Intracoronary Versus Intravenous Low-Dose Tirofiban in Patients With ST-Elevation Myocardial Infarction: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: This meta-analysis aimed to evaluate the effects of intracoronary (IC) low-dose tirofiban versus intravenous (IV) administration on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: All published randomised controlled trials (RCTs) comparing the effects of IC low-dose tirofiban (a bolus of ≤10 ug/kg) versus IV administration in patients with STEMI were identified by searching PubMed, EMBASE, Cochrane Library, and ISI Web of Science from inception to June 2023, with no language restriction. The risk ratio (RR) with 95% confidence intervals (CI) and the weighted mean difference (WMD) with 95% CI were calculated. RESULTS: Eleven RCTs involving 1,802 patients were included. Compared with the IV group, IC low-dose tirofiban was associated with improved major adverse cardiac events rate (RR 0.595, 95% CI 0.442-0.802; p=0.001), left ventricular ejection fraction (WMD 1.982, 95% CI 0.565-3.398; p=0.006), thrombolysis in myocardial infarction (TIMI) flow grade (RR 1.065, 95% CI 1.004-1.131; p=0.037), and TIMI myocardial perfusion grade (RR 1.194, 95% CI 1.001-1.425; p=0.049). The two groups had no significant difference in bleeding events (RR 0.952, 95% CI 0.709-1.279; p=0.745). CONCLUSIONS: Intracoronary low-dose tirofiban administration may be a safe and effective alternative to IV administration in STEMI patients.

Histological and transcriptomic analysis of Fance-deficient PGCs reveal the possible mechanisms of their depletion.

In brief: Fanconi anemia results in subfertility and germ cell deficiency in women. We present histological and RNA-seq analysis of Fance-deficient primordial germ cells to explore the possible mechanisms of their progressive depletion. Abstract: Primordial germ cells (PGCs) development is a subtle and complex regulatory process. Fance is an important substrate molecule necessary for the activation of the Fanconi anemia pathway, and its homozygous mutant causes massive oogonia loss as early as embryonic day 13.5 (E13.5). Here, we present histological and RNA-seq analysis of Fance-deficient PGCs to explore the possible mechanisms responsible for its progressive depletion of germ cells. In Fance-/- embryos, the reduction of PGCs was already evident at E9.5 and the progressive loss of PGCs led to the PGCs being almost exhausted at E12.5. An increase of apoptotic cells was detected among Fance-/- PGCs, which may intuitively explain their reduced number in embryos. Moreover, abnormal cell proliferation and accumulating DNA damage were detected in E12.5 Fance-/- PGCs. We identified 3026 differentially expressed genes in E12.5 Fance-/- PGCs compared to Fance+/+. KEGG pathway analysis revealed that the upregulated genes were highly associated with 'lysosome', and various metabolism pathways, whereas the downregulated genes were mainly enriched in 'cell cycle', 'oocyte meiosis', 'ribosome', and various DNA repair pathways. In addition, multiple genes of various cell death pathways were found to be differentially expressed in E12.5 Fance-/- PGCs, indicating that PGCs death in Fance-/- embryos might diverge from canonical apoptosis. These findings indicate that Fance is essential for PGCs survival and the potential mechanisms involve cell cycle regulation, DNA damage repair, cell death prevention, and by regulating lysosome and ribosome function. Our results provide an important reference for further studies.

Promoter hypermethylation analysis of host genes in cervical intraepithelial neoplasia and cervical cancers on histological cervical specimens.

BACKGROUND: DNA methylation is an essential factor in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer. The aim was to investigate the diagnostic value provided by methylation biomarkers of six tumor suppressor genes (ASTN1, DLX1, ITGA4, RXFP3, SOX17 and ZNF671) for cervical precancerous lesions and cervical cancer. METHODS: The histological cervical specimens of 396 cases including 93 CIN1, 99 CIN2, 93 CIN3 and 111 cervical cancers were tested for methylation-specific PCR assay (GynTect®) of score and positive rate. Among them, 66 CIN1, 93 CIN2, 87 CIN3 and 72 cervical cancers were further used for paired analysis. A chi-square test was used to analyze the difference of methylation score and positive rate in cervical specimens. The paired t-test and paired chi-square test were for analyzing the methylation score and positive rate in paired CIN and cervical cancer cases. The specificity, sensitivity, odds ratio (OR) and 95% confidence interval (95% CI) of the GynTect® assay for CIN2 or worse (CIN2 +) and CIN3 or worse (CIN3 +) were evaluated. RESULTS: According to the chi-square test trend, hypermethylation increased with severity of the lesions as defined by histological grading (P = 0.000). The methylation score above 1.1 was more common in CIN2 + than in CIN1. The DNA methylation scores in the paired groups of CIN1, CIN3 and cervical cancer were significant differences (P = 0.033, 0.000 and 0.000, respectively), except for CIN2 (P = 0.171). While the positive rate of GynTect® in each paired group had no difference (all P > 0.05). The positive rate of every methylation marker in the GynTect® assay showed differences in four cervical lesion groups (all P < 0.05). The specificity of GynTect® assay for detection of CIN2 + /CIN3 + were higher than high-risk human papillomavirus test. With CIN1 as a reference, the positive status of GynTect®/ZNF671 were significantly higher in CIN2 + : odds ratio (OR) 5.271/OR 13.909, and in CIN3 + : OR 11.022/OR 39.150, (all P < 0.001). CONCLUSION: The promoter methylation of six tumor suppressor genes is related to the severity of cervical lesions. The GynTect® assay based on cervical specimens provides diagnostic values for detecting CIN2 + and CIN3 + .

