Children with Hutchinson-Gilford progeria syndrome (HGPS) succumb to myocardial infarction and stroke in their teen years. Endothelial dysfunction is an early event in more common forms of atherosclerosis. Endothelial pathobiology may contribute to HGPS, but a comprehensive characterization of endothelial function in HGPS has not been performed. iPSCs derived from fibroblasts of HGPS patients or unaffected relatives were differentiated into endothelial cells (ECs). Immunofluorescent signal of the pluripotent stem cell markers SSEA4, Oct4, Sox2 and TRAI-60 was similar in HGPS or control iPSCs. Following the differentiation, FACS analysis and immunocytochemistry for CD31 and CD144 revealed a smaller percentage of ECs from HGPS iPSCs. Immunostaining for Lamin A revealed nuclear dysmorphology in HGPS iPSC-ECs. Furthermore, these cells were significantly larger and rounded, and they proliferated less, features which are typical of senescent endothelial cells. HGPS iPSC-ECs manifested less Dil-Ac-LDL uptake; less DAF-2DA staining for nitric oxide generation and formed fewer networks in matrigel in vitro. In immunodeficient mice injected with iPSC-ECs, HGPS iPSC-ECs generated a sparser vascular network compared to the control, with reduced capillary number. Telomere length (T/S ratio) of HGPS iPSC-EC was reduced as assessed by mmqPCR. iPSC-ECs derived from HGPS patients have dysmorphic appearance, abnormal nuclear morphology, shortened telomeres, reduced replicative capacity and impaired functions in vitro and in vivo. Targeting the endothelial abnormality in patients with HGPS may provide a new therapeutic avenue for the treatment of this condition. Abbreviations: HGPS: Hutchinson-Gilford progeria syndrome; ZMPSTE24: Zinc metallopeptidase STE24; FTI: Farnesyltransferase inhibitors; VSMCs: Vascular smooth muscle cells; iPSC: Induced pluripotent stem cells; EC: Endothelial cells; hTERT: Human telomerase reverse transcriptase; VEGF: vascular endothelial growth factor; DAF-FM DA: 3-Amino, 4-aminomethyl-2',7'-difluorofluorescein diacetate; BMP4: Bone Morphogenetic Protein 4; mmqPCR: mono chrome multiplex PCR; SCG: single-copy gene; CSI: Cell shape index.

OBJECTIVE

Recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) is mainly due to PV reconnections. Patient-specific tissue characteristics that may contribute remain unidentified. This study aimed to assess the relationship between the bipolar electrogram voltage amplitudes recorded from the PV-left atrial (LA) junction and acute PV reconnection sites.

METHODS

Three-dimensional LA voltage maps created before an extensive encircling PVI in 47 AF patients (31 men; mean age 62 ± 11 years) were examined for an association between the EGM voltage amplitude recorded from the PV-LA junction and acute post-PVI PV reconnections (spontaneous PV reconnections and/or ATP-provoked dormant PV conduction).

RESULTS

Acute PV reconnections were observed in 17 patients (36%) and in 24 (3%) of the 748 PV segments (16 segments per patient) and were associated with relatively high bipolar voltage amplitudes (3.26 ± 0.85 vs. 1.79 ± 1.15 mV, p < 0.0001) and a relatively low mean force-time integral (FTI) (428 ± 56 vs. 473 ± 76 gs, p = 0.0039) as well as FTI/PV-LA bipolar voltage (137 [106, 166] vs. 295 [193, 498] gs/mV, p < 0.0001). An analysis of the receiver operating characteristic curves revealed a high prognostic performance of the LA bipolar voltage and FTI/PV-LA bipolar voltage for acute PV reconnections (areas under the curve: 0.86 and 0.89, respectively); the best cutoff values were >2.12 mV and ≤183 gs/mV, respectively.

CONCLUSIONS

The PV-LA voltage on the PV-encircling ablation line and FTI/PV-LA voltage were related to the acute post-PVI PV reconnections. A more durable ablation strategy is warranted for high-voltage zones.

BACKGROUND

A novel real-time lesion size index (LSI) that incorporates contact force (CF), time, and power has been developed for safe and effective catheter ablation. The optimal LSI was evaluated to eliminate gap formation during pulmonary vein isolation (PVI).

RESULTS

Consecutive patients were enrolled, who underwent their first PVI using a fiber-optic CF-sensing catheter for atrial fibrillation between December 2016 and October 2017. The CF parameters, force-time integral (FTI), and LSI for 3095 ablation points in 34 patients were evaluated. The FTI and LSI in the lesions with gaps or dormant conduction (gaps/DC) were significantly lower than those in the lesion without gaps/DC (FTI: 140.5 ± 54.5 and 232.4 ± 121.4 g s, P < 0.0001; LSI: 4.0 ± 0.6 and 4.7 ± 0.9, P < 0.0001, respectively). On receiver operating characteristic curve analysis, the optimal LSI threshold was 4.05 (sensitivity, 63.4%; specificity, 76.3%). The LSI of <5.25 predicted a gap or DC with a high sensitivity (sensitivity, 97.6%; specificity, 25.7%). In the posterior wall, which was 37% thinner than the nonposterior wall, a lower LSI of <3.95 showed a relatively high sensitivity (92.3%) and specificity (65.6%).

