Cardiac-Specific Inactivation of LPP3 in Mice Leads to Myocardial Dysfunction and Heart Failure

Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P \u3c 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes

Lateral overgrowth of germanium for monolithic integration of germanium-on-insulator on silicon

A technique to locally grow germanium-on-insulator (GOI) structure on silicon (Si) platform is studied. On (001) Si wafer, silicon dioxide (SiO2) is thermally grown and patterned to define growth window for germanium (Ge). Crystalline Ge is grown via selective hetero-epitaxy, using SiO2 as growth mask. Lateral overgrowth of Ge crystal covers SiO2 surface and neighboring Ge crystals coalesce with each other. Therefore, single crystalline Ge sitting on insulator for GOI applications is achieved. Chemical mechanical polishing (CMP) is performed to planarize the GOI surface. Transmission electron microscopy (TEM) analysis, Raman spectroscopy, and time-resolved photoluminescence (TRPL) show high quality crystalline Ge sitting on SiO2. Optical response from metal-semiconductor-metal (MSM) photodetector shows good optical absorption at 850 nm and 1550 nm wavelength. © 2015 Elsevier B.V. All rights reserved

High loading of nanostructured ceramics in polymer composite thick films by aerosol deposition

Low temperature fabrication of Al2O3-polyimide composite substrates was carried out by an aerosol deposition process using a mixture of Al2O3 and polyimide starting powders. The microstructures and dielectric properties of the composite thick films in relation to their Al2O3 contents were characterized by X-ray diffraction analysis. As a result, the crystallite size of α-Al2O3 calculated from Scherrer's formula was increased from 26 to 52 nm as the polyimide ratio in the starting powders increased from 4 to 12 vol.% due to the crushing of the Al2O3 powder being reduced by the shock-absorbing effect of the polyimide powder. The Al2O3-polyimide composite thick films showed a high loss tangent with a large frequency dependence when a mixed powder of 12 vol.% polyimide was used due to the nonuniform microstructure with a rough surface. The Al2O3-polyimide composite thick films showed uniform composite structures with a low loss tangent of less than 0.01 at 1 MHz and a high Al2O3 content of more than 75 vol.% when a mixed powder of 8 vol.% polyimide was used. Moreover, the Al2O3-polyimide composite thick films had extremely high Al2O3 contents of 95 vol.% and showed a dense microstructure close to that of the Al2O3 thick films when a mixed powder of 4 vol.% polyimide was used

Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC

A CREDENCE Trial Substudy

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.OBJECTIVES: The study compared the performance for detection and grading of coronary stenoses using artificial intelligence-enabled quantitative coronary computed tomography angiography (AI-QCT) analyses to core lab-interpreted coronary computed tomography angiography (CTA), core lab quantitative coronary angiography (QCA), and invasive fractional flow reserve (FFR). BACKGROUND: Clinical reads of coronary CTA, especially by less experienced readers, may result in overestimation of coronary artery disease stenosis severity compared with expert interpretation. AI-based solutions applied to coronary CTA may overcome these limitations. METHODS: Coronary CTA, FFR, and QCA data from 303 stable patients (64 ± 10 years of age, 71% male) from the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia) trial were retrospectively analyzed using an Food and Drug Administration-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination. RESULTS: Disease prevalence was high, with 32.0%, 35.0%, 21.0%, and 13.0% demonstrating ≥50% stenosis in 0, 1, 2, and 3 coronary vessel territories, respectively. Average AI-QCT analysis time was 10.3 ± 2.7 minutes. AI-QCT evaluation demonstrated per-patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94%, 68%, 81%, 90%, and 84%, respectively, for ≥50% stenosis, and of 94%, 82%, 69%, 97%, and 86%, respectively, for detection of ≥70% stenosis. There was high correlation between stenosis detected on AI-QCT evaluation vs QCA on a per-vessel and per-patient basis (intraclass correlation coefficient = 0.73 and 0.73, respectively; P < 0.001 for both). False positive AI-QCT findings were noted in in 62 of 848 (7.3%) vessels (stenosis of ≥70% by AI-QCT and QCA of <70%); however, 41 (66.1%) of these had an FFR of <0.8. CONCLUSIONS: A novel AI-based evaluation of coronary CTA enables rapid and accurate identification and exclusion of high-grade stenosis and with close agreement to blinded, core lab-interpreted quantitative coronary angiography. (Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia [CREDENCE]; NCT02173275).proofepub_ahead_of_prin

