ABSTRACT
One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Quantitative Trait Loci , Veterans , Humans , Male , Genetic Variation , Longitudinal Studies , Polymorphism, Single Nucleotide , United States , United States Department of Veterans Affairs , FemaleABSTRACT
The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.
ABSTRACT
Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.
ABSTRACT
IN738LC is a conventional-cast Ni-based superalloy intended for power generation and aerospace applications. Typically, ultrasonic shot peening (USP) and laser shock peening (LSP) are utilized to enhance cracking, creep, and fatigue resistance. In this study, the optimal process parameters for USP and LSP were established by observing the microstructure and measuring the microhardness of the near-surface region of IN738LC alloys. The LSP impact region (modification depth) was approximately 2500 µm, which was much higher than the USP impact depth of 600 µm. The observation of the microstructural modification and resulting strengthening mechanism revealed that the build-up of dislocations upon peening with plastic deformation was crucial for alloy strengthening in both methods. In contrast, significant strengthening via γ' shearing was observed only in the USP-treated alloys.
ABSTRACT
(1) Background: Contrary to a tenet of the funnel-shaped pediatric larynx with the cricoid level being narrowest, recent studies show the glottis and subglottis as the narrowest levels. To locate the functionally narrowest level of the larynx, we reported normal laryngeal dimensions and their croup-related changes in young children. (2) Methods: We reviewed normal plain neck radiographs recorded for the evaluation of minor trauma or foreign bodies in 504 children aged ≤4 years who visited the emergency department from 2016 through 2021. Using computed tomography-based localization of the glottis, we radiographically defined the subglottis and cricoid. At these levels, we measured diameters and calculated cross-sectional areas (CSAs) on the radiographs. The values were compared to the equivalent values of a 1:1 age-matched population with croup. (3) Results: In the study population (n = 401), the narrowest diameter and CSA were observed in the glottis. In detail, the mean anteroposterior/transverse diameters were 9.8/3.4 mm at the glottis, 8.5/5.6 mm at the subglottis, and 7.4/6.8 mm at the cricoid (p < 0.001), respectively. In the same order, the mean CSAs were 26.5, 38.1, and 40.5 mm2 (p < 0.001). All dimensions were narrower in the croup population (p < 0.001). We found croup-related narrowing, namely reductions in the transverse diameter and CSA that were more severe closer to the glottis (p < 0.001), without differences per level in the anteroposterior diameter. (4) Conclusions: This study confirms the glottis as the narrowest level of the larynx in young children. In addition, level-based differences in croup-related narrowing suggest some point between the glottis and subglottis as the functionally narrowest level.
ABSTRACT
OBJECTIVES: The Regional CardioCerebroVascular Center (RCCVC) project was initiated to improve clinical outcomes for patients with acute myocardial infarction or stroke in non-capital areas of Korea. The purpose of this study was to evaluate the outcomes and issues identified by the Busan RCCVC project in the treatment of ST-segment elevation myocardial infarction (STEMI). METHODS: Among the patients who were registered in the Korean Registry of Acute Myocardial Infarction for the RCCVC project between 2007 and 2019, those who underwent percutaneous coronary intervention (PCI) for STEMI at the Busan RCCVC were selected, and their medical data were compared with a historical cohort. RESULTS: In total, 1161 patients were selected for the analysis. Ten years after the implementation of the Busan RCCVC project, the median door-to-balloon time was reduced from 86 (interquartile range [IQR], 64-116) to 54 (IQR, 44-61) minutes, and the median symptom-to-balloon time was reduced from 256 (IQR, 180-407) to 189 (IQR, 118-305) minutes (p<0.001). Inversely, the false-positive PCI team activation rate increased from 0.6% to 21.4% (p<0.001). However, the 1-year cardiovascular death and major adverse cardiac event rates did not change. Even after 10 years, approximately 75% of the patients had a symptom-to-balloon time over 120 minutes, and approximately 50% of the patients underwent inter-hospital transfer for primary PCI. CONCLUSIONS: A decade after the implementation of the Busan RCCVC project, although time parameters for early reperfusion therapy for STEMI improved, at the cost of an increased false-positive PCI team activation rate, survival outcomes were unchanged.