CONCLUSIONS

The LSI can be used to predict gaps/DC during the PVI procedure. An LSI of 5.2 may be a suitable target for effective lesion formation. An LSI of 4.0 may be acceptable in the posterior wall, especially in areas adjacent to the esophagus.

We have recently reported that CXCR7, the alternate high affinity SDF-1 receptor, is induced during monocyte-to-macrophage differentiation, leading to increased macrophage phagocytosis linked to atherosclerosis. Statins, the most widely used medications for atherosclerosis, were shown to have pleiotropic beneficial effects independent of their cholesterol-lowering activity. This study aimed to determine whether induction of CXCR7 during macrophage differentiation is inhibited by statins and its significance on macrophage physiology. Here we show for the first time that atorvastatin dose-dependently inhibited CXCR7 mRNA and protein expression in THP-1 macrophages, without affecting the other SDF-1 receptor, CXCR4. Pharmacotherapy relevant dose of atorvastatin affected neither cell viability nor macrophage differentiation. Suppression of CXCR7 expression was completely reversed by supplementation with mevalonate. Inhibition of squalene synthase, the enzyme committed to cholesterol biosynthesis, also decreased CXCR7 induction, albeit not as efficacious as atorvastatin. However, the geranylgeranyl transferase inhibitor, GGTI-286, the farnesyl transferase inhibitor, FTI-276, and the Rho kinase inhibitor, Y-27632, all failed to mimic the effect of atorvastatin, suggesting that the protein prenylation pathways are not critical for atorvastatin inhibition of CXCR7 induction. Interestingly, the dramatic effect of atorvastatin was only partially mimicked by other statins including pravastatin, fluvastatin, mevastatin, and simvastatin. Furthermore, activation of CXCR7 by SDF-1, TC14012, or I-TAC all prompted macrophage migration, which was significantly suppressed by atorvastatin treatment, but not by the CXCR4 antagonist. We conclude that atorvastatin modulates macrophage migration by down-regulating CXCR7 expression, suggesting a new CXCR7-dependent mechanism of atorvastatin to benefit atherosclerosis treatment beyond its lipid lowering effect.

Mast cells are the major effector cells in immunoglobulin E (IgE)-mediated allergy. The high affinity IgE receptor FcεRI, as well as G protein-coupled receptors (GPCRs) on the mast cell surface signals to phosphoinositide 3-kinase γ (PI3Kγ) to initiate degranulation, cytokine release, and chemotaxis. PI3Kγ is therefore considered as a target for treatment of allergic disorders. However, leukocyte PI3Kγ is key to many functions in innate and adaptive immunity, and attenuation of host defense mechanisms is an expected adverse effect that complicates treatment of chronic illnesses. PI3Kγ operates as a p110γ/p84 or p110γ/p101 complex, where p110γ/p84 requires Ras activation. Here we investigated if modulation of Ras-isoprenylation could target PI3Kγ activity to attenuate PI3Kγ-dependent mast cell responses without impairment of macrophage functions. In murine bone marrow-derived mast cells, GPCR stimulation triggers activation of N-Ras and H-Ras isoforms, which is followed by the phosphorylation of protein kinase B (PKB/Akt) relayed through PI3Kγ. Although K-Ras is normally not activated in Ras wild-type cells, it is able to compensate for genetically deleted N- and H-Ras isoforms. Inhibition of Ras isoprenylation with farnesyltransferase inhibitor FTI-277 leads to a significant reduction of mast cell degranulation, cytokine production, and migration. Complementation experiments expressing PI3Kγ adaptor proteins p84 or p101 demonstrated a differential sensitivity towards Ras-inhibition depending on PI3Kγ complex composition. Mast cell responses are exclusively p84-dependent and were effectively controlled by FTI-277. Similar results were obtained when GTP-Ras was inactivated by overexpression of the GAP-domain of Neurofibromin-1 (NF-1). Unlike mast cells, macrophages express p84 and p101 but are p101-dominated and thus remain functional under treatment with FTI-277. Our work demonstrates that p101 and p84 have distinct physiological roles, and that Ras dependence of PI3Kγ signaling differs between cell types. FTI-277 reduces GPCR-activated PI3Kγ responses in p84-expressing but not p101-containing bone marrow derived cells. However, prenylation inhibitors have pleiotropic effects beyond Ras and non-tolerable side-effects that disfavor further clinical validation. Statins are, however, clinically well-established drugs that have previously been proposed to block mast cell degranulation by interference with protein prenylation. We show here that Simvastatin inhibits mast cell degranulation, but that this does not occur via Ras-PI3Kγ pathway alterations.