The effect of scan and patient parameters on the diagnostic performance of AI for detecting coronary stenosis on coronary CT angiography

Publisher Copyright: © 2022 The AuthorsObjectives: To determine whether coronary computed tomography angiography (CCTA) scanning, scan preparation, contrast, and patient based parameters influence the diagnostic performance of an artificial intelligence (AI) based analysis software for identifying coronary lesions with ≥50% stenosis. Background: CCTA is a noninvasive imaging modality that provides diagnostic and prognostic benefit to patients with coronary artery disease (CAD). The use of AI enabled quantitative CCTA (AI-QCT) analysis software enhances our diagnostic and prognostic ability, however, it is currently unclear whether software performance is influenced by CCTA scanning parameters. Methods: CCTA and quantitative coronary CT (QCT) data from 303 stable patients (64 ± 10 years, 71% male) from the derivation arm of the CREDENCE Trial were retrospectively analyzed using an FDA-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination. The algorithm's diagnostic performance measures (sensitivity, specificity, and accuracy) for detecting coronary lesions of ≥50% stenosis were determined based on concordance with QCA measurements and subsequently compared across scanning parameters (including scanner vendor, model, single vs dual source, tube voltage, dose length product, gating technique, timing method), scan preparation technique (use of beta blocker, use and dose of nitroglycerin), contrast administration parameters (contrast type, infusion rate, iodine concentration, contrast volume) and patient parameters (heart rate and BMI). Results: Within the patient cohort, 13% demonstrated ≥50% stenosis in 3 vessel territories, 21% in 2 vessel territories, 35% in 1 vessel territory while 32% had 400 mg/ml 95.2%; p = 0.0287) in the context of low injection flow rates. On a per patient basis there were no significant differences in AI diagnostic performance measures across all measured scanner, scan technique, patient preparation, contrast, and individual patient parameters. Conclusion: The diagnostic performance of AI-QCT analysis software for detecting moderate to high grade stenosis are unaffected by commonly used CCTA scanning parameters and across a range of common scanning, scanner, contrast and patient variables. Condensed abstract: An AI-enabled quantitative CCTA (AI-QCT) analysis software has been validated as an effective tool for the identification, quantification and characterization of coronary plaque and stenosis through comparison to blinded expert readers and quantitative coronary angiography. However, it is unclear whether CCTA screening parameters related to scanner parameters, scan technique, contrast volume and rate, radiation dose, or a patient's BMI or heart rate at time of scan affect the software's diagnostic measures for detection of moderate to high grade stenosis. AI performance measures were unaffected across a broad range of commonly encountered scanner, patient preparation, scan technique, intravenous contrast and patient parameters.publishersversionpublishe

Causes of death and demographic characteristics of victims of meteorological disasters in Korea from 1990 to 2008

