a promising non-pharmacological strategy for increasing systemic nitric oxide and improving endothelial function in elderly populations. The purpose of this randomized, placebo-controlled, double-blind, crossover clinical trial was to determine the effects of short-term dietary nitrate (NO ) supplementation, in the form of beetroot juice, on resting macrovascular endothelial function and endothelial resistance to whole-arm ischemia-reperfusion (IR) injury in postmenopausal women at two distinct stages of menopause.
METHODS
Early-postmenopausal [1-6 years following their final menstrual period (FMP), = 12] and late-postmenopausal (6+ years FMP, = 12) women consumed nitrate-rich (400 mg NO /70 mL) and nitrate-depleted beetroot juice (approximately 40 mg NO /70 mL, placebo) daily for 7 days. Brachial artery flow-mediated dilation (FMD) was measured pre-supplementation (Day 0), and approximately 24 h after the last beetroot juice (BR) dose (Day 8, post-7-day BR). Consequently, FMD was measured immediately post-IR injury and 15 min later (recovery).
RESULTS
Results of the linear mixed-effects model revealed a significantly greater increase in resting FMD with 7 days of BR compared to BR (mean difference of 2.21, 95% CI [0.082, 4.34], = 0.042); however, neither treatment blunted the decline in post-IR injury FMD in either postmenopausal group. Our results suggest that 7-day BR-mediated endothelial protection is lost within the 24-h period following the final dose of BR.
CONCLUSION
Our findings demonstrate that nitrate-mediated postmenopausal endothelial protection is dependent on the timing of supplementation in relation to IR injury and chronobiological variations in dietary nitrate metabolism.
CLINICAL TRIAL REGISTRATION
https://classic.clinicaltrials.gov/ct2/show/NCT03644472.
PubMed: 38915856
DOI: 10.3389/fnut.2024.1359671 -
Frontiers in Neurology 2024This systematic review and meta-analysis aims to systematically evaluate the effectiveness and safety of acupuncture in the treatment of aspiration caused by post-stroke...
OBJECTIVE
This systematic review and meta-analysis aims to systematically evaluate the effectiveness and safety of acupuncture in the treatment of aspiration caused by post-stroke dysphagia.
METHODS
A computer search was conducted in nine databases, including the China National Knowledge Infrastructure (CNKI), China Science and Technology Journal (VIP), Wan-fang Database, China Biomedical Literature Database (CBM), PubMed, Web of Science, Cochrane Library, Embase, and Chinese Clinical Trial Registry (ChiCTR), from their inception until April 2024. Clinical randomized controlled trials comparing acupuncture combined therapy or single therapy with control interventions for the treatment of aspiration caused by post-stroke dysphagia were included. The primary outcome measure was the Penetration Aspiration Scale (PAS), and secondary outcome measures included the overall effective rate, video fluoroscopic swallowing study (VFSS), and hyoid bone displacement. The statistical analysis was performed using RevMan 5.3 and Stata 16.0.
RESULTS
A total of 16 articles involving 1,284 patients were included. The meta-analysis results showed that acupuncture combined therapy or single therapy was more effective in improving PAS scores compared to conventional rehabilitation therapy or balloon dilation of the catheter [WMD = -1.05, 95% CI (-1.30, -0.80), = 0.82, = 0.00 < 0.05]. It was also more effective in improving VFSS scores [WMD = 1.32, 95% CI (0.08, 2.55), = 2.09, = 0.04 < 0.05] and hyoid bone displacement [WMD = 2.02, 95% CI (0.86, 3.18), = 3.41, = 0.00 < 0.05]. Additionally, acupuncture had a higher overall effective rate [WMD = 1.21, 95% CI (1.14, 1.29), = 5.76, = 0.00 < 0.05] and a lower incidence of adverse events. Sensitivity analysis indicated that the literature had minimal impact on the results, and bias tests showed no publication bias.
CONCLUSION
Acupuncture combined therapy and acupuncture single therapy can effectively improve aspiration caused by post-stroke dysphagia with a low incidence of adverse events. However, due to the low quality of the included literature, more high-quality randomized controlled trials are still needed to confirm the effectiveness and safety of acupuncture in the treatment of aspiration caused by post-stroke dysphagia.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023462707, identifier CRD42023462707.