Keywords: IgE (Immunoglobulin E); PIK3CG; Ras family proteins; allergy; inflammation; p101; p84; phosphoinositide-3-kinase (PI3K).

Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a disorder of premature ageing caused by mutation of the lamin A gene, the same causal gene involved in Hutchinson-Gilford syndrome (HGS). We previously reported the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). Recently, it has been reported that UVA induced abnormal truncated form of lamin A, called progerin, as well as HGS-like abnormal nuclear structures in normal human fibroblasts, being more frequent in the elderly, suggesting that lamin A may be involved in the regulation of photoageing. The objective of this study was to elucidate the sensitivity to cell damage induced by oxidative stress or UVA in fibroblasts from APS/AWS patient. Using immunofluorescence staining and flow cytometry analysis, the amount of early apoptotic cells and degree of intra-cellular reactive oxygen species (ROS) generation were higher in H2 02 - or UVA-treated APS/AWS fibroblasts than in normal fibroblasts, suggesting that repeated UV exposure may induce premature ageing of the skin in APS/AWS patients and that protecting against sunlight is possibly important for delaying the emergence of APS/AWS symptoms. In addition, we demonstrated that H2 O2 -, or UVA-induced apoptosis and necrosis in normal and APS/AWS fibroblasts were enhanced by farnesyltransferase inhibitor (FTI) treatment, indicating that FTI might not be useful for treating our APS/AWS patient.

Little is known about respiratory morbidity and asthma risk in preterm infants (PTIs) with a gestational age (GA) over 32 weeks. This was a prospective study carried out from birth to 7-8 years, comparing two groups: (a) PTIs (GAs 32 weeks + 1 day to 35 weeks + 0 days, without comorbidities) and (b) full-term infants (FTIs; GA ≥ 37 weeks). Risk and protective factors for bronchiolitis and asthma were identified. A total of 232 children (116/group) were included. Sixty-six (56.9%) PTIs and 43 (37.1%) FTIs presented bronchiolitis (p = 0.002). Recurrent wheezing was 52 (44.8%) on PTIs versus 36 (31.0%) on FTIs (p = 0.03). Asthma at school aged was 27 (23.3%) on PTIs and 8 (6.9%) on FTIs (p = 0.020). Asthma risk factors were only detected in group A.Conclusion: PTIs had a higher prevalence of bronchiolitis, recurrent wheezing and asthma; risk factors for asthma are the following: older siblings, allergic father, atopic dermatitis and antibiotic treatment in the first 3 years of life and prematurity itself, which also acted as protective factor for atopic dermatitis. What is known: • In recent decades, there has been a significant increase in the birth of premature babies and consequently, also in the pathologies secondary to the prematurity: a greater number of complications and disorders related to the development and maturation of many organs and systems, especially the respiratory system. Several studies, especially in full-term infants and very preterm infants, have tried to elucidate the risk factors that may influence the development of persistent or chronic respiratory problems such asasthma, but little is known about the aetiology of these disorders in the late or moderate preterm infants. Inthis group of children, the role played by certain factors (early use of antibiotics, chorioamnionitis, smokeexposure, paternal asthma, etc.) on late respiratory morbidity, or asthma, is inconclusive. • Moderate-to-late preterm infants are more predisposed to developing recurrent wheezing/asthma and should adopt control measures. What is new: • Our work provides data related to little-understood aspects of respiratory diseases in this group of late or moderate preterm infants (gestational age between 32 weeks plus 1 day and 35 weeks plus 0 days), by monitoring their evolution from birth to 7-8 years of age, compared with another group of full-term newborns. We aimed to establish the prevalence of bronchiolitis and recurrent wheezing in these children during their first years of life. • The prevalence of school-aged asthma and the risk factors for contracting it were also investigated.

Thyroid incidentalomas (TIs) are being frequently detected on positron emission tomography (PET) scan. The risk of malignancy in these focal hot spots is substantially high as compared to incidentalomas detected on ultrasonography (USG)/magnetic resonance imaging/computed tomography (CT). Majority of the studies on the prevalence of TIs in PET and the risk of malignancy in them are retrospective and have had varied results. Very few prospective studies are available and very few Indian studies have been done on the subject. Hence, this study was undertaken to evaluate the clinical significance of TIs detected on fluorodeoxyglucose (FDG)-PET scan. The study included all patients undergoing FDG-PET scan for nonthyroid illness from October 2015 to October 2016. Twenty-three consecutive patients detected to have focal TI (FTI) were prospectively evaluated with detailed history and clinical examination, serum thyroid-stimulating hormone, total T4 and total T3 levels, USG neck, fine-needle aspiration cytology (FNAC), and surgery when indicated. The prevalence of FTI was 2.26%. Out of the 23 FTI cases, 19 patients agreed to undergo further evaluation and malignancy was detected in 5 patients (all papillary carcinomas) making a risk of malignancy of 26.3%. There was no significant correlation between CT attenuation characteristics and size of benign and malignant PETomas or between the maximum standardized uptake value (SUV_max) of benign and malignant PETomas. Hence, the risk of malignancy in thyroid PETomas is substantially high and warrants USG-guided FNAC and further work-up. Their SUV_maxvalues, size, and CT attenuation characteristics do not contribute in differentiating benign from malignant lesions.