<p>Abstract</p> <p>Background</p> <p>Meteorological disasters are an important component when considering climate change issues that impact morbidity and mortality rates. However, there are few epidemiological studies assessing the causes and characteristics of deaths from meteorological disasters. The present study aimed to analyze the causes of death associated with meteorological disasters in Korea, as well as demographic and geographic vulnerabilities and their changing trends, to establish effective measures for the adaptation to meteorological disasters.</p> <p>Methods</p> <p>Deaths associated with meteorological disasters were examined from 2,045 cases in Victim Survey Reports prepared by 16 local governments from 1990 to 2008. Specific causes of death were categorized as drowning, structural collapse, electrocution, lightning, fall, collision, landslide, avalanche, deterioration of disease by disaster, and others. Death rates were analyzed according to the meteorological type, specific causes of death, and demographic and geographic characteristics.</p> <p>Results</p> <p>Drowning (60.3%) caused the greatest number of deaths in total, followed by landslide (19.7%) and structural collapse (10.1%). However, the causes of deaths differed between disaster types. The meteorological disaster associated with the greatest number of deaths has changed from flood to typhoon. Factors that raised vulnerability included living in coastal provinces (11.3 times higher than inland metropolitan), male gender (1.9 times higher than female), and older age.</p> <p>Conclusions</p> <p>Epidemiological analyses of the causes of death and vulnerability associated with meteorological disasters can provide the necessary information for establishing future adaptation measures against climate change. A more comprehensive system for assessing disaster epidemiology needs to be established.</p

Development and validation of a quantitative coronary CT Angiography model for diagnosis of vessel-specific coronary ischemia

Background: Noninvasive stress testing is commonly used for detection of coronary ischemia but possesses variable accuracy and may result in excessive health care costs. Objectives: This study aimed to derive and validate an artificial intelligence-guided quantitative coronary computed tomography angiography (AI-QCT) model for the diagnosis of coronary ischemia that integrates atherosclerosis and vascular morphology measures (AI-QCTISCHEMIA) and to evaluate its prognostic utility for major adverse cardiovascular events (MACE). Methods: A post hoc analysis of the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) and PACIFIC-1 (Comparison of Coronary Computed Tomography Angiography, Single Photon Emission Computed Tomography [SPECT], Positron Emission Tomography [PET], and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve) studies was performed. In both studies, symptomatic patients with suspected stable coronary artery disease had prospectively undergone coronary computed tomography angiography (CTA), myocardial perfusion imaging (MPI), SPECT, or PET, fractional flow reserve by CT (FFRCT), and invasive coronary angiography in conjunction with invasive FFR measurements. The AI-QCTISCHEMIA model was developed in the derivation cohort of the CREDENCE study, and its diagnostic performance for coronary ischemia (FFR ≤0.80) was evaluated in the CREDENCE validation cohort and PACIFIC-1. Its prognostic value was investigated in PACIFIC-1. Results: In CREDENCE validation (n = 305, age 64.4 ± 9.8 years, 210 [69%] male), the diagnostic performance by area under the receiver-operating characteristics curve (AUC) on per-patient level was 0.80 (95% CI: 0.75-0.85) for AI-QCTISCHEMIA, 0.69 (95% CI: 0.63-0.74; P < 0.001) for FFRCT, and 0.65 (95% CI: 0.59-0.71; P < 0.001) for MPI. In PACIFIC-1 (n = 208, age 58.1 ± 8.7 years, 132 [63%] male), the AUCs were 0.85 (95% CI: 0.79-0.91) for AI-QCTISCHEMIA, 0.78 (95% CI: 0.72-0.84; P = 0.037) for FFRCT, 0.89 (95% CI: 0.84-0.93; P = 0.262) for PET, and 0.72 (95% CI: 0.67-0.78; P < 0.001) for SPECT. Adjusted for clinical risk factors and coronary CTA-determined obstructive stenosis, a positive AI-QCTISCHEMIA test was associated with an HR of 7.6 (95% CI: 1.2-47.0; P = 0.030) for MACE. Conclusions: This newly developed coronary CTA-based ischemia model using coronary atherosclerosis and vascular morphology characteristics accurately diagnoses coronary ischemia by invasive FFR and provides robust prognostic utility for MACE beyond presence of stenosis.info:eu-repo/semantics/acceptedVersio

Functional Role of the Polymorphic 647 T/C Variant of ENT1 (SLC29A1) and Its Association with Alcohol Withdrawal Seizures

Adenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1. Our functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild-type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level. Together with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans