Usefulness of the mini nutritional assessment short-form for evaluating nutritional status in patients with nontuberculous mycobacterial pulmonary disease: a prospective cross-sectional study.

BACKGROUND: Although the Mini Nutritional Assessment (MNA) is recognized as a useful tool for evaluating nutritional status in patients with various diseases, its applicability in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) remains undetermined. METHODS: We designed a prospective cross-sectional study to investigate whether the MNA Short-Form (MNA-SF) score can serve as a screening tool to assess the nutritional status of patients with NTM-PD. The MNA-SF was conducted upon patient enrollment, and correlation analyses were performed to compare MNA-SF scores with other nutritional measurements and disease severity. Multivariable logistic regression analyses were conducted to evaluate the association between MNA-SF scores and NTM-PD severity. RESULTS: The 194 patients with NTM-PD included in the analysis had a median age of 65.0 (59.0-69.0) years; 59.3% (n = 115) had low MNA-SF scores (< 12). The low MNA-SF group exhibited a lower body mass index (19.7 vs. 22.4 kg/m2, p < 0.001) and fat-free mass index (14.7 vs. 15.6 kg/m2, p < 0.001) than the normal MNA-SF group, as well as higher incidences of sarcopenia (20.0% vs. 6.3%, p = 0.008) and adipopenia (35.7% vs. 5.1%, p < 0.001). However, no significant differences in calorie and protein intakes were observed between the two groups. Low MNA-SF scores were associated with radiographic severity (adjusted odds ratio 2.72, 95% confidence interval 1.38-5.36) but not with forced vital capacity. CONCLUSIONS: The MNA-SF can effectively assess the nutritional status of patients with NTM-PD and can serve as an important clinical indicator in NTM-PD where treatment timing is determined by clinical judgment.

High-level production of keratinocyte growth factor 2 in Escherichia coli.

Recombinant human keratinocyte growth factor 2 (KGF-2), also known as repifermin, is used in various therapeutic applications. However, KGF-2 production has not been optimized for facilitating large-scale production. Therefore, we attempted to attain high-level production of bioactive KGF-2. KGF-2 was fused with 6HFh8 (6HFh8-KGF-2) at the tobacco etch virus protease cleavage site. The 6HFh8-KGF-2 was expressed in Escherichia coli with high expression levels of approximately 33% and 20% of soluble protein in flask culture and 5 L fermentation, respectively. 6HFh8-KGF-2 was purified via nickel affinity chromatography. To maintain a stable form of KGF-2, the conditions of the cleavage reaction were optimized based on the isoelectric point. KGF-2 was purified via ion-exchange chromatography to high purity (>99%) with an optimal purification yield (91%). Circular dichroism spectroscopy demonstrated that purified KGF-2 had a secondary structure and thermal stability similar to that of commercial KGF-2. Bioactivity assays indicated that purified KGF-2 could induce MCF-7 cell proliferation in the same manner as commercial KGF-2. These results demonstrate that bioactive KGF-2 was overexpressed in E. coli and purified to high quality. Our findings indicated that bioactive KGF-2 can be produced in large quantities in E. coli.

Feasibility of UTE-MRI-based radiomics model for prediction of histopathologic subtype of lung adenocarcinoma: in comparison with CT-based radiomics model.

OBJECTIVES: To assess the feasibility of the UTE-MRI radiomic model in predicting the micropapillary and/or solid (MP/S) patterns of surgically resected lung adenocarcinoma. MATERIALS AND METHODS: We prospectively enrolled 74 lesions from 71 patients who underwent UTE-MRI and CT before curative surgery for early lung adenocarcinoma. For conventional radiologic analysis, we analyzed the longest lesion diameter and lesion characteristics at both UTE-MRI and CT. Radiomic features were extracted from the volume of interest of the lesions and Rad-scores were generated using the least absolute shrinkage and selection operator with fivefold cross-validation. Six models were constructed by combining the conventional radiologic model, UTE-MRI Rad-score, and CT Rad-score. The areas under the curves (AUCs) of each model were compared using the DeLong method. Early recurrence after curative surgery was analyzed, and Kaplan-Meier survival analysis was performed. RESULTS: Twenty-four lesions were MP/S-positive, and 50 were MP/S-negative. The longitudinal size showed a small systematic difference between UTE-MRI and CT, with fair intermodality agreement of lesion characteristic (kappa = 0.535). The Rad-scores of the UTE-MRI and CT demonstrated AUCs of 0.84 and 0.841, respectively (p = 0.98). Among the six models, mixed conventional, UTE-MRI, and CT Rad-score model showed the highest diagnostic performance (AUC = 0.879). In the survival analysis, the high- and low-risk groups were successfully divided by the Rad-score in UTE-MRI (p = 0.01) and CT (p < 0.01). CONCLUSION: UTE-MRI radiomic model predicting MP/S positivity is feasible compared with the CT radiomic model. Also, it was associated with early recurrence in the survival analysis. CLINICAL RELEVANCE STATEMENT: A radiomic model utilizing UTE-MRI, which does not present a radiation hazard, was able to successfully predict the histopathologic subtype of lung adenocarcinoma, and it was associated with the patient's recurrence-free survival. KEY POINTS: • No studies have reported the ultrashort echo time (UTE)-MRI-based radiomic model for lung adenocarcinoma. • The UTE-MRI Rad-score showed comparable diagnostic performance with CT Rad-score for predicting micropapillary and/or solid histopathologic pattern. • UTE-MRI is feasible not only for conventional radiologic analysis, but also for radiomics analysis.

Production of a 135-residue long N-truncated human keratinocyte growth factor 1 in Escherichia coli.

BACKGROUND: Palifermin (trade name Kepivance®) is an amino-terminally truncated recombinant human keratinocyte growth factor 1 (KGF-1) with 140 residues that has been produced using Escherichia coli to prevent and treat oral mucositis following radiation or chemotherapy. In this study, an amino-terminally shortened KGF-1 variant with 135 residues was produced and purified in E. coli, and its cell proliferation activity was evaluated. RESULTS: We expressed soluble KGF-1 fused to thioredoxin (TRX) in the cytoplasmic fraction of E. coli to improve its production yield. However, three N-truncated forms (KGF-1 with 140, 138, and 135 residues) were observed after the removal of the TRX protein from the fusion form by cleavage of the human enterokinase light chain C112S (hEKL C112S). The shortest KGF-1 variant, with 135 residues, was expressed by fusion with TRX via the hEKL cleavage site in E. coli and purified at high purity (> 99%). Circular dichroism spectroscopy shows that purified KGF-1135 had a structure similar to that of the KGF-1140 as a random coiled form, and MCF-7 cell proliferation assays demonstrate its biological activity. CONCLUSIONS: We identified variations in N-terminus-truncated KGF-1 and selected the most stable form. Furthermore, by a simple two-step purification, highly purified KGF-1135 was obtained that showed biological activity. These results demonstrate that KGF-1135 may be considered an alternative protein to KGF-1.

Visual Aura in Non-Migraine Headaches: A Population Study.

BACKGROUND: Visual aura (VA) occurs mostly in migraine with aura (MA), but some case studies have reported aura in non-migraine headaches. Thus, information of VA in non-migraine headaches is scarce. Aim of this study was to investigate the prevalence and impact of VA in non-migraine headache and compare it with that of migraine headache. METHODS: This study was a nationwide population-based study. We used an internet-based headache diagnosis questionnaire to diagnose headache, and various modules to evaluate clinical features and comorbidities of participants with headache. We defined migraine headache as migraine and probable migraine (PM), whereas non-migraine headache was defined as a headache but not migraine or PM. VA was defined as a self-reporting VA rating scale score ≥ 3. RESULTS: Of the 3,030 participants, 1,431 (47.2%) and 507 (16.7%) had non-migraine headache and migraine headache, respectively. VA prevalence was much lower in the non-migraine headache group than in the migraine headache group (14.5% [207/1,431] vs. 26.0% [132/507], P < 0.001). In subjects with non-migraine headache, those with VA had a markedly higher number of headache days per 30 days (median [25th-75th percentiles]: 2.0 [1.0-5.0] vs. 2.0 [1.0-3.0], P < 0.001), and headache-related disability (6.0 [3.0-16.0] vs. 2.0 [0.0-7.0], P < 0.001) than those without VA. VA prevalence did not differ significantly according to age and sex. CONCLUSION: Non-migraine headache with VA patients had more severe symptoms than those without VA. These findings may improve the understanding of VA and the management of individuals with non-migraine headache.

Genomic characteristics of invasive mucinous adenocarcinoma of the lung with multiple pulmonary sites of involvement.

Invasive mucinous adenocarcinoma (IMA) of the lung frequently presents with diffuse pneumonic-type features or multifocal lesions, which are regarded as a pattern of intrapulmonary metastases. However, the genomics of multifocal IMAs have not been well studied. We performed whole exome sequencing on samples taken from 2 to 5 regions in seven patients with synchronous multifocal IMAs of the lung (24 regions total). Early initiating driver events, such as KRAS, NKX2-1, TP53, or ARID1A mutations, are clonal mutations and were present in all multifocal IMAs in each patient. The tumor mutational burden of multifocal IMAs was low (mean: 1.13/mega base), but further analyses suggested intra-tumor heterogeneity. The mutational signature analysis found that IMAs were predominantly associated with endogenous mutational process (signature 1), APOBEC activity (signatures 2 and 13), and defective DNA mismatch repair (signature 6), but not related to smoking signature. IMAs synchronously located in the bilateral lower lobes of two patients with background usual interstitial pneumonia had different mutation types, suggesting that they were double primaries. In conclusion, genomic evidence found in this study indicated the clonal intrapulmonary spread of diffuse pneumonic-type or multifocal IMAs, although they can occur in multicentric origins in the background of usual interstitial pneumonia. IMAs exhibited a heterogeneous genomic landscape despite the low somatic mutation burden. Further studies are warranted to determine the clinical significance of the genomic characteristics of IMAs in expanded cohorts.

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle.

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.

Plant-derived human recombinant growth factors and serum albumin maintain stemness of human-induced pluripotent stem cells.

Stem cells are an important therapeutic source for recovery and regeneration, as their ability of self-renewal and differentiation offers an unlimited supply of highly specialized cells for therapeutic transplantation. Growth factors and serum are essential for maintaining the characteristics of stem cells in culture and for inducing differentiation. Because growth factors are produced mainly in bacterial (Escherichia coli) or animal cells, the use of such growth factors raises safety concerns that need to be resolved for the commercialization of stem cell therapeutics. To overcome this problem, studies on proteins produced in plants have been conducted. Here, we describe the functions of plant-derived fibroblast growth factor 2 (FGF2) and human serum albumin in the maintenance and differentiation of human-induced pluripotent stem cells (hiPSCs). Plant-derived FGF2 and human epidermal growth factor EGF were able to differentiate hiPSCs into neural stem cells (NSCs). These NSCs could differentiate into neuronal and glial cells. Our results imply that culturing stem cells in animal-free culture medium, which is composed of plant-derived proteins, would facilitate stem cell application research, for example, for cell therapy, by reducing contamination risk.

Synthetic Extracellular Volume Fraction Derived Using Virtual Unenhanced Attenuation of Blood on Contrast-Enhanced Cardiac Dual-Energy CT in Nonischemic Cardiomyopathy.

BACKGROUND. Current methods for calculating the myocardial extracellular volume (ECV) fraction require blood sampling to determine the serum hematocrit. Synthetic hematocrit and thus synthetic ECV may be derived using unenhanced attenuation of blood. By use of virtual unenhanced (VUE) attenuation of blood, contrast-enhanced dual-energy CT (DECT) may allow synthetic ECV calculations without unenhanced acquisition. OBJECTIVE. The purpose of this study was to compare synthetic ECV calculated using synthetic hematocrit derived from VUE images and conventional ECV calculated using serum hematocrit, both of which were obtained by contrast-enhanced DECT, with ECV derived from MRI used as the reference standard. METHODS. This retrospective study included 51 patients (26 men and 25 women; mean age, 59.9 ± 15.6 [SD] years) with nonischemic cardiomyopathy who, as part of an earlier prospective investigation, underwent equilibrium phase contrast-enhanced cardiac DECT and cardiac MRI and had serum hematocrit measured within 6 hours of both tests. A separate retrospective sample of 198 patients who underwent contrast-enhanced thoracic DECT performed on the same day for suspected pulmonary embolism and serum hematocrit measurement was identified to derive a synthetic hematocrit formula using VUE attenuation of blood by linear regression analysis. In the primary sample, two radiologists independently used DECT iodine maps to obtain the conventional ECV using serum hematocrit and the synthetic ECV using synthetic hematocrit based on the independently derived formula. The concordance correlation coefficient (CCC) was computed between conventional ECV and synthetic ECV from DECT. Conventional ECV and synthetic ECV from DECT were compared with the ECV derived from MRI in Bland-Altman analyses. RESULTS. In the independent sample, the linear regression formula for synthetic hematocrit was as follows: synthetic hematocrit = 0.85 × (VUE attenuation of blood) - 5.40. In the primary sample, the conventional ECV and synthetic ECV from DECT showed excellent agreement (CCC, 0.95). Bland-Altman analysis showed a small bias of -0.44% (95% limits of agreement, -5.10% to 4.22%) between MRI-derived ECV and conventional ECV from DECT as well as a small bias of -0.78% (95% limits of agreement, -5.25% to 3.69%) between MRI-derived ECV and synthetic ECV from DECT. CONCLUSION. Synthetic ECV and conventional ECV derived from DECT show excel lent agreement and a comparable association with ECV derived from cardiac MRI. CLINICAL IMPACT. Synthetic hematocrit from VUE attenuation of blood may allow myocardial tissue characterization on DECT without the inconvenience of blood sampling.

Effect of chitinase-3-like protein 1 on glucose metabolism: In vitro skeletal muscle and human genetic association study.

We investigated the effect of chitinase-3-like protein 1 (CHI3L1) on glucose metabolism and its underlying mechanisms in skeletal muscle cells, and evaluated whether the observed effects are relevant in humans. CHI3L1 was associated with increased glucose uptake in skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner, and with increased intracellular calcium levels via PAR2. The improvement in glucose metabolism observed in an intraperitoneal glucose tolerance test on male C57BL/6J mice supported this association. Inhibition of the CaMKK was associated with suppression of CHI3L1-mediated glucose uptake. Additionally, CHI3L1 was found to influence glucose uptake through the PI3K/AKT pathway. Results suggested that CHI3L1 stimulated the phosphorylation of AS160 and p38 MAPK downstream of AMPK and AKT, and the resultant GLUT4 translocation. In primary myoblast cells, stimulation of AMPK and AKT was observed in response to CHI3L1, underscoring the biological relevance of CHI3L1. CHI3L1 levels were elevated in cells under conditions that mimic exercise in vitro and in exercised mice in vivo, indicating that CHI3L1 is secreted during muscle contraction. Finally, similar associations between CHI3L1 and metabolic parameters were observed in humans alongside genotype associations between CHI3L1 and diabetes at the population level. CHI3L1 may be a potential therapeutic target for the treatment of diabetes.

Comparison of artery-based methods for ordinal grading of coronary artery calcium on low-dose chest computed tomography.

OBJECTIVES: To identify the optimal artery-based method for ordinal grading of coronary artery calcium (CAC) on non-electrocardiogram (ECG)-gated low-dose chest computed tomography (LDCT) among three methods. METHODS: A total of 120 asymptomatic subjects who underwent both LDCT and ECG-gated calcium scoring CT on the same day were retrospectively enrolled. Three cardiothoracic radiologists independently assessed CAC severity on LDCT (1.25-mm and 2.5-mm slice thickness) and classified it into four categories (none, mild, moderate, or severe) using three artery-based ordinal scoring methods (extent-based scoring, Weston scoring, and length-based scoring). Inter- and intra-observer CAC severity agreements of each method were assessed by Fleiss kappa statistics. Agreements between each method and ECG-gated calcium scoring CT were assessed by weighted kappa statistics. RESULTS: The inter-observer agreement was highest with length-based method for both 1.25-mm (Fleiss kappa 0.735 for extent-based method, 0.801 for Weston score, and 0.813 for length-based method) and 2.5-mm slice thickness evaluation (Fleiss kappa 0.755 for extent-based method, 0.776 for Weston score, and 0.833 for extent-based method). Agreement across the three grading methods for the same observer was poor to moderate on 1.25-mm (Fleiss kappa 0.379-0.441) and moderate on 2.5-mm thickness evaluation (Fleiss kappa 0.427-0.461). Agreement of CAC severity between each method and ECG-gated calcium scoring CT was highest with the length-based method for all three observers on both 1.25-mm (weighted kappa 0.773-0.786) and 2.5-mm (weighted kappa 0.794-0.825) LDCT images. CONCLUSION: Among the three artery-based ordinal grading methods, the length-based method appears to be the most reliable for evaluating CAC on non-ECG-gated LDCT. KEY POINTS: • The length-based method showed the highest inter-observer agreement and the highest agreement with the ECG-gated calcium scoring CT, compared with the extent-based method and the Weston score.

Effective production of human growth factors in Escherichia coli by fusing with small protein 6HFh8.

BACKGROUND: Growth factors (GFs) are signaling proteins that affect cellular processes such as growth, proliferation, and differentiation. GFs are used as cosmeceuticals, exerting anti-wrinkle, anti-aging, and whitening effects, and also as pharmaceuticals to treat wounds, growth failure, and oral mucositis. However, in mammalian and bacterial cells, low productivity and expression in inclusion bodies, respectively, of GFs does not satisfy the consumer demand. Here, we aimed to develop a bacterial expression system that produces high yields of soluble GFs that can be purified in their native forms. RESULTS: We present Fh8, an 8-kDa peptide from Fasciola hepatica with an N-terminal hexa-histidine (6HFh8), as a fusion partner for enhanced human GF production in recombinant Escherichia coli. The fusion partner harboring a tobacco etch virus (TEV) protease cleavage site was fused to the N-terminus of 10 human GFs: acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), epidermal growth factor (EGF), human growth hormone (hGH), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor 165 (VEGF165), keratinocyte growth factor 1 (KGF-1), placental growth factor (PGF), stem cell factor (SCF), and tissue inhibitor of metalloproteinase 1 (TIMP-1). The fusion proteins were expressed in E. coli under the control of T7 promoter at three temperatures (25 °C, 30 °C, and 37 °C). All individual fusion proteins, except for SCF and TIMP-1, were successfully overexpressed in cytoplasmic soluble form at more than one temperature. Further, the original aFGF, IGF-1, EGF, and VEGF165 proteins were cleaved from the fusion partner by TEV protease. Five-liter fed-batch fermentation approaches for the 6HFh8-aFGF (lacking disulfide bonds) and 6HFh8-VEGF165 (a cysteine-rich protein) were devised to obtain the target protein at concentrations of 9.7 g/l and 3.4 g/l, respectively. The two GFs were successfully highly purified (> 99% purity). Furthermore, they exerted similar cell proliferative effects as those of their commercial equivalents. CONCLUSIONS: We demonstrated that 6HFh8-GF fusion proteins could be overexpressed on a g/l scale in the cytoplasm of E. coli, with the GFs subsequently highly purified and maintaining their biological activity. Hence, the small protein 6HFh8 can be used for efficient mass-production of various GFs.

Ultrahigh-field cardiovascular magnetic resonance T1 and T2 mapping for the assessment of anthracycline-induced cardiotoxicity in rat models: validation against histopathologic changes.

BACKGROUND: Chemotherapy-induced cardiotoxicity is a well-recognized adverse effect of chemotherapy. Quantitative T1-mapping cardiovascular magnetic resonance (CMR) is useful for detecting subclinical myocardial changes in anthracycline-induced cardiotoxicity. The aim of the present study was to histopathologically validate the T1 and T2 mapping parameters for the evaluation of diffuse myocardial changes in rat models of cardiotoxicity. METHODS: Rat models of cardiotoxicity were generated by injecting rats with doxorubicin (1 mg/kg, twice a week). CMR was performed with a 9.4 T ultrahigh-field scanner using cine, pre-T1, post-T1 and T2 mapping sequences to evaluate the left ventricular ejection fraction (LVEF), native T1, T2, and extracellular volume fraction (ECV). Histopathological examinations were performed and the association of histopathological changes with CMR parameters was assessed. RESULTS: Five control rats and 36 doxorubicin-treated rats were included and classified into treatment periods. In the doxorubicin-treated rats, the LVEF significantly decreased after 12 weeks of treatment (control vs. 12-week treated: 73 ± 4% vs. 59 ± 9%, P = 0.01).  Increased native T1 and ECV were observed after 6 weeks of treatment (control vs. 6-week treated: 1148 ± 58 ms, 14.3 ± 1% vs. 1320 ± 56 ms, 20.3 ± 3%; P = 0.005, < 0.05, respectively). T2 values also increased by six weeks of treatment (control vs. 6-week treated: 16.3 ± 2 ms vs. 10.3 ± 1 ms, P < 0.05). The main histopathological features were myocardial injury, interstitial fibrosis, inflammation, and edema. The mean vacuolar change (%), fibrosis (%), and inflammation score were significantly higher in 6-week treated rats than in the controls (P = 0.03, 0.03, 0.02, respectively). In the univariable analysis, vacuolar change showed the highest correlation with native T1 value (R = 0.60, P < 0.001), and fibrosis showed the highest correlation with ECV value (R = 0.78, P < 0.001). In the multiple linear regression analysis model, vacuolar change was a significant factor for change in native T1 (P = 0.01), and vacuolar change and fibrosis were significant factors for change in ECV (P = 0.006, P < 0.001, respectively) by adding other histopathological parameters (i.e., inflammation and edema scores) CONCLUSIONS: Quantitative T1 and T2 mapping CMR is a useful non-invasive tool reflecting subclinical histopathological changes in anthracycline-induced cardiotoxicity.

Serial T1 mapping of right ventricle in pulmonary hypertension: comparison with histology in an animal study.

BACKGROUND: Right ventricular (RV) free wall fibrosis is an important component of adverse remodeling with RV dysfunction in pulmonary hypertension (PH). However, no previous reports have compared cardiovascular magnetic resonance (CMR) findings and histological analysis for RV free wall fibrosis in PH. We aimed to assess the feasibility of CMR T1 mapping with extracellular volume fraction (ECV) for evaluating the progression of RV free wall fibrosis in PH, and compared imaging findings to histological collagen density through an animal study. METHODS: Among 42 6-week-old Wistar male rats, 30 were classified according to disease duration (baseline before monocrotaline injection, and 2, 4, 6 and 8 weeks after injection) and 12 were used to control for aging (4 and 8 weeks after the baseline). We obtained pre and post-contrast T1 maps for native T1 and ECV of RV and left ventricular (LV) free wall for six animals in each disease-duration group. Collagen density of RV free wall was calculated with Masson's trichrome staining. The Kruskall-Wallis test was performed to compare the groups. Native T1 and ECV to collagen density were analyzed with Spearman's correlation. RESULTS: The mean values of native T1, ECV and collagen density of the RV free wall at baseline were 1541 ± 33 ms, 17.2 ± 1.3%, and 4.7 ± 0.5%, respectively. The values of RV free wall did not differ according to aging (P = 0.244, 0.504 and 0.331, respectively). However, the values significantly increased according to disease duration (P < 0.001 for all). Significant correlations were observed between native T1 and collagen density (r = 0.770, P < 0.001), and between ECV and collagen density for the RV free wall (r = 0.815, P < 0.001) in PH. However, there was no significant difference in native T1 and ECV values for the LV free wall according to the disease duration from the baseline (P = 0.349 and 0.240, respectively). CONCLUSIONS: We observed significantly increased values for native T1 and ECV of the RV free wall without significant increase of the LV free wall according to the disease duration of PH, and findings were well correlated with histological collagen density.