Subject(s)
Myocardial Infarction , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Myocardial Infarction/therapy , Registries , ST Elevation Myocardial Infarction/therapy , Time FactorsABSTRACT
ABSTRACT: Acute variceal bleeding, a crucial complication of liver cirrhosis requires high energy expenditures but gastrointestinal bleeding limits enteral feeding in the acute stage. We investigated the safety and efficacy of ω-3 fatty acid-enriched parenteral nutrition in acute variceal bleeding patients.In this retrospective study, a total of 208 cirrhotic patients with acute variceal bleeding who underwent parenteral nutrition in the absence of enteral nutrition were enrolled. Among the patients, 86 patients received ω-3 fatty-acid-enriched parenteral nutrition. The primary endpoint was to evaluate the duration of hospital stay and the presence of clinical complications of liver cirrhosis.The mean age of the patients enrolled was 54.9 years-old and 185 patients (88.9%) were male. The cause of liver cirrhosis, Child-Pugh score and comorbidities were statistically not different. Patients with ω-3 enriched parenteral nutrition had a significantly lower systolic blood pressure and total bilirubin levels. The difference in the in-hospital mortality (Pâ=â.813) or rate of complications (Pâ=â.880) was not statistically significant. The duration of hospital stay was significantly shorter in the patients who underwent ω-3 fatty acid-enriched parenteral nutrition (10.7â±â7.3 vs 7.9â±â4.2âdays, Pâ=â.001).In liver cirrhosis patients with acute variceal bleeding, ω-3 fatty acid-enriched parenteral nutrition significantly decreased the length of hospital stay. Further prospective studies to consolidate these findings are warranted.
Subject(s)
Esophageal and Gastric Varices , Fatty Acids, Omega-3 , Esophageal and Gastric Varices/complications , Esophageal and Gastric Varices/therapy , Female , Gastrointestinal Hemorrhage/complications , Gastrointestinal Hemorrhage/therapy , Humans , Length of Stay , Liver Cirrhosis/complications , Male , Middle Aged , Parenteral Nutrition/adverse effects , Prospective Studies , Retrospective StudiesABSTRACT
Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.
Subject(s)
Alternative Splicing/genetics , Carcinogenesis/metabolism , Embryonic Development/genetics , Hematopoiesis/genetics , Melanoma/metabolism , Thymocytes/metabolism , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Apoptosis/genetics , Carcinogenesis/genetics , Cell Proliferation/genetics , Genomics , HEK293 Cells , Humans , Lectins, C-Type/metabolism , Lymphopenia/genetics , Lymphopenia/metabolism , Melanoma/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymerase Chain Reaction , RNA-Seq , Real-Time Polymerase Chain Reaction , Receptors, Antigen, T-Cell/metabolism , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , Thymus Gland/embryology , Thymus Gland/metabolismABSTRACT
Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.
Subject(s)
Astrocytes/pathology , Induced Pluripotent Stem Cells/pathology , Mucolipidoses/pathology , Neural Stem Cells/pathology , Neuraminidase/metabolism , Oligodendroglia/pathology , Teratoma/pathology , Astrocytes/metabolism , Autophagy , Cell Differentiation , Humans , Induced Pluripotent Stem Cells/metabolism , Lysosomes , Mucolipidoses/genetics , Mucolipidoses/metabolism , Mutation , Neural Stem Cells/metabolism , Neuraminidase/genetics , Oligodendroglia/metabolism , Phenotype , Teratoma/genetics , Teratoma/metabolismABSTRACT
BACKGROUND: It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS. METHODS AND RESULTS: This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death. CONCLUSIONS: In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.
Subject(s)
Aortic Valve Stenosis/diagnosis , Aortic Valve/diagnostic imaging , Echocardiography/methods , Heart Valve Prosthesis Implantation , Heart Ventricles/diagnostic imaging , Ventricular Function, Left/physiology , Aged , Aortic Valve/surgery , Aortic Valve Stenosis/physiopathology , Aortic Valve Stenosis/surgery , Disease Progression , Female , Follow-Up Studies , Heart Ventricles/physiopathology , Humans , Male , Prognosis , Retrospective Studies , Severity of Illness IndexABSTRACT
Histone deacetylase inhibitors (HDACis) are well-known epigenetic regulators with therapeutic potential in various diseases. Recent studies have shown that HDACis are involved in immune-mediated anti-cancer effects and may modulate the activity of immunotherapy agents. CG-745, a histone deacetylase inhibitor, has shown anti-cancer effects in pancreatic cancer, colorectal cancer, and non-small cell lung cancer. However, the exact role of CG-745 within the immune system is largely unknown. In this study, we have shown that CG-745 induces microenvironment changes promoting anti-cancer effect of anti-PD-1 antibody in syngeneic mouse models. Specifically, CG-745 induces or extends IL-2 and IFN-γ expression with or without additional stimulation, and increases proliferation of cytotoxic T cells and NK cells, while inhibiting proliferation of regulatory T cells. The analysis of immune cell distribution in the tumor microenvironment and spleen reveals that CG-745 suppresses M2 macrophage polarization and decreases the myeloid-derived suppressor cells. Recent advances in immunotherapy highlight the anti-cancer effects of immune checkpoint inhibitor despite a relatively limited clinical benefit in the subset of patients. Our results indicate that CG-745 enables the synergistic effects of the immune checkpoint inhibitor combination therapy in various cancers by suppressing tumor microenvironment.
