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Background: The impact of body mass index (BMI) on hospital mortality in patients with acute heart failure has been well documented in Asian populations. However, the relationship between BMI, hospital-associated disability (HAD), and hospitalization costs in patients with heart failure is poorly understood. This study aimed to explore the impact of BMI on HAD and hospitalization costs for acute heart failure in Japan., Methods: From April 2012 to March 2020, the Japanese Registry of All Cardiac and Vascular Disease Diagnosis Procedure Combination (JROAD-DPC) database was used to identify patients with acute heart failure. All patients were categorized into five groups according to the World Health Organization Asian BMI criteria. The hospitalization costs and HAD were evaluated., Results: Among the 238,160 eligible patients, 15.7% were underweight, 42.2% were normal, 16.7% were overweight, 19.3% were obese I, and 6.0% were obese II, according to BMI. The prevalence of HAD was 7.43% in the total cohort, and the risk of HAD increased with a lower BMI. Restricted cubic spline analysis showed a U-shaped relationship between BMI and hospitalization costs for all ages. Furthermore, developing HAD was associated with greater costs compared with non-HAD, regardless of BMI category., Conclusions: We found that the lower the BMI, the higher the incidence of HAD. A U-shaped association was confirmed between BMI and hospitalization costs, indicating that hospitalization costs increased for both lower and higher BMI regardless of age. BMI could be an important and informative risk stratification tool for functional outcomes and economic burdens., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background and Aims: Gut microbial lipopolysaccharide (LPS) induces endotoxemia, an independent risk factor for cardiovascular disease (CVD). However, no studies have demonstrated how structural differences in each bacterial LPS contribute to endotoxemia. Here, we investigated the effects of different acyl chains in the lipid A moiety of LPS on endotoxemia and the subsequent immune response and atherosclerotic plaque formation., Methods: Apoe -/- mice were intraperitoneally administered 2 mg/kg of Escherichia coli-derived LPS (E. LPS, as a representative of hexa-acylated lipid A), Bacteroides-derived LPS (B. LPS, as a representative of penta- or tetra-acylated lipid A), or saline (control) once a week, six times. An immunohistological assessment was performed on plaque sections., Results: E. LPS administration induced endotoxemia, but B. LPS and saline did not. In E. LPS-treated mice, total plaque areas in the aortic root were significantly increased, and neutrophil accumulation and increased formation of neutrophil extracellular traps (NETs) were observed at the plaque lesions, but not in B. LPS-treated mice. A single dose of E. LPS significantly increased the accumulation of neutrophils in plaque lesions on day 3, and NET formation on day 7. E. LPS also increased interleukin-1 beta (IL-1β) production in plaque lesions on day 7. Furthermore, NET formation and IL-1β production were also observed in human coronary plaques., Conclusions: We identified a previously unknown link between structural differences in LPS and atherosclerosis. Lowering microbial LPS activity may reduce NET formation in plaques and prevent CVD progression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: We had previously reported an increase in trimethylamine N-oxide (TMAO) levels in patients with both compensated and decompensated heart failure (HF) and alteration in gut microbiota composition using 16S rRNA gene amplicon analysis. Although a metagenome-wide analysis showed that choline-TMA lyase levels increased in HF patients, which TMA generation pathway from choline, carnitine, or betaine contributes to the increase in TMAO levels in HF needs to be elucidated., Methods: We conducted a metagenome-wide shotgun sequencing analysis of gut microbiota and measured the TMAO levels in plasma of 22 HF patients during the compensated phase and 11 age-, sex-, and comorbidity-matched control subjects, whose gut microbiota compositions were reported in a previous 16S rRNA-based analysis., Results: The abundance of cntA/B was positively correlated with TMAO, especially in HF patients, whereas that of cutC/D or betaine reductase was not correlated either in controls or HF patients. The abundance of cntA/B was mainly derived from the genera Escherichia and Klebsiella either in controls or HF patients., Conclusion: TMAO levels in plasma depend on the abundance of cntA/B in HF. Although it is difficult to exclude the involvement of confounding factors, microbial dysbiosis connecting the abundance of cntA/B in the gut and the increase of TMAO in plasma can be a therapeutic target for HF., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: This study examined the impact of CD14 ++ CD16 + monocytes on coronary plaque vulnerability, as assessed by optical coherence tomography (OCT), and investigated their association with daily glucose fluctuation. Although increased CD14 ++ CD16 + monocyte levels have been reported to increase cardiovascular events, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without diabetes mellitus (DM) remains unclear., Methods: This prospective observational study included 50 consecutive patients with CAD, receiving lipid-lowering therapy and undergoing coronary angiography and OCT. Patients were divided into 3 tertiles according to the CD14 ++ CD16 + monocyte percentages assessed by flow cytometry. Standard OCT parameters were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30-70%). Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE)., Results: CD14 ++ CD16 + monocytes negatively correlated with fibrous cap thickness (r = -0.508, p < 0.01). The presence of thin-cap fibroatheroma (TCFA) was increased stepwise according to the tertile of CD14 ++ CD16 + monocytes (0 [tertile 1] vs. 5 [tertile 2] vs. 10 [tertile 3], p < 0.01). CD14 ++ CD16 + monocytes were a significant determinant of TCFA (OR 1.279, p = 0.001). In non-DM patients, a significant relationship was found between CD14 ++ CD16 + monocytes and MAGE (r = 0.477, p = 0.018)., Conclusions: CD14 ++ CD16 + monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14 ++ CD16 + monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14 ++ CD16 + monocytes could be a possible therapeutic target for coronary plaque stabilization., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free or conventionally raised (Conv) ApoE-deficient ( ApoE -/- ) mice were fed chow diet and euthanized at 20 weeks of age. We found that the lack of gut microbiota in ApoE -/- mice caused a significant increase in the plasma and hepatic cholesterol levels compared with Conv ApoE -/- mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the enterohepatic fibroblast growth factor 15, fibroblast growth factor receptor 4 axis, and reduction of cholesterol 7α-hydroxylase and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared with Conv ApoE -/- mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background: The difference of arterial healing response following everolimus-eluting stent (EES) or sirolimus-eluting stent (SES) implantation in patients with ST-segment elevated myocardial infarction (STEMI) has not been compared in detail., Methods: Thirty-five patients with STEMI were randomly implanted with an EES or SES (23 EES, 12 SES). At seven months, neointimal thickness (NIT) and strut malapposition were evaluated by optical coherence tomography (OCT) and the grade and heterogeneity of neointimal coverage (NIC) and development of intra-stent thrombi were evaluated by angioscopy., Results: No significant differences were noted in clinical events experienced by the two groups, although one patient with an EES died following a papillary muscle rupture and one patient with a SES experienced sub-acute stent thrombosis. On OCT, although the EES implants showed a greater NIT than the SES implants (94.8 ± 88.8 μm vs 65.6 ± 63.3 μm, P<0.0001), both the EES and SES showed an excellent suppression of neointimal proliferation in the culprit lesion of STEMI. The frequency of uncovered and malapposed struts of EES was significantly lower than that of SES (2.7% vs. 15.7%, P<0.0001, 0.7% vs. 2.3%, P<0.0001, respectively). The ratio of stents fully covered with neointima of EES group was significantly higher than that of SES group (P=0.04). Angioscopic analysis also showed greater dominant NIC grade with homogenous NIC in EES than in SES (P=0.03, P=0.0002, respectively). The incidence of massive intra-stent thrombus of EES was lower than that of SES (P=0.05)., Conclusion: For patients with STEMI, EES may promote better arterial healing response than SES., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Despite being a relatively widely-used non-invasive parameter of endothelial dysfunction, little is known regarding the relationship between flow-mediated dilatation (FMD) and coronary plaque vulnerability in patients with coronary artery disease (CAD)., Methods: 111 CAD patients (age; 68.9 ± 9.3) who underwent both coronary intervention and FMD were enrolled. Spectral analyses of intravascular ultrasound radiofrequency data for both culprit and non-culprit lesions were performed using Virtual Histology software. Plaque burden was described based on fibrotic, fibro-fatty, dense calcium, and necrotic core (NC) components, and thin-cap fibroatheroma (TCFA) was defined as focal NC rich (> 10%) plaques touching the lumen with a percent-plaque volume exceeding 40%., Results: Averaged %FMD was 2.86 ± 2.03% (median 2.27%, 25th 1.40%, 75th 4.20%). NC volumes were negatively correlated with log%FMD for both culprit and non-culprit lesions (P = 0.001, r = 0.31 and P = 0.03, r = 0.21, respectively). We divided the patients into three tertiles according to %FMD; 38 were lower (≤ 1.75%), 41 were middle (> 1.75%, but ≤ 3.5%), and 32 were upper tertile (> 3.5%). The prevalence rate of TCFA increased with decreasing %FMD tertile and the incidence of major adverse cardiac events was significantly higher in lower %FMD tertile. Multivariate logistic regression analyses showed that the most powerful predictive factor for TCFA was log%FMD (P < 0.0001), and ROC curve analysis identified %FMD of < 2.81% (AUC = 0.82, sensitivity: 91.2%, specificity: 66.7%) as the optimal cut-off point for predicting the presence of TCFA., Conclusions: Impaired endothelial function in brachial arteries may be associated with whole coronary plaque vulnerability and poor clinical outcome in patients with CAD., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon-gamma (IFN-γ) by CD4(+) IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell-depleted splenic APCs. In contrast, no enhanced IFN-γ secretion by CD4(+) LPLs and primed splenic CD4(+) T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4(+) IELs and induce remarkable IFN-γ secretion upon antigenic stimulation in vivo., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A new method to separate lateral diffusion of lipids in spherical large unilamellar vesicles from the rotational and the translational diffusion of the vesicle as a whole is proposed. The lateral diffusion coefficient DL is obtained as a time-dependent part of the observed diffusion coefficient in vesicles of 800-nm diameters, by systematically changing the diffusion time interval of the high-field-gradient NMR measurement. Although the lipid is in a confined space, the DL of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine is (1.5±0.6)×10(-11) m(2) s(-1) in the fluid state at 45°C, more than one order of magnitude faster than the rotational and the translational diffusion coefficients of the vesicle by the hydrodynamic continuum model. The method provides a potential for quantifying the lateral diffusion of lipids and proteins in fluid bilayer vesicles as model cell membranes in a natural manner., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Squamous cell carcinoma (SCC) antigen, including intracellular serine protease inhibitors, is widely used as a laboratory marker for cancers of squamous cell origin. Clinical evidences suggest that increased tissue-expression of SCC antigen predicts an invasive phenotype of cancer cells. Herein, we demonstrated that over-expression of SCC antigen increased the rate of EGF-stimulated cell migration. In the search for the underlying molecular mechanism, we have discovered that SCC antigen was translocated to the plasma membrane upon EGF stimulation and co-localized with polymerized-actin at lamellipodia. We further showed that, co-expression of Cdc42, a downstream target of the EGF receptor, enhanced translocation of the SCC antigen, while co-expression of dominant-inhibitory Cdc42 diminished its translocation. These results suggest that EGF-Cdc42 signal regulates the translocation of SCC antigen to the plasma membrane. Lamellipodia at the leading edge might be a site of action of SCC antigen.

