RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.

Heart failure is one of the leading causes of death worldwide. RhoA, a small GTPase, governs actin dynamics in various tissue and cell types, including cardiomyocytes; however, its involvement in cardiac function has not been fully elucidated. Here, we generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice, which demonstrated a significantly shorter lifespan with left ventricular dilation and severely impaired ejection fraction. We found that the cardiac tissues of the cKO mice exhibited structural disorganization with fibrosis and also exhibited enhanced senescence compared with control mice. In addition, we show that cardiomyocyte mitochondria were structurally abnormal in the aged cKO hearts. Clearance of damaged mitochondria by mitophagy was remarkably inhibited in both cKO cardiomyocytes and RhoA-knockdown HL-1 cultured cardiomyocytes. In RhoA-depleted cardiomyocytes, we reveal that the expression of Parkin, an E3 ubiquitin ligase that plays a crucial role in mitophagy, was reduced, and expression of N-Myc, a negative regulator of Parkin, was increased. We further reveal that the RhoA-Rho kinase axis induced N-Myc phosphorylation, which led to N-Myc degradation and Parkin upregulation. Re-expression of Parkin in RhoA-depleted cardiomyocytes restored mitophagy, reduced mitochondrial damage, attenuated cardiomyocyte senescence, and rescued cardiac function both in vitro and in vivo. Finally, we found that patients with idiopathic dilated cardiomyopathy without causal mutations for dilated cardiomyopathy showed reduced cardiac expression of RhoA and Parkin. These results suggest that RhoA promotes Parkin-mediated mitophagy as an indispensable mechanism contributing to cardioprotection in the aging heart.

Pretransfer Aspirin Administration and Its Impact on Angiographic Outcomes for Patients with ST-Elevation Myocardial Infarction.

Although guidelines recommend early aspirin administration after diagnosis of ST-elevation myocardial infarction (STEMI), the decision of pretransfer aspirin administration is at the discretion of the primary physicians. Therefore, this study aimed to determine whether pretransfer aspirin administration was associated with better angiographical outcomes in patients with STEMI. This study compared the angiographic findings of thrombolysis in myocardial infarction (TIMI) flow grade in the infarct-related artery before percutaneous coronary intervention (PCI) between patients who received pretransfer aspirin and those who did not. In total, 28 patients (11.2%) were administered aspirin before transfer and 219 (88.8%) were administered aspirin upon arrival at the hospital. Propensity score matching yielded 135 patients [27 patients (20%) who were administered aspirin before transfer and 108 patients (80%) who were administered aspirin upon arrival at the hospital]. Patients who received pretransfer aspirin had a higher rate of TIMI-3 flow before PCI compared to those who did not receive pretransfer aspirin [8 (28.6%) versus 15 (6.8%), P < 0.01, in all study patients; 8 (26.6%) versus 7 (6.5%), P < 0.01, in propensity-score-matched patients]. Multivariable logistic regression analysis revealed that pretransfer aspirin administration was significantly associated with the presence of TIMI-3 flow before PCI, independent of age, gender, transfer time, and statin use (OR: 5.43, 95% CI: 1.94-15.2, P < 0.01, in all study patients; OR: 6.17, 95% CI: 1.86-20.46, P < 0.01, in propensity-score-matched patients). Pretransfer aspirin administration could lead to the early restoration of coronary blood flow in patients with STEMI, supporting its active use in STEMI care.

Impact of coronary plaque characteristics on periprocedural myocardial injury in elective percutaneous coronary intervention.