PubMed: 38915795
DOI: 10.3389/fneur.2024.1305056 -
BioRxiv : the Preprint Server For... Jun 2024related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking...
related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking treatment options, leading to high mortality amongst patients. Here, using an inducible, cardiomyocyte-specific lamin A/C depletion mouse model, we conducted a comprehensive transcriptomic study, combining both bulk and single nucleus RNA sequencing, and spanning -DCM disease progression, to identify potential disease drivers. Our refined analysis pipeline identified 496 genes already misregulated early in disease. The expression of these genes was largely driven by disease specific cardiomyocyte sub-populations and involved biological processes mediating cellular response to DNA damage, cytosolic pattern recognition, and innate immunity. Indeed, DNA damage in -DCM hearts was significantly increased early in disease and correlated with reduced cardiomyocyte lamin A levels. Activation of cytosolic pattern recognition in cardiomyocytes was independent of cGAS, which is rarely expressed in cardiomyocytes, but likely occurred downstream of other pattern recognition sensors such as IFI16. Altered gene expression in cardiac fibroblasts and immune cell infiltration further contributed to tissue-wide changes in gene expression. Our transcriptomic analysis further predicted significant alterations in cell-cell communication between cardiomyocytes, fibroblasts, and immune cells, mediated through early changes in the extracellular matrix (ECM) in the -DCM hearts. Taken together, our work suggests a model in which nuclear damage in cardiomyocytes leads to activation of DNA damage responses, cytosolic pattern recognition pathway, and other signaling pathways that activate inflammation, immune cell recruitment, and transcriptional changes in cardiac fibroblasts, which collectively drive -DCM pathogenesis.
PubMed: 38915720
DOI: 10.1101/2024.06.11.598511 -
BioRxiv : the Preprint Server For... Jun 2024ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to...
BACKGROUND
ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found ACLY gene expression is reduced; however the impact this might have on cardiac function and/or metabolism has not been previously studied. As new ACLY inhibitors are in development for cancer and other disorders, such understanding has added importance.
METHODS
Cardiomyocytes, ex-vivo beating hearts, and in vivo hearts with ACLY inhibited by selective pharmacologic (BMS303141, ACLYi) or genetic suppression, were studied. Regulation of ACLY gene/protein expression, and effects of ACLYi on function, cytotoxicity, tricarboxylic acid (TCA)-cycle metabolism, and redox and NAD+/NADH balance were assessed. Mice with cardiac ACLY knockdown induced by AAV9-acly-shRNA or cardiomyocyte tamoxifen-inducible Acly knockdown were studied.
RESULTS
Acly gene expression was reduced more in obese patients with heart failure and preserved EF (HFpEF) than HF with reduced EF. In vivo pressure-overload and in vitro hormonal stress increased ACLY protein expression, whereas it declined upon fatty-acid exposure. Acute ACLYi (1-hr) dose-dependently induced cytotoxicity in adult and neonatal cardiomyocytes, and caused substantial reduction of systolic and diastolic function in myocytes and ex-vivo beating hearts. In the latter, ATP/ADP ratio also fell and lactate increased. U13C-glucose tracing revealed an ACLYdependent TCA-bypass circuit in myocytes, where citrate generated in mitochondria is transported to the cytosol, metabolized by ACLY and then converted to malate to re-enter mitochondria,bypassing several NADH-generating steps. ACLYi lowered NAD+/NADH ratio and restoring this balance ameliorated cardiomyocyte toxicity. Oxidative stress was undetected with ACLYi. Adult hearts following 8-weeks of reduced cardiac and/or cardiomyocyte ACLY downregulation exhibited ventricular dilation and reduced function that was prevented by NAD augmentation. Cardiac dysfunction from ACLY knockdown was worse in hearts subjected to sustained pressureoverload, supporting a role in stress responses.
CONCLUSIONS
ACLY supports normal cardiac function through maintenance of the NAD+/NADH balance and is upregulated by hemodynamic and hormonal stress, but depressed by lipid excess. ACLY levels are most reduced in human HFpEF with obesity potentially worsening cardio-metabolic reserve.