Parietal endoderm-like cells, including Engelbreth-Holm-Swarm tumor and differentiated F9 embryonal carcinoma cells, produce huge amounts of basement membrane components, including laminin-1 (alpha1beta1gamma1). We employed a double-lox system-based gene-swapping strategy in F9 cells to replace the laminin alpha1 gene with a laminin alpha5 minigene. The gene-swapped F9 cells secreted laminin-10 (alpha5beta1gamma1) consisting of the exogenous alpha5 subunit and endogenous beta1 and gamma1 subunits on differentiation. The laminin-10 concentration in the conditioned medium exceeded 10 mg/l, which is 10-fold higher than the concentrations achieved by conventional recombinant expression systems. The gene-swapped F9 cells deposited basement membrane-like matrices containing laminin-10 on culture dishes, offering a novel microenvironment for in vitro cell manipulation.

Engelbreth-Holm-Swarm (EHS) tumor produces large amounts of basement membrane (BM) components, which are widely used as cell culture substrates mimicking BM functions. EHS tumor arose spontaneously in an ST/Eh strain mouse and has been propagated by transplantation. In the present study, we established a cell line, EHSPEL (EHS Parietal Endoderm-Like), which can be cultured ex vivo and preserves the capacity to form tumors in vivo. EHSPEL cells secreted large amounts of laminin-1 into the medium and deposited BM components onto dishes. To further characterize EHSPEL cells, their gene expression profile was compared to those of parietal endoderm cells from Reichert's membrane at embryonic day 13.5, differentiated F9 embryonal carcinoma cells, and PYS-2 parietal endoderm cells. These analyses outlined not only common features of parietal endoderm-like cells that underlie the efficient production of BM components, but also germline cell-like features of EHSPEL cells, at least some of which may play crucial roles in their capacity to form tumors that accumulate abundant BM components in vivo. Karyotyping of EHSPEL cells using chromosome painting probes showed a large number of interchromosomal rearrangements and partial chromosome hyperploidy. Exogenous introduction of a human laminin-alpha(4)-EGFP fusion protein into EHSPEL cells resulted in the production and deposition of human-mouse-hybrid laminin-8. This strategy should be applicable for creating efficient systems to produce chimeric laminins as well as BM-like gels with modified biological activity.

Porcine thyroid follicles cultured in suspension for 96 h synthesized and secreted thyroid hormones in the presence of thyrotropin (TSH). The secretion of newly synthesized hormones was assessed by determining the contents of thyroxine (T4) and triiodothyronine (T3) in the media and by paperchromatographic analysis of 125I-labelled hormones in the media where the follicles were cultured in the presence and absence of inhibitors of hormone synthesis. The hormone synthesis and secretion was modified by exogenously added NaI (0.1-100 microM). The maximal response was obtained at 1 microM. Thyroid peroxidase (TPO) activity in the cultured follicles with TSH for 96 h was dose-dependently inhibited by NaI. One hundred microM of NaI completely inhibited TSH-induced TPO activity. Moreover, both epidermal growth factor (EGF: 10(-9) and 10(-8) M) and phorbol 12-myristate 13-acetate (PMA: 10(-8) and 10(-7) M) inhibited de novo hormone synthesis. An induction of TPO activity by TSH was also inhibited by either agent. These data provide direct evidences that thyroid hormone synthesis is regulated by NaI as well as TSH at least in part via regulation of TPO activity and also that both EGF and PMA are inhibitory on thyroid hormone formation.