OBJECTIVES: To investigate the relationship between periprocedural myocardial injury (PMI) and plaque characteristics detected by multidetector computed tomography (MDCT) and cardiac magnetic resonance imaging (CMR). MATERIALS AND METHODS: This observational retrospective study, between July 2012 and October 2019, included chronic coronary syndrome patients undergoing elective percutaneous coronary intervention (PCI) after MDCT and CMR. High-intensity plaque (HIP) on non-contrast T1-weighted imaging was defined as a coronary plaque-to-myocardium signal intensity ratio of ≥ 1.4. High-risk plaque (HRP) in MDCT displayed ≥ 2 features: positive remodeling, low-attenuation plaque, spotty calcification, and napkin-ring sign. PMI was defined as an increase in cardiac troponin T levels > 5 times the upper normal limit at 24 h after PCI. RESULTS: Ninety-five target lesions in 76 patients (mean age ± standard deviation, 67 years ± 9; 62 males [82%]) were included. Twenty-one patients (24 lesions) were assigned to the PMI group, while 55 patients (71 lesions) to the non-PMI group. Presence of HRP characteristics on MDCT and HIP on CMR was significantly higher in the PMI group. Multivariate logistic regression analysis showed that HRP in MDCT and HIP in CMR were significant independent predictors of PMI. Target lesions with HRP on MDCT and HIP on CMR were significantly more likely to develop PMI. In 141 plaques with ≥ 50% stenosis (76 patients), patients with PMI had significantly more frequent HRP in MDCT and HIP in CMR in target and non-target lesions. CONCLUSIONS: MDCT and CMR can play an important role in the detection of high-risk lesions for PMI following elective PCI. KEY POINTS: • Multivariate logistic regression analysis showed that high-risk plaque on MDCT and high-intensity plaque on MRI were significant independent predictors of periprocedural myocardial injury (PMI). • Target lesions with high-risk plaque on MDCT and high-intensity plaque on CMR were significantly more likely to develop PMI. • In 141 plaques with ≥ 50% stenosis, patients with PMI were significantly more likely to have high-risk plaques on MDCT and high-intensity plaque on CMR in target and non-target lesions.

Prognostic Value of Novel Natriuretic Peptide Index After Percutaneous Coronary Intervention.

BACKGROUND: The predictive value of both atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) is well known. This study evaluated the prognostic value of a novel natriuretic peptide index (NPI) combining ANP and BNP. Methods and Results: This study included 849 consecutive patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). Patients were followed up clinically for up to 3 years or until the occurrence of major adverse cardiac events (MACE). The primary endpoint was a composite of all-cause death and non-fatal myocardial infarction. The NPI (pg/mL) was defined as √ANP×BNP. MACE occurred in 73 patients (8.6%) during the follow-up period. Receiver operating characteristic curve analysis showed the highest area under the curve for NPI (0.779) compared with ANP and BNP (0.773 and 0.755, respectively). A risk analysis of MACE occurrence adjusted for the multivariable model showed the highest hazard ratio (HR) for NPI (1.33; 95% confidence interval [CI] 1.18-1.51; P<0.001) compared with ANP and BNP (HR 1.25 [95% CI 1.13-1.39] and 1.30 [95% CI 1.13-1.49], respectively; P<0.001). The NPI was a significant independent predictor of MACE, among other clinical parameters, in the multivariable analysis. CONCLUSIONS: Compared with ANP and BNP, the NPI was more effective in predicting future adverse events after PCI.

Significance of End-Diastolic Forward Flow in Patients With Repaired Tetralogy of Fallot　- Its Interaction With the Left Ventricular Property and End Organ Damage.

BACKGROUND: Although right ventricular (RV) enlargement may affect RV diastolic dysfunction assessed by end-diastolic forward flow (EDFF) in patients with repaired tetralogy of Fallot (TOF), EDFF may also be modified by left ventricular (LV) hemodynamics. We hypothesized that EDFF is affected by LV hemodynamics, not limited to RV diastolic stiffening.Methods and Results: Among 145 consecutive patients with repaired TOF who underwent catheterization, hemodynamic properties in 47 with consistent EDFF and 75 without EDFF were analyzed. Compared with patients without EDFF, those with EDFF had a large RV volume with a high regurgitant fraction. Although cardiac index and central venous pressure (CVP) were similar, contrast injection augmented CVP and LV end-diastolic pressure (EDP) in patients with vs. those without EDFF, suggesting compromised diastolic reserve. In patients with EDFF, the velocity-time integral (VTI) of EDFF was positively correlated with LVEDP and systemic vascular resistance, in addition to RV EDP. EDFF-VTI was correlated with hepatic venous wedge pressure and markers of hepatic dysfunction. Subanalysis of the older (≥6 years) half of the study cohort revealed that EDFF was associated with bi-atrial enlargement independent of RV volume, highlighting the pronounced role of EDFF on the diastolic property in the aged cohort. CONCLUSIONS: EDFF-VTI in patients with repaired TOF reflects RV diastolic dysfunction, affected by the left heart system. EDFF-VTI indicates blood stagnation, which may be attributed to end-organ damage.

Predictive Value of CHADS2, CHA2DS2-VASc and R2-CHADS2 Scores for Short- and Long-Term Major Adverse Cardiac Events in Non-ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Non-ST-elevation myocardial infarction (NSTEMI) carries a poor prognosis, and accurately prognostication has significant clinical importance. In this study, we analyzed the predictive value of the CHADS2, CHA2DS2-VASc, and R2-CHADS2scores for major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI) in patients with NSTEMI using data from a prospective multicenter registry.Methods and Results: The registry included 440 consecutive patients with NSTEMI and coronary artery disease who underwent successful PCI. Patients were clinically followed for up to 3 years or until the occurrence of MACE. MACE was defined as a composite of all-cause death and nonfatal MI. During the follow-up period, 55 patients (12.5%) experienced MACE. Risk analysis of MACE occurrence, adjusted for the multivariable model, demonstrated a significant increase in risk with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores. Kaplan-Meier analysis showed a higher incidence of MACE in patients with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores, both in the short- and long-term periods. CONCLUSIONS: Patients with NSTEMI and higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores displayed a greater incidence of MACE.

Role of Rho Kinase in Regulating Arterial Stiffness in Anesthetized Rabbits.

The effects of Rho kinase inhibitors fasudil and ripasudil on arterial stiffness were assessed using anesthetized rabbits, where the aortic ß and femoral ß were measured as a stiffness parameter at each arterial region. Intravenous administration of fasudil and ripasudil dose-dependently decreased blood pressure and femoral vascular resistance and increased femoral arterial blood flow, which appeared according to their in vitro potencies for Rho kinase inhibition. Both drugs increased the aortic ß but decreased the femoral ß at hypotensive doses. These results suggest that the inhibition of Rho kinase contributes to reducing elastic recoil in the aorta and an increase in compliance in the femoral artery. In addition, the Rho kinase-associated Ca2+-independent mechanism of arterial vascular smooth muscle contraction may be essential in the regulation of femoral arterial stiffness.

Differential Effects of Ca2+ Channel Blockers Nifedipine and Cilnidipine on Arterial Elasticity in the Aortic and Femoral Arterial Segments of Anesthetized Rabbits.

Ca2+ channel blockers have potent vasodilatory effects and excellent efficacy in preserving organ blood flow. These hemodynamic actions may be partly controlled by the functional stiffness of conduit arteries. In this study, we assessed the effects of the L-type Ca2+ channel blocker nifedipine on aortic and femoral arterial stiffness (referred to as aortic ß and femoral ß, respectively) in anesthetized rabbits. To further clarify the involvement of the autonomic nervous system, we compared the effects of nifedipine with those of the L/N-type Ca2+ channel blocker cilnidipine. Further, the effect of the α-adrenergic receptor blocker doxazosin on the effects of nifedipine on arterial elasticity was examined. An antihypertensive dose of nifedipine (300 µg/kg, administered intravenously) was found to increase the aortic ß but hardly affected the femoral ß. An antihypertensive dose of cilnidipine (30 µg/kg, administered intravenously) increased the aortic ß but decreased the femoral ß. Interestingly, nifedipine decreased the femoral ß in the presence of the α-adrenoceptor blocker doxazosin (1 mg/kg, administered intravenously). These effects suggest that L-type Ca2+ channel blockers essentially increase vascular elasticity via the decrement in arterial stiffness in the femoral artery segment, which is modified by the presence or absence of the inhibitory effect of each drug on reflex sympathetic nerve activity, while decreasing vascular elasticity via the increment in arterial stiffness in the aortic segment independently of sympathetic nerve activity.

Bladder training for treating overactive bladder in adults.