Effectiveness of TruScreen for detecting CIN2+ in women with ThinPrep cytologic test results indicating atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions.

Objective: To evaluate the effectiveness of TruScreen (TS) for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women with abnormal ThinPrep cytologic test (TCT) results. Methods: 466 women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) were enrolled and underwent TS, colposcopy and biopsy examination. Results: Compared with the high-risk human papillomavirus (hrHPV) test for CIN2+, significantly higher specificity of TS, combined TS and hrHPV (69.6 and 75.0 vs 36.8% in ASCUS; 59.0 and 69.9 vs 30.1% in LSIL), significantly higher positive predictive value of combined TS and hrHPV were observed (32.7 vs 24.6% in ASCUS; 47.9 vs 35.6% in LSIL). Conclusion: TS combined with hrHPV showed better performance in diagnosing CIN2+ in ASCUS/LSIL.

Optical Coherence Tomography Can Reduce Colposcopic Referral Rates in Patients With High-Risk Human Papillomavirus.

OBJECTIVE: This study aimed to evaluate the feasibility of combined human papillomavirus (HPV) and optical coherence tomography (OCT) cervical cancer screening strategies. MATERIALS AND METHODS: The OCT and cytology results were compared with the pathological results to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and immediate cervical intraepithelial neoplasia grade 3 or worse (CIN3+) risk. The authors compared the efficiency of colposcopy by using different triage strategies. They discussed differentiation in OCT screening in different age groups. RESULTS: Eight hundred thirteen participants with high-risk HPV-positive and cervical cytology results underwent OCT before colposcopy between March 1 and October 1, 2021. The HPV16/18 genotyping with OCT triage has a specificity of CIN3+ lesions (61.1%; 95% CI = 57.6%-64.6%), intraepithelial neoplasia grade 2 or worse (CIN2+) (66.0%; 95% CI = 62.4%-69.6%). The HPV16/18 genotyping with cytology triage has a specificity of CIN3+ (44.0%; 95% CI = 40.4%-47.6%), CIN2+ (47.0%; 95% CI = 43.2%-50.8%). The OCT triage has a higher positive predictive value compared with the cytology, with a significant difference in CIN2+ lesions (45.0%; 95% CI = 38.8%-51.3% vs 29.2%; 95% CI = 24.7%-33.7%). CONCLUSIONS: The combination of OCT and high-risk HPV triage (both genotyping and nongenotyping) had a similar immediate CIN3+ risk stratification and reduced the number of colposcopies compared with the cytological triage strategy.

Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial.

INTRODUCTION: Cesarean scar defect (CSD) is a long-term outcome of cesarean section (CS) and associated with numerous gynecological and obstetric problems. Previous studies indicate that infection may be a risk factor for CSD. Adjunctive azithromycin was shown to reduce the risk of postoperative infection in patients undergoing non-elective primary cesarean delivery in labor or after the rupture of membranes compared with standard antibiotic prophylaxis. This study investigated the protective effect of adjunctive azithromycin in combination with single-dose cephalosporin against CSD in women undergoing non-elective cesarean delivery. MATERIAL AND METHODS: A randomized, double-blind, controlled clinical trial was conducted in a University hospital in Shanghai, China. A total of 242 women who underwent their first non-elective CS were randomly assigned to receive 1500 mg cefuroxime sodium plus 500 mg intravenous azithromycin (n = 121; experimental group) or 1500 mg cefuroxime sodium plus a placebo (n = 121; placebo group). The primary outcome was CSD prevalence, as determined by transvaginal ultrasound and saline infusion sonohysterography within 6 months of delivery. Secondary outcomes were changes in infectious indicators (eg hypersensitive C-reactive protein and procalcitonin), postoperative morbidity, and use of postoperative antibiotics. We also examined the operative procedure, pathogenic microorganism cultures, and fetal outcomes. Outcomes were compared between groups with the chi-squared test, Fisher's exact test, or Student's t test. RESULTS: Between May 2018 and May 2021, 121 women were randomized to each arm. Because the sonographic follow up was disrupted by the coronavirus disease 2019 pandemic and strict management policies, we merged the follow-up time points (6 weeks and 6 months) into a single time period (6 weeks to 6 months); 104 and 108 women in the experimental and placebo groups, respectively, completed the first sonographic follow up. CSD was diagnosed by sonography in 34/104 (32.7%) and 50/108 (46.3%) patients in the experimental and placebo groups, respectively (relative risk 0.71, 95% confidence interval 0.50-0.99; p = 0.043). Characteristics of CSD and short-term infection outcomes did not differ between groups. CONCLUSIONS: A single dose of intravenous 500 mg azithromycin adjunctive to single-dose cefuroxime prophylaxis significantly reduced the incidence of CSD in women undergoing non-elective CS.