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BACKGROUND: The PLEIO (comParison of ticagreLor and clopidogrEl on mIcrocirculation in patients with acute cOronary syndrome) study showed that 6 months of ticagrelor therapy significantly improved microvascular dysfunction in acute coronary syndrome (ACS) patients with stent implantation compared to clopidogrel. Improved microvascular function may affect myocardial blood flow (MBF). We compared the effects of ticagrelor and clopidogrel on MBF over a 6-month follow-up period among patients diagnosed with ACS treated with percutaneous coronary intervention (PCI). METHODS: In the PLEIO trial, 120 participants were randomized to receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily after at least 6 months. 13 N-ammonia positron emission tomography (PET) imaging was performed in 94 patients to measure MBF at the 6-month follow-up visit. RESULTS: On a per-patient level, MBF (1.88⯱â¯0.52 versus 1.67⯱â¯0.64 mL/min per gram, Pâ¯=â¯.01) was significantly higher with ticagrelor compared with clopidogrel in the hyperemic state, but not under resting state (0.75⯱â¯0.24 versus 0.75⯱â¯0.19 mL/min per gram, Pâ¯=â¯.84). On a culprit-vessel analysis, the resting MBF was similar (0.69⯱â¯0.20 versus 0.70⯱â¯0.21, Pâ¯=â¯.89) between the two groups. However, the hyperemic MBF and myocardial flow reserve in the ticagrelor group were significantly higher compared with clopidogrel (1.75⯱â¯0.46 versus 1.52⯱â¯0.59, Pâ¯=â¯.03 and 2.71⯱â¯0.89 versus 2.20⯱â¯0.81, Pâ¯=â¯.02, respectively). These differences were not observed in non-culprit vessels. CONCLUSIONS: Maintenance treatment of ticagrelor increased the hyperemic MBF and myocardial flow reserve compared with clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02618733.
Subject(s)
Acute Coronary Syndrome/therapy , Clopidogrel/therapeutic use , Coronary Circulation/drug effects , Coronary Vessels/physiopathology , Positron-Emission Tomography/methods , Ticagrelor/therapeutic use , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/physiopathology , Ammonia , Coronary Angiography , Coronary Circulation/physiology , Coronary Vessels/diagnostic imaging , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Microcirculation , Middle Aged , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/therapeutic use , Prospective Studies , Time FactorsABSTRACT
Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4+ T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation/immunology , Inflammation/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Animals , Caco-2 Cells , Cell Line, Tumor , Colitis/drug therapy , Colitis/immunology , Colitis/metabolism , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Female , HCT116 Cells , HeLa Cells , Humans , Hypoxia/drug therapy , Hypoxia/immunology , Hypoxia/metabolism , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Prolyl-Hydroxylase Inhibitors/pharmacology , Trefoil Factor-3/immunology , Trefoil Factor-3/metabolismABSTRACT
BACKGROUND: Ticagrelor reduced the rate of myocardial infarction and death compared with clopidogrel in patients with acute coronary syndrome. However, little is understood about chronic treatment of ticagrelor on microvascular dysfunction. The objective of this study was to assess the impact of ticagrelor maintenance treatment on microvascular system and coronary flow in comparison with clopidogrel. METHODS: This study was a nonblinded, open-label, parallel-group, prospective, randomized controlled trial that enrolled 120 patients with acute coronary syndrome requiring stent implantation. Patients were randomized into the ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter) group. The primary end point was coronary microvascular dysfunction as measured by an index of microcirculatory resistance (IMR) at 6 months after treatment. RESULTS: The baseline clinical characteristics and physiological parameters, such as fractional flow reserve, coronary flow reserve, and IMR, did not differ between the ticagrelor and clopidogrel groups. Six-month follow-up physiological data showed that the IMR value was significantly lower in the ticagrelor group than the clopidogrel group (15.57±5.65 versus 21.15±8.39, P<0.01), and coronary flow reserve was higher in the ticagrelor group than in the clopidogrel group (3.85±0.72 versus 3.37±0.76, P<0.01). However, there was no difference in fractional flow reserve (0.87±0.08 versus 0.87±0.09, P=0.94) between the 2 groups. The