BACKGROUND: Overactive bladder (OAB) is a common chronic and bothersome condition. Bladder training is widely prescribed as a first-line treatment for OAB, but the efficacy has been systematically evaluated for urinary incontinence rather than OAB alone. OBJECTIVES: To evaluate the benefits and harms of bladder training for treating adults with OAB compared to no treatment, anticholinergics, ß3-adrenoceptor agonists, or pelvic floor muscle training (PFMT) alone or in combination. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 6 November 2022. SELECTION CRITERIA: We included randomized controlled trials involving adults aged 18 years or older with non-neurogenic OAB. We excluded studies of participants whose symptoms were caused by factors outside the urinary tract (e.g. neurologic disorders, cognitive impairment, gynecologic diseases). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported cure or improvement, 2. symptom- and condition-related quality of life (QoL), and 3. ADVERSE EVENTS: Secondary outcomes included 4. participant-reported satisfaction, 5. number of incontinence episodes, 6. number of urgency episodes, and 7. number of micturition episodes. For the purpose of this review, we considered two time points: immediately after the treatment (early phase) and at least two months after the treatment (late phase). We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 15 trials with 2007 participants; participants in these trials were predominantly women (89.3%). We assessed the risk of bias of results for primary and secondary outcomes, which across all studies was similar and predominantly of high risk of bias, and none were at low risk of bias. The certainty of evidence was low to very low, with some moderate, across measured outcomes. Bladder training versus no treatment: three studies involving 92 participants compared bladder training to no treatment. The evidence is very uncertain about the effects of bladder training on cure or improvement at the early phase (risk ratio (RR) 17.00, 95% confidence interval (CI) 1.13 to 256.56; 1 study, 18 participants; very low-certainty evidence). Bladder training may reduce the number of incontinence episodes (mean difference (MD) -1.86, 95% CI -3.47 to -0.25; 1 study, 14 participants; low-certainty evidence). No studies measured symptom- and condition-related QoL, number of adverse events, participant-reported satisfaction, number of urgency episodes, or number of micturition episodes in the early phase. Bladder training versus anticholinergics: seven studies (602 participants) investigated the effects of bladder training versus anticholinergic therapy. Bladder training may be more effective than anticholinergics on cure or improvement at the early phase (RR 1.37, 95% CI 1.10 to 1.70; 4 studies, 258 participants; low-certainty evidence). The evidence is very uncertain about the effects of bladder training on symptom- and condition-related QoL (standardized mean difference (SMD) -0.06, 95% CI -0.89 to 0.77; 2 studies, 117 participants; very low-certainty evidence). Although the evidence is very uncertain, there were fewer adverse events in the bladder training group than in the anticholinergics group (RR 0.03, 95% CI 0.01 to 0.17; 3 studies, 187 participants; very low-certainty evidence). The evidence is very uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.36, 95% CI -0.27 to 1.00; 2 studies, 117 participants; very low-certainty evidence), the number of urgency episodes per 24 hours (MD 0.70, 95% CI -0.62 to 2.02; 2 studies, 92 participants; very low-certainty evidence), and the number of micturition episodes per 24 hours (MD -0.35, 95% CI -1.90 to 1.20; 3 studies, 175 participants; very low-certainty evidence). No studies measured participant-reported satisfaction in the early phase. Bladder training versus PFMT: three studies involving 203 participants compared bladder training to PFMT. The evidence is very uncertain about the different effects between bladder training and PFMT on symptom- and condition-related QoL at the early phase (SMD 0.10, 95% CI -0.19 to 0.40; 2 studies, 178 participants; very low-certainty evidence). There were no adverse events in either group at the early phase (1 study, 97 participants; moderate-certainty evidence). The evidence is uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.02, 95% CI -0.35 to 0.39, 1 study, 81 participants; low-certainty evidence) and very uncertain about the number of micturition episodes per 24 hours (MD 0.10, 95% CI -1.44 to 1.64; 1 study, 81 participants; very low-certainty evidence). No studies measured cure or improvement, participant-reported satisfaction, or number of urgency episodes in the early phase. Although we were interested in studies examining bladder training versus ß3-adrenoceptor agonists, in combination with ß3-adrenoceptor agonists versus ß3-adrenoceptor agonists alone, and in combination with PFMT versus PFMT alone, we did not identify any eligible studies for these comparisons. AUTHORS' CONCLUSIONS: This review focused on the effect of bladder training to treat OAB. However, most of the evidence was low or very-low certainty. Based on the low- or very low-certainty evidence, bladder training may cure or improve OAB compared to no treatment. Bladder training may be more effective to cure or improve OAB than anticholinergics, and there may be fewer adverse events. There may be no difference in efficacy or safety between bladder training and PFMT. More well-designed trials are needed to reach a firm conclusion.

Feasibility study for a downsized comparative thyroid assay with measurement of brain thyroid hormones and histopathology in rats: Case study with 6-propylthiouracil and sodium phenobarbital at high dose.

Concern has been raised that thyroid hormone disruptors (THDs) may potentially interfere with the developing brain, but effects of mild suppression of maternal THs by environmental contaminants on neonatal brain development are not fully understood. The comparative thyroid assay (CTA) is a screening test for offspring THDs, but it requires several animals and is criticized that reliance on serum THs alone as predictive markers of brain malfunction is inadequate. To verify feasibility of the downsized CTA but additional examination of brain THs levels and histopathology, we commenced internal-validation studies. This paper presents the data of the study where 6-propylthiouracil (6-PTU, 10 ppm) and sodium phenobarbital (NaPB, 1000 ppm) were dosed by feeding from gestational days (GD)6-20, and from GD6 to lactation day 21. The modified CTA detected 6-PTU-induced severe (>70%) suppression of serum THs in dams, with >50% suppressed serum/brain TH levels in offspring and brain heterotopia in postnatal day 21 pups. The modified CTA also detected NaPB-induced mild (<35%) suppression of serum THs in dams, with mild (<35%) reduction of serum/brain TH levels in fetuses but not in pups. These findings suggest that the modified CTA may have a potential as a screening test for offspring THDs.

The Impact of the COVID-19 Pandemic and Associated Control Measures on the Mental Health of the General Population : A Systematic Review and Dose-Response Meta-analysis.

BACKGROUND: To what extent the COVID-19 pandemic and its containment measures influenced mental health in the general population is still unclear. PURPOSE: To assess the trajectory of mental health symptoms during the first year of the pandemic and examine dose-response relations with characteristics of the pandemic and its containment. DATA SOURCES: Relevant articles were identified from the living evidence database of the COVID-19 Open Access Project, which indexes COVID-19-related publications from MEDLINE via PubMed, Embase via Ovid, and PsycInfo. Preprint publications were not considered. STUDY SELECTION: Longitudinal studies that reported data on the general population's mental health using validated scales and that were published before 31 March 2021 were eligible. DATA EXTRACTION: An international crowd of 109 trained reviewers screened references and extracted study characteristics, participant characteristics, and symptom scores at each timepoint. Data were also included for the following country-specific variables: days since the first case of SARS-CoV-2 infection, the stringency of governmental containment measures, and the cumulative numbers of cases and deaths. DATA SYNTHESIS: In a total of 43 studies (331 628 participants), changes in symptoms of psychological distress, sleep disturbances, and mental well-being varied substantially across studies. On average, depression and anxiety symptoms worsened in the first 2 months of the pandemic (standardized mean difference at 60 days, -0.39 [95% credible interval, -0.76 to -0.03]); thereafter, the trajectories were heterogeneous. There was a linear association of worsening depression and anxiety with increasing numbers of reported cases of SARS-CoV-2 infection and increasing stringency in governmental measures. Gender, age, country, deprivation, inequalities, risk of bias, and study design did not modify these associations. LIMITATIONS: The certainty of the evidence was low because of the high risk of bias in included studies and the large amount of heterogeneity. Stringency measures and surges in cases were strongly correlated and changed over time. The observed associations should not be interpreted as causal relationships. CONCLUSION: Although an initial increase in average symptoms of depression and anxiety and an association between higher numbers of reported cases and more stringent measures were found, changes in mental health symptoms varied substantially across studies after the first 2 months of the pandemic. This suggests that different populations responded differently to the psychological stress generated by the pandemic and its containment measures. PRIMARY FUNDING SOURCE: Swiss National Science Foundation. (PROSPERO: CRD42020180049).

Reversible complete atrioventricular block in a neonate with maternal anti-Sjögren's syndrome-associated antibody: atypical phenotype of autoimmune congenital heart block.