[Compound heterozygous NDUFS1 variants identified in a Chinese pedigree affected with mitochondrial respiratory chain complex I deficiency].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree with suspected mitochondrial functional defects through combined next-generation sequencing (NGS), copy number variation sequencing (CNV-seq), and mitochondrial DNA (mtDNA) sequencing. METHODS: Clinical data of the proband and his family members were collected. The patient and his parents were subjected to family-trio whole-exome sequencing (WES), CNV-seq and mtDNA variant detection. Candidate variant was verified by Sanger sequencing. RESULTS: Trio-WES revealed that the proband has carried compound heterozygous variants of the NDUFS1 gene, including a paternally derived c.64C>T (p.R22X) nonsense variant and a maternally derived c.845A>G (p.N282S) missense variant. Both variants may cause loss of protein function. No variant that may cause the phenotype was identified by CNV-seq and mtDNA variant analysis. CONCLUSION: Children with suspected mitochondrial disorders may have no specific syndromes or laboratory findings. A comprehensive strategy including mtDNA testing may facilitate the diagnosis and early clinical interventions.

Association between serum uric acid levels and coronary artery disease in different age and gender: a cross-sectional study.

BACKGROUND: The association between uric acid (UA) and coronary artery disease (CAD) was controversial. It was still unclear how the UA level changes with age and gender. AIMS: To confirm the relationship between the change of UA with age and gender and CAD, especially in elderly people. METHODS: 8285 individuals were investigated. The changes of UA and hyperuricemia in female and male with age were analyzed. The associations of UA, and hyperuricemia with CAD in different age and sex were assessed. RESULTS: Individuals were stratified into four groups according to their age: ≤ 39 years; 40-59 years; 60-79 years, and ≥ 80 years. The level of UA and the proportion of hyperuricemia increased significantly with age in female (P < 0.001), but showed a downward trend in male (P < 0.001). After adjusting for confounding factors, hyperuricemia remained an independent risk factor for the incident of CAD in all women (P = 0.029). In ≥ 80 year groups of female, UA and hyperuricemia became independent risk factors for the incident of CAD in the univariate and multivariate logistic regression analyses (all P ≤ 0.001). DISCUSSION: The level of UA showed significantly different changes with age in different gender. The relationship between UA and CAD showed differences in different age and sex. CONCLUSIONS: There were significant correlations between UA, hyperuricemia, and CAD only in female, particularly in the ≥ 80 year elderly women, but not in men.

The protease inhibitor E64d improves ox-LDL-induced endothelial dysfunction in human aortic endothelial cells.

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis. E64d, a cysteine protease inhibitor, blocks the elastolytic activity of cathepsin essential for vascular matrix remodeling and reduces neurovascular endothelial apoptosis. The objective of this study was to investigate the effects and the underling mechanisms of E64d on ox-LDL-induced endothelial dysfunction in human aortic endothelial cells (HAECs). HAECs were treated with various concentrations of ox-LDL (0-200 mg/L) for 24 h with or without E64d. The results showed that E64d attenuated ox-LDL-induced increase in soluble intercellular adhesion molecule-1 (sICAM-1) concentration and reduction in endothelial nitric oxide synthase (eNOS) expression, prevented ox-LDL-induced reduction in cell viability and migration ability of HAECs. E64d decreased the protein expression of cathepsin B (CTSB), Beclin 1, and microtubule-associated protein light chain 3 (LC3)-II, but not p62. LC3 puncta and autophagosome formation were also reduced by E64d in HAECs. Moreover, E64d decreased the production of MDA and increased the activity of SOD. The results showed that E64d ameliorated ox-LDL-induced endothelial dysfunction in HAECs.

Fance deficiency inhibits primordial germ cell proliferation associated with transcription-replication conflicts accumulate and DNA repair defects.