improvement in IMR after 6 months of treatment was higher in the ticagrelor group (P<0.01). Analyses of 223 nonculprit vessels of registered patients based on physiological results showed no differences in baseline fractional flow reserve (0.93±0.13 versus 0.92±0.09, P=0.58), coronary flow reserve (3.62±1.27 versus 3.51±1.24, P=0.16), or IMR (21.37±12.37 versus 24.19±21.08, P=0.22) or in follow-up fractional flow reserve (0.91±0.09 versus 0.91±0.08, P=0.67), coronary flow reserve (3.91±1.22 versus 3.75±1.16, P=0.36), or IMR (19.43±10.32 versus 21.52±18.90, P=0.34) between the 2 groups. CONCLUSIONS: Compared with clopidogrel, 6 months of ticagrelor therapy significantly improved microvascular dysfunction in acute coronary syndrome patients with stent implantation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02618733.
Subject(s)
Acute Coronary Syndrome/therapy , Clopidogrel/therapeutic use , Coronary Circulation/drug effects , Hemodynamics/drug effects , Microcirculation/drug effects , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/therapeutic use , Ticagrelor/therapeutic use , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/physiopathology , Aged , Clopidogrel/adverse effects , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/instrumentation , Platelet Aggregation Inhibitors/adverse effects , Prospective Studies , Republic of Korea , Stents , Ticagrelor/adverse effects , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: It is unclear whether asymmetry itself plays a role in developing eccentric aortic regurgitation (AR) in patients with tricuspid aortic valve (TAV). The aim of this study was to determine whether an asymmetric aortic valve structure may have association with the development of eccentric AR in patients with TAV. METHODS: Of the 164 410 patients who underwent echocardiography between January 2006 and January 2018 at Dong-A University Hospital, 306 (mean age 69.9 ± 12.6 years; 62% men) eccentric AR were identified. After excluding patients with bicuspid and prolapsed AV, 104 patients who had eccentric AR with TAV were enrolled for the study. Comprehensive echocardiographic AV cusp measurements were compared to those of 104 age- and gender-matched control patients with central AR. RESULTS: In the eccentric and central AR groups, 66 (63.5%) and 48 patients (46.2%) had asymmetric AV, respectively. Mean cusp height was significantly larger in the eccentric AR group than in the central AR group (1.8 ± 0.3 cm vs 1.7 ± 0.2 cm, P = 0002). Furthermore, the mean cusp area and average asymmetry index of the cusp area were also significantly larger in the eccentric AR group than in the central AR group (2.6 ± 0.8 cm2 vs 2.3 ± 0.6 cm2 , P = 0.001, and 7.1 ± 4.5% vs 4.9 ± 2.5%, P < 0.001, respectively). CONCLUSION: AV asymmetry indices of eccentric AR were significantly larger than those of patients with central AR. These data suggest that the presence of asymmetric AV might have association with the development of eccentric AR in patients with TAV.
Subject(s)
Aortic Valve Insufficiency/diagnostic imaging , Aortic Valve/abnormalities , Echocardiography/methods , Tricuspid Valve/diagnostic imaging , Aged , Female , Humans , MaleABSTRACT
BACKGROUND: Aortic dilatation is a major risk factor for aortic dissection. The aim of the present study was to assess the relationship between left ventricular (LV) geometry and maximal ascending aorta (MAA). METHODS: We reviewed data from patients who were diagnosed with acute type A aortic dissection and who underwent surgical management from December 2002 to March 2016 at Dong-A University Hospital. Among 151 patients with non-Marfan aortic dissection in the study, 50 who had echocardiography preoperatively were investigated and MAA diameter was analyzed by LV geometric patterns. RESULTS: Patients' mean age was 59.6 ± 13.5 years and 38.0% were male. The mean MAA diameter was 52.9 ± 8.5 mm. MAA diameter was significantly correlated with LV mass index (r = 0.62, P < 0.001). On analysis by LV geometry, MAA diameter showed a significant difference between the 4 groups (P = 0.02), and the eccentric and concentric hypertrophy groups showed significantly larger MAA diameter than the other two groups. CONCLUSION: MAA diameter was associated with LV mass index and was significantly different between LV geometry types. In this study, not only concentric hypertrophy but also eccentric LV hypertrophy was related to larger MAA in type A aortic dissection patients.