The fetus of anti-Sjögren's syndrome-associated antibody-positive mother developed complete atrioventricular block at 39 weeks of gestation and required urgent ventricular pacing after birth. Unexpectedly, the patient recovered from the atrioventricular block within a few days. Fraction analysis of maternal anti-Sjögren's syndrome-associated antibody revealed positivity for isolated anti-Ro/SSA 60 kDa antibody, which is abnormal as most patients with complete atrioventricular block present with anti-Ro/SSA 52 kDa positivity, which may indicate a potentially atypical late and reversible manifestation of an autoimmune congenital atrioventricular block in this patient.

Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice.

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.

Prevention of Contrast-Induced Nephropathy After Cardiovascular Catheterization and Intervention With High-Dose Strong Statin Therapy in Japan　- The PREVENT CINC-J Study.

BACKGROUND: Previous studies have reported that high-dose strong statin therapy reduces the incidence of contrast-induced nephropathy (CIN) in statin naïve patients; however, the efficacy of high-dose strong statins for preventing CIN in real-world clinical practice remains unclear. The aim of this study was to evaluate the efficacy of strong statin therapy in addition to fluid hydration for preventing CIN after cardiovascular catheterization.Methods and Results: This prospective, multicenter, randomized controlled trial included 420 patients with chronic kidney disease who underwent cardiovascular catheterization. They were assigned to receive high-dose pitavastatin (4 mg/day × 4 days) on the day before and of the procedure and 2 days after the procedure (Statin group, n=213) or no pitavastatin (Control group, n=207). Isotonic saline hydration combined with a single bolus of sodium bicarbonate (20 mEq) was scheduled for administration to all patients. In the control group, statin therapy was continued at the same dose as that before randomization. CIN was defined as a ≥0.5 mg/dL increase in serum creatinine or ≥25% above baseline at 48 h after contrast exposure. Before randomization, 83% of study participants were receiving statin treatment. The statin group had a higher incidence of CIN than the control group (3.0% vs. 0%, P=0.01). The 12-month rate of major adverse cardiovascular events was similar between the 2 groups. CONCLUSIONS: High-dose pitavastatin increases the incidence of CIN in this study population.

Biotinylated peptides substituted with D-amino acids with high stability as anti-anaphylactic agents targeting platelet-activating factor.

Platelet-activating factor (PAF) is an important lipid mediator of anaphylaxis and therefore can be an anti-anaphylactic agent target. Recently, we reported that several synthetic biotinylated peptides containing a Tyr-Lys-Asp-Gly sequence markedly inhibited the bioactivities of PAF in vitro and in vivo; it also inhibited anaphylactic reactions such as hypothermia, hypotension, and vascular permeability in vivo. Here, we report the anti-anaphylactic effects of three biotinylated heptapeptides (peptide 1: H-Lys(biotinyl)-Trp-Tyr-Lys-Asp-Gly-Asp-OH, peptide 2: H-D -Lys(biotinyl)-Trp-Tyr-Lys-Asp-Gly-Asp-OH, and peptide 3: H-D -Lys(biotinyl)-Trp-Tyr-Lys-Asp-Gly-D -Asp-OH). The experiment using tryptophan fluorescence spectroscopy showed that the interaction of peptides 2 and 3 with PAF was larger than that of peptide 1. Experiments using a rat model of hind paw edema showed that peptides 1, 3, and 2 inhibited PAF-induced edema by 67.9%, 69.3%, and 79.3%, respectively. In a mouse model of anaphylaxis, both peptides 2 and 3 showed inhibitory effects on anaphylactic hypothermia, whereas peptide 1 did not. Furthermore, experiments involving in vitro rat plasma stability of peptides showed that both peptides 3 and 2 were more stable in plasma compared to peptide 1 (84.0%, 51.8%, and 0%, remained after 6 h, respectively). Our results suggest that both peptides 2 and 3 may show systemic and local inhibitory effects as anti-anaphylactic agents targeting PAF.

Chronological T-wave alternation before and after the onset of arrhythmogenic right ventricular cardiomyopathy.