PubMed: 38915649
DOI: 10.1101/2024.06.09.598152 -
BioRxiv : the Preprint Server For... Jun 2024-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure...
-Related Dilated Cardiomyopathy: Single-Cell Transcriptomics during Patient-derived iPSC Differentiation Support Cell type and Lineage-specific Dysregulation of Gene Expression and Development for Cardiomyocytes and Epicardium-Derived Cells with Lamin A/C Haploinsufficiency.
-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C ( ) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. Molecular mechanisms of disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of -Related DCM using induced pluripotent stem cells derived from a family with a heterozygous splice-site mutation. We differentiated one mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (4 Patient and 8 Control) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes (CM) and Epicardium-Derived Cells (EPDC). Data integration and comparative analyses of Patient and Control cells found cell type and lineage differentially expressed genes (DEG) with enrichment to support pathway dysregulation. Top DEG and enriched pathways included: 10 genes and RNA polymerase II transcription in Pluripotent cells (PP); and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, and EMT in CM; and epigenetic regulation and and mTORC1 signaling in EPDC. Top DEG also included: and other X-linked genes, six imprinted genes: , , , , , , and enriched gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs as proposed in other disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.
PubMed: 38915555
DOI: 10.1101/2024.06.12.598335 -
BMC Cardiovascular Disorders Jun 2024Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon... (Comparative Study)
Comparative Study
Drug-coated balloon angioplasty with provisional stenting versus primary stenting for the treatment of de novo coronary artery lesions: REC-CAGEFREE I trial rationale and design.
BACKGROUND
Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain.
STUDY DESIGN
The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization.
DISCUSSION
The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting.
TRIAL REGISTRATION
Registered on clinicaltrial.gov (NCT04561739).
Topics: Humans; Angioplasty, Balloon, Coronary; Treatment Outcome; Coated Materials, Biocompatible; Cardiovascular Agents; China; Paclitaxel; Coronary Artery Disease; Time Factors; Cardiac Catheters; Female; Male; Middle Aged; Multicenter Studies as Topic; Stents; Aged; Drug-Eluting Stents; Equivalence Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 38914951
DOI: 10.1186/s12872-024-03974-0 -
Translational Vision Science &... Jun 2024To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
PURPOSE
To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
METHODS
This study recruited 138 subjects (eyes): 102 with neovascular age-related macular degeneration (nAMD), 18 with diabetic macular edema (DME), and 18 with cataract (control group). AH samples underwent analysis using Olink Target 96 proteomics and Metabolon's metabolomics platform Data analysis included correlation, differential abundance, and gene-set analysis.
RESULTS
In total, 756 proteins and 408 metabolites were quantified in AH. Total AH protein concentration was notably higher in nAMD (3.2-fold) and DME (4.1-fold) compared to controls. Pseudophakic eyes showed higher total AH protein concentrations than phakic eyes (e.g., 1.6-fold in nAMD) and a specific protein signature indicative of matrix remodeling. Unexpectedly, pupil-dilating drugs containing phenylephrine/tropicamide increased several AH proteins, notably interleukin-6 (5.4-fold in nAMD). Correcting for these factors revealed functionally relevant protein correlation clusters and disease-relevant, differentially abundant proteins across the groups. Metabolomics analysis, for which the relevance of confounder adjustment was less apparent, suggested insufficiently controlled diabetes and chronic hyperglycemia in the DME group.
CONCLUSIONS
AH protein concentration, pseudophakia, and pupil dilation with phenylephrine/tropicamide are important confounding factors for AH protein analyses. When these factors are considered, AH analyses can more clearly reveal disease-relevant factors.
TRANSLATIONAL RELEVANCE
Considering AH protein concentration, lens status, and phenylephrine/tropicamide administration as confounders is crucial for accurate interpretation of AH protein data.
Topics: Humans; Aqueous Humor; Female; Proteomics; Male; Aged; Metabolomics; Eye Proteins; Middle Aged; Cataract; Diabetic Retinopathy; Macular Edema; Wet Macular Degeneration; Aged, 80 and over
PubMed: 38913008
DOI: 10.1167/tvst.13.6.17 -
Frontiers in Medicine 2024Systemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high...