Immunoreactive-endothelin (ir-ET) concentrations were determined in peripheral maternal blood and in umbilical cord blood just after delivery. The concentrations in both the umbilical artery (2.83 +/- 1.36 pmol/l plasma, Mean +/- SD) and vein (3.37 +/- 1.53 pmol/l) were significantly higher than those found in maternal venous blood (1.43 +/- 1.02 pmol/l). On the other hand, ir-ET levels in maternal blood were not significantly different when compared with those found in non-pregnant women (1.50 +/- 0.83 pmol/l). No significant difference of ir-ET levels between the umbilical artery and vein was observed. A highly significant correlation (r = 0.60, p less than 0.01) of ir-ET levels between the umbilical artery and vein was observed. Also, a significant correlation (r = 0.48, p less than 0.01) between umbilical vein and maternal vein ir-ET levels with a weaker correlation (r = 0.36, p less than 0.05) between umbilical artery and maternal vein ir-ET levels was demonstrated. The present study indicates that ir-ET may be actively secreted in fetal circulation and the plasma levels in maternal and fetal circulation may have a possible relation.

In cultured porcine thyroid cells, during 60 min incubation phorbol 12-myristate 13-acetate (PMA) had no effect on basal cyclic AMP accumulation and slightly stimulated cyclic AMP accumulation evoked by thyroid stimulating hormone (TSH) or forskolin. Cholera toxin-induced cyclic AMP accumulation was significantly stimulated by PMA. On the other hand, cyclic AMP accumulation evoked by prostaglandin E1 or E2 (PGE1 or PGE2) was markedly depressed by simultaneous addition of PMA. These opposing effects of PMA on cyclic AMP accumulation evoked by PGE and cholera toxin were observed in a dose-related fashion, with half-maximal effect of around 10(-9) M in either case. The almost same effects of PMA on cyclic AMP accumulation in basal and stimulated conditions were also observed in freshly prepared thyroid cells. The present study was performed in the presence of phosphodiesterase inhibitor, 3-iso-butyl-1-methylxanthine (IBMX), indicating that PMA affected adenylate cyclase activity. Therefore, it is suggested that PMA may modulate the production of cyclic AMP in response to different stimuli, possibly by affecting several sites in the adenylate cyclase complex in thyroid cells.

Effects of phorbol esters and epidermal growth factor (EGF) on prostaglandin E2 production by cultured porcine thyroid cells were examined. Both phorbol 12-myristate 13-acetate (PMA) and EGF stimulated prostaglandin E2 production by the cells in dose related fashion. PMA stimulated prostaglandin E2 production over fifty-fold with the dose of 10(-7) M compared with control. EGF (10(-7) M) also stimulated it about ten-fold. The ED50 values of PMA and EGF were respectively around 1 X 10(-9) M and 5 X 10(-10) M. Thyroid stimulating hormone (TSH), however, did not stimulate prostaglandin E2 production from 1 to 24-h incubation. The release of radioactivity from [3H]-arachidonic acid prelabeled cells was also stimulated by PMA and EGF, but not by TSH. These results indicate that both PMA and EGF are potent stimulators of prostaglandin E2 production, associated with the activity to stimulate arachidonic acid release in porcine thyroid cells.

The activity of thyroid peroxidase (TPO) in porcine follicles cultured for 96 h in suspension with five hormones (5H) still attained over 50% of that in the freshly isolated follicles. On the other hand, the activity in those cultured with 5H + TSH (6H) was several times higher than that cultured with 5H after 96 h, although an initial decrease of TPO activity during the first 24 h of culture was observed in both conditions. The ability of follicles to metabolize iodide (uptake and organification) when cultured with 6H for 96 h was also several times higher than that of those cultured with 5H. The half-maximal dose of TSH for stimulation of TPO activity and iodide metabolism was 0.03-0.04 mU/ml and the effect was mediated by cAMP. These results indicate that in porcine thyroid follicles in primary suspension culture, TPO activity as well as the ability of iodide metabolism is induced by chronic TSH stimulation. In addition, epidermal growth factor (EGF, 10(-9)M) and phorbol 12-myristate 13-acetate (PMA, 10(-8) M) completely inhibited TSH stimulation on both activities and also basal (5H) activity of iodide metabolism.