Subclinical cardiac perforation by cardiac implantable electronic device leads detected by cardiac computed tomography.

BACKGROUND: The relationship between the characteristics of cardiac implantable electronic device (CIED) leads and subclinical cardiac perforations remains unclear. This study aimed to evaluate the incidence of subclinical cardiac perforation among various CIED leads using cardiac computed tomography (CT). METHODS: A total of 271 consecutive patients with 463 CIED leads, who underwent cardiac CT after CIED implantation, were included in this retrospective observational study. Cardiac CT images were reviewed by one radiologist and two cardiologists. Subclinical perforation was defined as traversal of the lead tip past the outer myocardial layer without symptoms and signs related to cardiac perforation. We compared the subclinical cardiac perforation rates of the available lead types. RESULTS: A total of 219, 49, and 3 patients had pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy, respectively. The total subclinical cardiac perforation rate was 5.6%. Subclinical cardiac perforation by screw-in ventricular leads was significantly more frequent than that caused by tined ventricular leads (13.3% vs 3.3%, respectively, p = 0.002). There were no significant differences in the incidence of cardiac perforation between atrial and ventricular leads, screw-in and tined atrial leads, pacing and defibrillator ventricular leads, nor between magnetic resonance (MR)-conditional and MR-unsafe screw-in ventricular leads. Screw-in ventricular leads were significantly associated with subclinical cardiac perforation [odds ratio, 4.554; 95% confidence interval, 1.587-13.065, p = 0.005]. There was no case subclinical cardiac perforation by septal ventricular leads. CONCLUSIONS: Subclinical cardiac perforation by screw-in ventricular leads is not rare. Septal pacing may be helpful in avoiding cardiac perforation.

Usefulness of cardiac magnetic resonance images for prediction of sudden cardiac arrest in patients with mitral valve prolapse: a multicenter retrospective cohort study.

BACKGROUND: An association has been identified between mitral valve prolapse (MVP) and sudden cardiac arrest (SCA), and ventricular arrhythmias (VA). This study aimed to elucidate predictive factors for SCA or VA in MVP patients. METHODS: MVP patients who underwent cardiac magnetic resonance (CMR) were retrospectively included. Patients with other structural heart disease or causes of aborted SCA were excluded. Clinical characteristics (sex, age, body mass index, histories of diabetes, hypertension, and dyslipidemia) and electrocardiographic (PR interval, QRS duration, corrected QT interval, inverted T wave in the inferior leads, bundle branch block, and atrial fibrillation), echocardiographic [mitral regurgitation grade, prolapsing mitral leaflet, and right ventricular systolic pressure (RVSP)], and CMR [left atrial volume index, both ventricular ejection fractions, both ventricular end-diastolic and systolic volume indexes, prolapse distance, mitral annular disjunction, systolic curling motion, presence of late gadolinium enhancement (LGE), LGE volume and proportion] parameters were analyzed. RESULTS: Of the 85 patients [age, 54.0 (41.0-65.0) years; 46 men], seven experienced SCA or VA. Younger age and wide QRS complex were observed more often in the SCA/VA group than in the no-SCA/VA group. The SCA/VA group exhibited lower RVSP, more systolic curling motion and LGE, greater LGE volume, and higher LGE proportion. The presence of LGE [hazard ratio (HR), 19.8; 95% confidence interval (CI) 2.65-148.15; P = 0.004], LGE volume (HR 1.08; 95% CI 1.02-1.14; P = 0.006) and LGE proportion (HR 1.32; 95% CI 1.08-1.60; P = 0.006) were independently associated with higher risk of SCA or VA in MVP patients together with systolic curling motion in each model. CONCLUSIONS: The presence of systolic curling motion, high LGE volume and proportion, and the presence of LGE on CMR were independent predictive factors for SCA or VA in MVP patients.