Background: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder with complex pathogenesis. This study aimed to analyze the expression of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor-II (IGF-II) in patients with PCOS and its correlation with pregnancy outcomes.

Methods: A total of 104 PCOS patients admitted to the Cangzhou Central Hospital from January 2015 to February 2018 were selected as the PCOS group, and 92 healthy pregnant women who received health examinations in the hospital during the same period were selected as the control group. Levels of PDGF, EGF, and IGF-II in serum were detected. The expression of PDGF, EGF, and IGF-II in different populations were compared. Age at pregnancy, body mass index (BMI), waist-to-hip ratio before pregnancy, parity, family history of hypertension, family history of diabetes, and serological indicators of pregnant women in the PCOS group were collected, such as follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), fasting insulin (INS), and free testosterone index (FTI). Multivariate logistic regression was used to analyze the risk factors that affect the pregnancy outcomes of PCOS patients.

Results: The expression levels of PDGF, EGF, and IGF-II in the PCOS group were significantly higher than those in the control group (P<0.05). Among 76 pregnant PCOS patients, 34 cases had adverse pregnancy outcomes and 42 did not. Age at pregnancy, BMI before pregnancy, waist-to-hip ratio before pregnancy, LH, INS, FTI, PDGF, EGF, and IGF-II expression levels were positively correlated with the pregnancy outcome of PCOS patients (P<0.05). The BMI before pregnancy, waist-to-hip ratio before pregnancy, INS, FTI, and expression levels of PDGF, EGF, and IGF-II were revealed as independent risk factors that affect the pregnancy outcomes of PCOS patients (P<0.05).

Conclusions: The expression levels of PDGF, EGF, and IGF-II are high in PCOS patients. The BMI, waist-to-hip ratio before pregnancy, INS, FTI, and the expression levels of PDGF, EGF, IGF-II are independent risk factors that affect the pregnancy outcomes of PCOS patients. Corresponding measures should be actively taken for PCOS patients with high-risk factors to improve both maternal and infant outcomes.

Keywords: Platelet-derived growth factor (PDGF); epidermal growth factor (EGF); insulin-like growth factor-II (IGF-II); polycystic ovary syndrome (PCOS); pregnancy outcomes.

Aim: Magnesium (Mg) deficiency (known as grass tetany) is a serious metabolic disorder that affects grazing ruminants. We tested whether Mg-fertiliser can increase Mg concentration of Italian ryegrasses (Lolium multiflorum L.) including a cultivar (cv. Bb2067; 'Magnet'), bred to accumulate larger concentrations of Mg.

Methods: Under controlled environment (CE) conditions, three cultivars (cv. Bb2067, cv. Bb2068, cv. RvP) were grown in low-nutrient compost at six fertiliser rates (0-1500 μM MgCl₂.6H₂O). Under field conditions, the three cultivars in the CE condition and cv. Alamo were grown at two sites, and four rates of MgSO₄ fertiliser application rates (0-200 kg ha^-1 MgO). Multiple grass cuts were taken over two-years.

Results: Grass Mg concentration increased with increasing Mg-fertiliser application rates in all cultivars and conditions. Under field conditions, cv. Bb2067 had 11-73% greater grass Mg concentration and smaller forage tetany index (FTI) than other cultivars across the Mg-fertiliser application rates, sites and cuts. Grass dry matter (DM) yield of cv. Bb2067 was significantly (p < 0.05) smaller than cv. Alamo. The effect of Mg-fertiliser rate on DM yield was not significant (p ≥ 0.05).

Conclusions: Biofortification of grass with Mg through breeding and agronomy can improve the forage Mg concentration for grazing ruminants, even in high-growth spring grass conditions when hypomagnesaemia is most prevalent. Response to agronomic biofortification varied with cultivar, Mg-fertiliser rate, site and weather. The cost:benefit of these approaches and farmer acceptability, and the impact on cattle and sheep grazing on grasses biofortified with Mg requires further investigation.

Keywords: Forage tetany index (FTI); Grass staggers; Hypomagnesaemia; Italian ryegrass; Magnesium chloride; Magnesium sulphate.