Identification of arrhythmogenic right ventricular cardiomyopathy (ARVC) during childhood is challenging due to the lack of specific ECG manifestation. We report chronological ECG alteration before several years of the ARVC onset in two affected children. Their ECG at the age of 6 years was almost normal for their age, and their chronological ECGs exhibited inversion of T wave in inferior leads, which are typical for ARVC, developed at younger age than that in precordial leads. In addition, the leftmost T-wave inversion in the precordial lead shifted toward the left in our patients, which is a sharp contrast to its physiological transition.

Cell-to-cell contact-mediated regulation of tumor behavior in the tumor microenvironment.

Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.

Trends in survival of leukemia among children, adolescents, and young adults: A population-based study in Osaka, Japan.

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.

The impact of left atrium size on selection of the pulmonary vein isolation method for atrial fibrillation: Cryoballoon or radiofrequency catheter ablation.

BACKGROUND: Pulmonary vein isolation (PVI) is the cornerstone of ablation strategies for atrial fibrillation (AF), and noninferiority of cryoballoon (CB) over radiofrequency (RF) ablation has been previously reported. One of the risk factors of recurrence is left atrium (LA) enlargement. This study aimed to analyze the impact of LA enlargement on the selection of CB or RF ablation for AF patients. METHODS: A total of 2,224 AF patients (64.4 ±â€¯10.7 years, 65.5% male) who underwent PVI were analyzed retrospectively. Left atrial diameter (LAD) and volume (LAV) were measured using echocardiography before the procedures. LA enlargement was defined as LAD ≥40 mm and LAV index (LAVI) ≥35 mL/m2. Patients undergoing CB and RF ablation were propensity score matched, and 376 matched pairs were evaluated. RESULTS: Cox proportional hazard analysis revealed that LAD (95% CI, 1.01-1.05), LAV (95% CI, 1.01-1.02), and LAVI (95% CI, 1.01-1.03) were independent predictors of recurrence. CB showed equivalent clinical outcomes to those of RF with shorter procedure time required for patients without LA enlargement. CB was inferior to RF in patients with LA enlargement (LAD, 74.5% vs 84.6%, P = .028; LAVI, 74.7% vs 83.4%, P = .015), and large LAVI was associated with a higher prevalence of non-PV foci (35% vs 29%, P = .008). CONCLUSIONS: CB ablation may be recommended for patients without enlarged LA based on the short procedure time and efficacy, whereas RF would be more appropriate in large LAs. LAVI may be a valuable reference to predict PVI outcomes and in selecting the ablation method.

Impact of diagnosis-to-ablation time on non-pulmonary vein triggers and ablation outcomes in persistent atrial fibrillation.

INTRODUCTION: Non-pulmonary vein (PV) triggers are a major cause of atrial tachyarrhythmia (ATA) recurrence after catheter ablation. However, the effect of the diagnosis-to-ablation time (DAT) on non-PV triggers in persistent atrial fibrillation is unknown. METHODS AND RESULTS: This observational study evaluated 502 consecutive persistent AF patients who underwent initial ablation. We compared 408 patients whose DAT was <3 years with 94 patients whose DAT was ≥3 years. Following PV and posterior wall isolation, 193 non-PV triggers, including 50 AFs, 30 atrial tachycardias (ATs), and 113 repetitive atrial premature beats, were elicited and ablated in 137 (27%) patients. Specifically, 80 non-PV AF/AT triggers were provoked in 64 (13%) patients, being identified more frequently in the DAT ≥ 3 years group than in the DAT < 3 years group (20% vs. 11%, p = .025) especially with a higher prevalence of coronary sinus/inferior left atrial triggers. During a median follow-up of 770 days, the ATA recurrence-free rate was higher in the DAT < 3 years group than the DAT ≥ 3 years group (79% vs. 53% at 2 years, p < .001). In a multivariate analysis, female sex (odds ratio: 2.70, p = .002) and a longer DAT (odds ratio: 1.13/year, p = .008) were predictors of non-PV AF/AT triggers, and a longer DAT (hazard ratio: 1.12/year, p < .001) and non-PV AT/AF triggers (hazard ratio: 1.79, p = .009) were associated with ATA recurrence. CONCLUSION: Early ablation after the first diagnosis of persistent AF may reduce emerging non-PV AF/AT triggers and ATA recurrence.