Prognostic Value of Coronary Artery Disease-Reporting and Data System Score for Major Adverse Cardiac Events in Patients Attending the Emergency Department With Acute Chest Pain.

OBJECTIVE: This study aimed to compare the prognostic performance of Coronary Artery Disease (CAD)-Reporting and Data System (CAD-RADS) score with those of clinical risk factors and the extent of CAD classification for predicting major adverse cardiac events in emergency department patients. METHODS: A total of 779 patients with acute chest pain at low to intermediate risk for CAD underwent cardiac computed tomography angiography. The primary end point was early and late major adverse cardiac events. We developed the following models: model 1, clinical risk factors; model 2, clinical risk factors and CAD-RADS scores; model 3, clinical risk factors and extent of CAD. RESULTS: The C-statistics revealed that both CAD-RADS score and CAD extent improved risk stratification over the clinical risk factors (C-index for early events: C-index: 0.901 vs 0.814 and 0.911 vs 0.814; C-index for late events: 0.897 vs 0.808 and 0.905 vs 0.808; all P < 0.05). CONCLUSIONS: The CAD-RADS score had additional risk prediction benefits over clinical risk factors for emergency department patients.

ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by ß-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

Enhanced mating-type switching and sexual hybridization in heterothallic yeast Yarrowia lipolytica.

Yarrowia lipolytica is a non-conventional, heterothallic, oleaginous yeast with wide range of industrial applications. Increasing ploidy can improve advantageous traits for industrial applications including genetic stability, stress resistance, and productivity, but the construction of knockout mutant strains from polyploid cells requires significant effort due to the increased copy numbers of target genes. The goal of this study was to evaluate the effectiveness of a mating-type switching strategy by single-step transformation without a genetic manipulation vestige, and to optimize the conventional method for increasing ploidy (mating) in Y. lipolytica. In this study, mating-type genes in haploid Y. lipolytica cells were scarlessly converted into the opposite type genes by site-specific homologous recombination, and the resulting MATB-type cells were mated at low temperature (22°C) with addition of sodium citrate with each MATA-type haploid cell to yield a MATA/MATB-type diploid strain with genetic information from both parental strains. The results of this study can be used to increase ploidy and for whole genome engineering of a yeast strain with unparalleled versatility for industrial application.

Cardiotoxicity evaluation using magnetic resonance imaging in breast Cancer patients (CareBest): study protocol for a prospective trial.

BACKGROUND: Cardiovascular disease is second only to cancer recurrence as a determinant of lifespan in cancer survivors, and cancer therapy-related cardiac dysfunction is a clinically important risk factor. We aim to investigate the use of cardiac magnetic resonance imaging (MRI) to evaluate early tissue changes and perform functional assessment of chemo- and radiation-induced cardiotoxicity and to identify MRI prognostic indicators of cardiotoxicity in breast cancer patients. METHODS: A 3-min cardiac imaging protocol will be added to the breast MRI examination to diagnose cardiotoxicity in breast cancer patients. Standardized MRI-based evaluation of breast cancer and the left ventricular myocardium will be performed at baseline and at 3, 6, and 12 months and 2 years or more after cancer treatment. We will analyze both ventricular volume and ejection fraction (EF), strain of left ventricle (LV), native T1, extracellular volume fraction (ECV), and T2 values acquired in the mid LV. DISCUSSION: The primary result of this study will be the comparison of the prognostic value of MRI parameters (native T1, ECV, both ventricular systolic function and LV strain) for cardiotoxicity. The endpoint is defined as the occurrence of a major adverse cardiac event (MACE). The secondary outcome will be an assessment of the temporal relationships between contractile dysfunction and microstructural injury over 4 years using MRI. This study will assess the usefulness of quantitative MRI to diagnose cardiotoxicity and will clarify the temporal relationships between contractile dysfunction and microstructural injury of the LV myocardium using MRI during breast cancer treatment. TRIAL REGISTRATION: The protocol was registered at clinicaltrials.gov (Clinical trial no. NCT03301389) on October 4, 2017.