Background and objectives: Data concerning vaspin in obstetric aspects are limited and conflicting. The aim of the study was to evaluate vaspin concentrations in the serum and urine of women with excessive gestational weight gain (EGWG) in the early post-partum period (i.e., 48 h after delivery), when placental function no longer influences the results. Materials and Methods: The study subjects were divided into two groups of 28 healthy controls and 38 mothers with EGWG. Maternal body composition and hydration status were evaluated by the bioelectrical impedance analysis (BIA) method. Concentrations of vaspin, fatty acid-binding protein 4 (FABP4), leptin, and ghrelin were determined via enzyme-linked immunosorbent assay (ELISA). Results: Serum vaspin levels were lower in the EGWG group, whereas no significant differences were noted between the groups, with regard to the urine vaspin concentrations. In both studied groups, the serum vaspin concentrations correlated positively with the urine FABP4 levels and negatively with gestational weight gain, body mass index gain in the period from pre-pregnancy to 48 h after delivery (ΔBMI), and fat tissue index (FTI). In the multiple linear regression models, the serum vaspin concentrations were positively dependent on the serum FABP4 levels, as well as negatively dependent on triglycerides, FTI, and ΔBMI. Conclusions: Our study revealed that the EGWG mothers were characterized by significantly lower serum vaspin concentrations in the early post-partum period compared with the subjects that had appropriate gestational weight gain. Our observation supports previous hypotheses that vaspin might be used as a marker of lipid metabolism in pregnancy and maternal adipose tissue. Considering the fact that FABP4 is widely referred to as a pro-inflammatory adipokine, further research on the protective role of vaspin seems crucial, especially in the context of its relationship to FABP4.

Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability.

Abbreviations: 3D: three-dimensional; APC/C: anaphase-promoting complex; ARL8B: ADP ribosylation factor like GTPase 8B; ATG: autophagy-related; BORC: BLOC-one-related complex; CDK: cyclin-dependent kinase; CENPE: centromere protein E; CIN: chromosomal instability; ConcA: concanamycin A; CQ: chloroquine; DAPI: 4,6-diamidino-2-penylinole; FTI: farnesyltransferase inhibitors; GFP: green fluorescent protein; H2B: histone 2B; KIF: kinesin family member; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; PDS5B: PDS5 cohesin associated factor B; SAC: spindle assembly checkpoint; PLEKHM2: pleckstrin homology and RUN domain containing M2; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; v-ATPase: vacuolar-type H⁺-translocating ATPase; WAPL: WAPL cohesion release factor.

Keywords: Chromosomal instability; chromosomes segregation; lysosome; mitosis; selective autophagy; toroidal nucleus.

OBJECTIVE

To investigate the relationship among serum reproductive hormone levels, serum homocysteine (Hcy) levels, metabolic syndrome (MS), and the components of MS in middle-aged and elderly males.

METHODS

Using the cluster and stratified sampling methods and a unified structured questionnaire, we conducted a survey among 948 men aged 40 - 80 years in the rural community, measured their basic physical parameters, and obtained their reproductive hormone levels, serum Hcy concentrations, and metabolism-related indicators. We collected 868 valid questionnaires along with their serum samples, divided the subjects into an MS and a non-MS control group in a 1:1 ratio, and measured their serum Hcy concentrations.

RESULTS

Among the subjects included, 132 were diagnosed with MS. Nonparametric tests showed statistically significant differences between the MS and non-MS groups in the waist circumference (WC), waist-hip ratio (WHR), body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) (P < 0.05), but not in age (P>> 0.05). Significant differences were also observed between the two groups in the levels of serum tT, SHBG, LH, and FTI (P < 0.05) , but not in the concentrations of serum Hcy (P>> 0.05). The concentration of serum Hcy exhibited no correlation with BMI, SBP, DBP, FBG, TG, and HDL-C (P>> 0.05) and had no influence on MS.

CONCLUSIONS

The concentration of serum Hcy is not significantly correlated with MS, nor with its components. The levels of male serum reproductive hormones are associated both with MS and with its components.

Background: Although ablation energy (AE) and force-time integral (FTI) are well-known active predictors of lesion characteristics, these parameters do not reflect passive tissue reactions during ablation, which may instead be represented by drops in local impedance (LI). This study aimed to investigate if additional LI data improves predicting lesion characteristics and steam pops.

Methods: RF applications at a range of powers (30 W, 40 W, and 50 W), contact forces (8 g, 15 g, 25 g, and 35 g), and durations (10-180 s) using perpendicular/parallel catheter orientations were performed in excised porcine hearts (N = 30). The correlation between AE, FTI, and lesion characteristics was examined, and the impact of LI (%LI drop (%LID) defined by the ΔLI divided by the initial LI) was additionally assessed.