BACKGROUND
Systemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high mortality rate. Although there is clinical evidence suggesting a potential correlation between SLE and heart failure (HF), the underlying shared mechanism is not fully understood. Therefore, it is imperative to explore the potential mechanisms and shared therapeutic targets between SLE and HF.
METHODS
The SLE and HF datasets were downloaded from the NCBI Gene Expression Omnibus database. Differentially expressed genes (DEGs) in both SLE and HF were performed using "limma" R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) analyses were conducted to analyze the enriched functions and pathways of DEGs in both SLE and HF datasets. Protein-Protein Interaction network (PPI) and the molecular complex detection (MCODE) plugins in the Cytoscape software were performed to identify the shared hub genes between SLE and HF datasets. R package "limma" was utilized to validate the expression of hub genes based on SLE (GSE122459) and HF (GSE196656) datasets. CIBERSORT algorithm was utilized to analyze the immune cell infiltration of SLE and HF samples based on SLE (GSE112087) and HF (GSE116250) datasets. A weighted gene co-expression network analysis (WGCNA) network was established to further validate the hub genes based on HF dataset (GSE116250). Molecular biology techniques were conducted to validate the hub genes.
RESULTS
999 shared DGEs were identified between SLE and HF datasets, which were mainly enriched in pathways related to Th17 cell differentiation. 5 shared hub genes among the common DGEs between SLE and HF datasets were screened and validated, including HSP90AB1, NEDD8, RPLP0, UBB, and UBC. Additionally, 5 hub genes were identified in the central part of the MEbrown module, showing the strongest correlation with dilated cardiomyopathy. HSP90AB1 and UBC were upregulated in failing hearts compared to non-failing hearts, while UBB, NEDD8, and RPLP0 did not show significant changes.
CONCLUSION
HSP90AB1 and UBC are closely related to the co-pathogenesis of SLE and HF mediated by immune cell infiltration. They serve as promising molecular markers and potential therapeutic targets for the treatment of SLE combined with HF.
PubMed: 38912340
DOI: 10.3389/fmed.2024.1402010 -
Cureus Jun 2024Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in...
Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.
PubMed: 38912084
DOI: 10.7759/cureus.62749 -
Journal of Indian Association of... 2024Pediatric upper gastrointestinal (UGI) endoscopy is an important procedure in the management of gastrointestinal pathologies. Conventionally, it has been the forte of...
INTRODUCTION
Pediatric upper gastrointestinal (UGI) endoscopy is an important procedure in the management of gastrointestinal pathologies. Conventionally, it has been the forte of medical gastroenterologists. However, unlike adults, the availability of pediatric gastroenterologists is limited, especially during emergency hours. We present our early experience of UGI endoscopy done by the department of pediatric surgery.
AIMS
The aim of this study was to study the feasibility and benefits of UGI endoscopy by pediatric surgeons.
MATERIALS AND METHODS
A retrospective descriptive study was carried out by the department of pediatric surgery of a tertiary-level medical college, from January 2017 to January 2022. Data were collected from electronic and physical medical records. Parameters included age, gender, indication for endoscopy, and procedures done endoscopically or based on endoscopic findings and complications.
RESULTS
One hundred and thirty endoscopies were done in 95 patients aged 1-16 years, from January 2017 to January 2022. The most common indication for UGI endoscopy was esophageal stricture (71 procedures in 41 patients), followed by UGI foreign body (18 cases). All other indications were mostly diagnostic, other than four patients with achalasia. Thirty of these patients underwent UGI endoscopy as an emergency procedure. Seventeen patients were followed through or had added procedures, with UGI endoscopy. There was one perforation when dilating an esophageal stricture who responded to conservative management.
CONCLUSION
UGI endoscopy is a valuable diagnostic and therapeutic procedure, which can be performed by pediatric surgeons after necessary training. It supplements decision-making in management, avoids waste of time in referring, avoids additional anesthesia, and is valuable in emergencies.
PubMed: 38912033
DOI: 10.4103/jiaps.jiaps_246_23