Subject(s)
Aorta/diagnostic imaging , Aortic Aneurysm, Thoracic/diagnosis , Aortic Dissection/diagnosis , Echocardiography, Doppler/methods , Heart Ventricles/diagnostic imaging , Hypertrophy, Left Ventricular/diagnosis , Tomography, X-Ray Computed/methods , Aortic Dissection/etiology , Aortic Dissection/physiopathology , Aortic Aneurysm, Thoracic/physiopathology , Female , Follow-Up Studies , Heart Ventricles/physiopathology , Humans , Hypertrophy, Left Ventricular/complications , Male , Middle Aged , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: Ginseng is believed to have antitumor activity. Autophagy is largely a prosurvival cellular process that is activated in response to cellular stressors, including cytotoxic chemotherapy; therefore, agents that inhibit autophagy can be used as chemosensitizers in cancer treatment. We examined the ability of Korean Red Ginseng extract (RGE) to prevent autophagic flux and to make hepatocellular carcinoma (HCC) cells become more sensitive to doxorubicin. METHODS: The cytotoxic effects of total RGE or its saponin fraction (RGS) on HCC cells were examined by the lactate dehydrogenase assay in a dose- or time-dependent manner. The effect of RGE or RGS on autophagy was measured by analyzing microtubule-associated protein 1A/1B-light chain (LC)3-II expression and LC3 puncta formation in HCC cells. Late-stage autophagy suppression was tested using tandem-labeled green fluorescent protein (GFP)-monomeric red fluorescent protein (mRFP)-LC3. RESULTS: RGE markedly increased the amount of LC3-II, but green and red puncta in tandem-labeled GFP-mRFP-LC3 remained colocalized over time, indicating that RGE inhibited autophagy at a late stage. Suppression of autophagy through knockdown of key ATG genes increased doxorubicin-induced cell death, suggesting that autophagy induced by doxorubicin has a protective function in HCC. Finally, RGE and RGS markedly sensitized HCC cells, (but not normal liver cells), to doxorubicin-induced cell death. CONCLUSION: Our data suggest that inhibition of late-stage autophagic flux by RGE is important for its potentiation of doxorubicin-induced cancer cell death. Therapy combining RGE with doxorubicin could serve as an effective strategy in the treatment of HCC.
ABSTRACT
AIMS: The early diastolic mitral annular velocity (e') and mitral E/e' criteria for clinically evaluating diastolic dysfunction in patients with atrial fibrillation (AF) are almost the same as in patients with sinus rhythm. In this study, we aimed to investigate whether e' is useful to assess diastolic function in AF patients. METHODS: Thirty patients who underwent successful electric cardioversion (EC) due to persistent AF and who maintained sinus rhythm for 1 month after EC were enrolled in this study. Transthoracic echocardiography was performed on all patients before and 1 month after EC. Standard diastolic parameters, the global longitudinal strain (GLS), and left ventricular (LV) twist were measured. RESULTS: Conventional Doppler parameters measured before EC were not significantly different from 1 month after EC. However, the lateral and septal e' were significantly decreased 1 month after EC (from 12.8 ± 2.5 to 9.8 ± 2.3 cm/s and from 9.5 ± 1.9 to 7.1 ± 1.5 cm/s, respectively, P < 0.001). Likewise, the lateral and septal E/e' were also significantly increased 1 month after EC (P < 0.001). The GLS was significantly improved from -15.9 ± 2.2% to -19.4 ± 2.4% after EC (P < 0.001), as was the LV twist (from 5.8 ± 1.7° to 9.1 ± 2.4°, P < 0.001). CONCLUSION: We demonstrated that e' was significantly higher in AF compared with during sinus rhythm in the same patients. Thus, in AF patients, diastolic dysfunction should be suspected even when e' values are normal.