Results: Three hundred seventy-five lesions without steam pops were examined. Ablation energy (W × s) and FTI (g × s) showed a positive correlation with lesion depth (ρ = 0.824:P < 0.0001 and ρ = 0.708:P < 0.0001), surface area (ρ = 0.507:P < 0.0001 and ρ = 0.562:P < 0.0001), and volume (ρ = 0.807:P < 0.0001 and ρ = 0.685:P < 0.0001). %LID also showed a positive correlation individually with lesion depth (ρ = 0.643:P < 0.0001), surface area (ρ = 0.547:P < 0.0001), and volume (ρ = 0.733:P < 0.0001). However, the combined indices of AE × %LID (AE multiplied by %LID) and FTI × %LID (FTI multiplied by %LID) provided significantly stronger correlation with lesion depth (ρ = 0.834:P < 0.0001 and ρ = 0.809:P < 0.0001), surface area (ρ = 0.529:P < 0.0001 and ρ = 0.656:P < 0.0001), and volume (ρ = 0.864:P < 0.0001 and ρ = 0.838:P < 0.0001). This tendency was observed regardless of the catheter placement (parallel/perpendicular). AE (P = 0.02) and %LID (P = 0.002) independently remained as significant predictors to predict steam pops (N = 27). However, the AE × %LID did not increase the predictive power of steam pops compared to the AE alone.

Conclusion: LI, when combined with conventional parameters (AE and FTI), may provide stronger correlation with lesion characteristics.

Keywords: Catheter ablation; Contact force; Impedance; Lesion; Power; Radiofrequency.

We discuss detection strategies for fractional topological insulators (FTIs) realizing time-reversal invariant analogues of fractional quantum Hall systems in the Laughlin universality class. Focusing on transport measurements, we study the effect of magnetic perturbations on the edge modes. We find that the modes show unexpected robustness against magnetic backscattering for moderate couplings and edge interactions, allowing for various phase transitions signaling the FTI phase. We also describe protocols for extracting the universal integer m characterizing the phase and the edge interaction parameter from the conductance of setups with magnets and a quantum point contact.

Objective: This study aimed to determine the relationship between serum testosterone levels and depressive symptoms in an adult male population.

Methods: We conducted a cross-sectional study of 1166 male participants from Zunyi, Guizhou, China. Each participant completed a questionnaire, a brief clinical exam, and had a fasting blood sample taken. We measured serum testosterone, sex hormone-binding globulin, and luteinizing hormone levels. Multiple linear regression was used to evaluate the effect of demographic factors on the relationship between the depressive symptom score and serum sex hormone levels.

Results: Mean testosterone, sex hormone-binding globulin, and luteinizing hormone levels were significantly higher in the depressive symptom group than in the non-depressed group. The mean calculated free serum testosterone level and free testosterone index (FTI) were significantly lower in the depressive symptom group than in the non-depressed group. Additionally, the mean FTI was significantly negatively correlated with the Beck Depression Inventory scale score in the multiple linear regression model (95% confidence interval: -3.274 to -0.406).

Conclusions: Decreased bioactive testosterone levels might be a contributing factor of depression in adult men. The FTI could be the most sensitive biomarker reflecting the level of bioavailable testosterone in patients with depression.

Keywords: Beck Depression Inventory scale; Depression; adult men; free testosterone index; luteinizing hormone; sex hormone.

UNASSIGNED

The clinical impact of a decrease in impedance during radiofrequency catheter ablation (RFCA) has not been fully clarified. The aim of the study was to analyze the impact of impedance decrease and to determine its optimal cutoff value during RFCA.

UNASSIGNED

We evaluated 34 consecutive patients (total 3264 lesions, mean age 66 ± 8.7 years, 10 females) who underwent their first ablation for atrial fibrillation (AF). The impedance decrease, average contact force (CF), application time, force-time integral (FTI), product of impedance decrease and application time (PIT), and the product of impedance decrease and FTI (PIFT) were measured for all lesions. Levels of cardiac troponin I (TrpI) were measured for assessment of myocardial injury. The incidence of intraprocedural pulmonary vein-left atrium reconnection or dormant conduction (reconnection) was determined. The relationships between the ablation parameters and the increase in TrpI (ΔTrpI) were evaluated. The predictive value of the parameters for reconnection was assessed using receiver operating characteristic (ROC) curve analysis.

UNASSIGNED

Reconnection was detected in 18 patients. Average FTI and PIT were significantly correlated with ΔTrpI (FTI: r2 = .19, P = .0090, PIT: r2 = .21, P = .0058). PIFT was correlated with ΔTrpI and was the best of the three indexes (PIFT: r2 = .29, P = .0010). In ROC curve analysis, the area under the curve for predicting reconnection was 0.71 and the optimal cutoff value was 5200 for PIFT (sensitivity 78%, specificity 63%).

UNASSIGNED

The combination of CF and a decrease in impedance could be important in the evaluation of myocardial lesions and reconnection during RFCA.

The aim of this study was to design an algorithm to quantify the plantar force transference of children from ages 2-6. In total, 319 healthy children without abnormal gait patterns, foot deformities or injuries, able to walk independently, and with normal BMIs were recruited, and their plantar force distributions were measured. Their plantar areas were divided into ten parts: the hallux, toes #2-5, the first to fifth metatarsal heads (1st-5th MTH), the mid-foot (MF), medial heel (MH) and lateral heel (LH), in which a relative force-time integral (FTIrel) (%) was calculated. Our results show that the FTIrel was significantly transferred along either the transverse or longitudinal arches. The middle of the forefoot and the toe areas were the two main loading regions in children aged 2-3, and posterior to anterior FTIrel shifting was typical. However, anterior to posterior and lateral to medial FTI transferences were found in children aged 5-6, and major loading was found in the heel area. Further, loading in the mid-foot varied with the child's development and was observed to tend to decrease over time. Overall, according to the algorithm designed in this study, these results demonstrated that the development of the arches, both in transverse and longitudinal directions, had already begun in early stages of toddlerhood. Meanwhile, the arches were an important attractor engaged in the windlass mechanism while walking, and they played a major role as bridges to promote posterior to anterior and medial to lateral force transference.

Metformin is a well-known AMPK (AMP-activated protein kinase) activator that suppresses cancer stem cells (CSCs) in some cancers. However, the mechanisms of the CSC-suppressing effects of metformin are not yet well understood. In this study, we investigated the CSC-suppressive effect of metformin via the mevalonate (MVA) pathway in colorectal cancer (CRC). Two colorectal cancer cell lines, HT29 and DLD-1 cells, were treated with metformin, mevalonate, or a combination of the two. We measured CSC populations by flow cytometric analysis (CD44+/CD133+) and by tumor spheroid growth. The expression of p-AMPK, mTORC1 (pS6), and key enzymes (HMGCR, FDPS, GGPS1, and SQLE) of the MVA pathway was also analyzed. We investigated the effects of metformin and/or mevalonate in xenograft mice using HT29 cells; immunohistochemical staining for CSC markers and key enzymes of the MVA pathway in tumor xenografts was performed. In both HT29 and DLD-1 cells, the CSC population was significantly decreased following treatment with metformin, AMPK activator (AICAR), HMG-CoA reductase inhibitor (simvastatin), or mTOR inhibitor (rapamycin), and was increased by mevalonate. The CSC-suppressing effect of these drugs was attenuated by mevalonate. The results of tumor spheroid growth matched those of the CSC population experiments. Metformin treatment increased p-AMPK and decreased mTOR (pS6) expression; these effects were reversed by addition of mevalonate. The expression of key MVA pathway enzymes was significantly increased in tumor spheroid culture, and by addition of mevalonate, and decreased upon treatment with metformin, AICAR, or rapamycin. In xenograft experiments, tumor growth and CSC populations were significantly reduced by metformin, and this inhibitory effect of metformin was abrogated by combined treatment with mevalonate. Furthermore, in the MVA pathway, CSC populations were reduced by inhibition of protein prenylation with a farnesyl transferase inhibitor (FTI-277) or a geranylgeranyl transferase inhibitor (GGTI-298), but not by inhibition of cholesterol synthesis with a squalene synthase inhibitor (YM-53601). In conclusion, the CSC-suppressive effect of metformin was associated with AMPK activation and repression of protein prenylation through MVA pathway suppression in colorectal cancer.

Keywords: cancer stem cells; colorectal cancer; metformin; mevalonate pathway; protein prenylation.

Aim: Assess the association and predictive value of geriatric nutritional risk index (GNRI), body composition, and bone mineral density (BMD) in hemodialysis (HD) patients.

Methods: Laboratory data, body composition parameters measured via body composition monitor, and radius, lumbar spine, femoral neck BMD measured using dual energy X-ray absorptiometry were assessed in all subjects on HD or online hemodiafiltration (HDF) at baseline. Regression analysis for GNRI, Cox proportional hazard analyses and comparison of multiple receiver operating characteristic (ROC) curves were performed.

Results: Among all 264 patients, age was 65±12 years and dialysis vintage was 79 (39-144) months. GNRI tertile (T)1, T2, and T3 were 88 (85-91), 94 (93-95), and 98 (97-101), respectively. Patients in GNRI T1 had lower fat tissue index (FTI), lean tissue index, and femoral neck, lumbar spine, and distal mid-third radius BMD, but higher overhydration/extracellular fluid than patients in GNRI T2 or T3 (P<0.05). GNRI was significantly associated with FTI, lean tissue index, and femoral neck, lumbar spine, and distal mid-third radius BMD (P<0.01). GNRI was a significant predictor of 2-year all-cause mortality (HR 0.92, P<0.05). Area under the ROC curve for all-cause mortality using traditional risk factors (age, sex, diabetes mellitus, cardiovascular disease, use of vasopressors for dialysis-related hypotension, and C-reactive protein) was 0.67 and changed by adding GNRI (0.78, P<0.05), FTI (0.75), or femoral neck BMD (0.66), respectively.

Conclusion: Associations between GNRI, body composition, and BMD were confirmed in HD patients. Combining GNRI with traditional risk factors improved mortality prediction in HD patients. This article is protected by copyright. All rights reserved.

Keywords: body composition; bone mineral density; geriatric nutritional risk index; hemodialysis patients; mortality.

Mediator is a large multiprotein complex that is required for the transcription of most, if not all, genes transcribed by RNA Polymerase II. A core set of subunits is essential to assemble a functional Mediator in vitro and, therefore, the corresponding loss-of-function mutants are expected to be lethal. The MED30 subunit is essential in animal systems, but is absent in yeast. Here, we report that MED30 is also essential for both male gametophyte and embryo development in the model plant Arabidopsis thaliana Mutant med30 pollen grains were viable and some were able to germinate and target the ovules, although the embryos aborted shortly after fertilization, suggesting that MED30 is important for the paternal control of early embryo development. When gametophyte defects were bypassed by specific pollen complementation, loss of MED30 led to early embryo development arrest. Later in plant development, MED30 promotes flowering through multiple signaling pathways; its downregulation led to a phase change delay, downregulation of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 (SPL3), FLOWERING LOCUS T (FTI) and SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1), and upregulation of FLOWERING LOCUS C (FLC).

Originating with the discovery of the quantum Hall effect (QHE) in condensed matter physics, topological order has been receiving increased attention also for classical wave phenomena. Topological protection enables efficient and robust signal transport; mechanical topological insulators (TIs), in particular, are easy to fabricate and exhibit interfacial wave transport with minimal dissipation, even in the presence of sharp edges, defects, or disorder. Here, we report the experimental demonstration of a phononic crystal Floquet TI (FTI). Hexagonal arrays of circular piezoelectric disks bonded to a PLA substrate, shunted through negative electrical capacitance, and manipulated by external integrated circuits, provide the required spatiotemporal modulation scheme to break time-reversal symmetry and impart a synthetic angular momentum bias that can induce strong topological protection on the lattice edges. Our proposed reconfigurable FTI may find applications for robust acoustic emitters and mechanical logic circuits, with distinct advantages over electronic equivalents in harsh operating conditions.

Background: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a serious liver disease with pathogenesis remaining unclear. This study aims to investigate the association between testosterone levels, stage (early, middle, or late, categorized according to clinical manifestation), severity scores, and clinical outcomes of HBV-ACLF.

Methods: This single-center observational study involved 160 male patients with HBV-ACLF, 151 chronic hepatitis B patients without liver failure (CHB) and 106 healthy controls (HC). Morning blood samples were collected and androgen levels analyzed by chemi-bioluminescent immunoassay. Time to death or liver transplantation within 90 days comprised the primary composite outcome.

Results: Serum levels of total testosterone (TT), free testosterone index (FTI), dehydroepiandrosterone sulfate and cortisol were significantly lower among HBV-ACLF than CHB and HC, while androstenedione was higher. Low TT, sex hormone binding globulin and FTI were associated with increased stage (of HBV-ACLF, ascites, and hepatic encephalopathy) and severity scores (Model for End-stage Liver Disease and Chinese Group on the Study of Severe Hepatitis B-ACLF scores). Low TT (< 142.39 ng/dL) was a risk factor for both the composite outcome and for death alone within 90 days. Multivariate analysis revealed TT to be an independent predictor for the composite outcome (hazard ratio 2.57, 95% CI 1.09-6.02; P = 0.030).

Conclusion: Low serum testosterone is common among male patients with HBV-ACLF and predictive of increased severity and worse outcome of the disease and may play an important role in the progression of HBV-ACLF.

Keywords: Acute-on-chronic liver failure; Androgen; Hepatitis B; Testosterone.

BACKGROUND

The characteristics of peritoneal membrane transport differ among patients, affecting the prescription of peritoneal dialysis (PD) modality and glucose exposure in order to achieve an effective dialysis. This study aims to verify the influence of glucose exposure load and peritoneal membrane transport on body composition and nutritional status changes after the first year of PD.

METHODS

We examined a cohort of 85 incident PD patients during the first year of treatment. We established a cut-off of 5% to define changes in dry weight (DW), lean tissue mass (LTM), and fat mass (FM).

RESULTS

In total, 50.6% of the patients presented DW gain, 41.2% showed LTM loss, and 65.9% presented FM gain. Over the time (T0 - T12), we found significant differences in DW, body mass index (BMI), adipose tissue mass (ATM), FM and fat tissue index (FTI). Patients with lower dialysate-to-plasma creatinine ratio showed DW and FM gain. We observed a higher percentage of nonfast transporters in DW gain when comparing with DW no gain. As for glucose exposure load, no body composition changes were seen.

CONCLUSIONS

Most patients presented DW gain, FM gain, and LTM loss. The characteristics of peritoneal membrane transport affected DW during the first year, changes being greater in nonfast than in fast transporters.