Fanconi anemia (FA) gene mutations are critical components in the genetic etiology of premature ovarian insufficiency (POI). Fance-/- mice detected meiotic arrest of primordial germ cells (PGCs) as early as embryonic day (E) 13.5 and exhibited decreased ovarian reserve after birth. However, the mechanism of Fance defect leading to dysgenesis of PGCs is unclear. We aimed to explore the effect of Fance defects on mitotic proliferation of PGCs. Combined with transcriptomic sequencing and validation, we examined the effect of Fance defects on cell cycle, transcription-replication conflicts (TRCs), and multiple DNA repair pathways in PGCs during active DNA replication at E11.5 and E12.5. Results showed Fance defects cause decreased numbers of PGCs during rapid mitosis at E11.5 and E12.5. Mitotic cell cycle progression of Fance-/- PGCs was blocked at E11.5 and E12.5, shown by decreased cell proportions in S and G2 phases and increased cell proportions in M phase. RNA-seq suggested the mechanisms involved in DNA replication and repair. We found Fance-/- PGCs accumulate TRCs during active DNA replication at E11.5 and E12.5. Fance-/- PGCs down-regulate multiple DNA repair pathways at E11.5 and E12.5 including the FA pathway, homologous recombination (HR) pathway, and base excision repair (BER) pathway. In conclusion, Fance defect impaired the mitotic proliferation of PGCs leading to rapidly decreased numbers and abnormal cell cycle distribution. Proliferation inhibition of Fance-/- PGCs was associated with accumulated TRCs and down-regulation of FA, HR, BER pathways. These provided a theoretical basis for identifying the inherited etiology and guiding potential fertility management for POI.

Efficacy of optical coherence tomography in the triage of women with minor abnormal cervical cytology before colposcopy.

OBJECTIVES: To evaluate the efficacy of Optical Coherence Tomography (OCT) for detecting cervical lesions in women with minor abnormal cytology results (atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL)). METHODS: A prospective study was conducted at gynecologic clinic from Mar 2021 to Sep 2021. The recruited women with cervical cytological findings of ASC-US or LSIL were inspected with OCT before colposcopy-directed cervical biopsy. The diagnostic performance of OCT, alone and in combination with high-risk human papillomavirus (hrHPV) testing were evaluated to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+)/CIN3 or worse (CIN3+). The rate of colposcopy referral and the immediate risk of CIN3+ of OCT were calculated. RESULTS: A total of 349 women with minor abnormal cervical cytology results were enrolled. For detection of CIN2+/CIN3+, the sensitivity and NPV of OCT were lower than those of hrHPV testing (CIN2+: 71.3% vs. 95.4%, 89.0% vs. 91.1%, P < 0.001; CIN3+: 75% vs. 93.8%, 96.5% vs. 95.6%, P < 0.001), but the specificity, accuracy and PPV were higher than those of hrHPV testing (CIN2+: 77.5% vs. 15.6%, 75.9% vs. 35.5%, 51.2% vs. 27.3%, P < 0.001; CIN3+: 69.4% vs. 13.6%, 69.9% vs. 20.9%, 19.8% vs. 9.9%, P < 0.001). OCT combined with hrHPV testing (CIN2+: 80.9%; CIN3+: 72.6%) showed higher specificity than that of OCT alone (P < 0.001). The colposcopy referral rate base on OCT classification was lower than that based on hrHPV testing (34.7% vs. 87.1%, P < 0.001). Patients with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology, the immediate CIN3+ risk in OCT negative cases was less than 4%. CONCLUSIONS: OCT alone or combination with hrHPV testing shows good performance for detecting CIN2+/CIN3+ in patients with ASC-US/LSIL cytology. OCT is an effective method for colposcopy triage in women with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology.

Comparative effectiveness of transvaginal repair vs. hysteroscopic resection in patients with symptomatic uterine niche.

Objective: To compare the efficacy of transvaginal repair and hysteroscopic resection in improving niche associated postmenstrual spotting. Methods: The improvement rate of postmenstrual spotting in women who underwent transvaginal repair or hysteroscopic resection treatment was assessed retrospectively in patients accepted at the Niche Sub-Specialty Clinic in International Peace Maternity and Child Health Hospital between June 2017 and June 2019. Postoperative spotting symptom within one year after surgery, pre- and postoperative anatomical indicators, women' satisfaction with menstruation and other perioperative parameters were compared between the two groups. Results: 68 patients in the transvaginal group and 70 patients in the hysteroscopic group were included for analysis. The improvement rate of postmenstrual spotting in the transvaginal group at the 3rd, 6th, 9th, and 12th months after surgery was 87%, 88%, 84%, and 85%, significantly higher than 61%, 68%, 66%, and 68% in the hysteroscopic group, respectively (P < 0.05). The total days of spotting improved significantly at the 3rd month after surgery but did not change over time within one year in each group (P > 0.05). After surgery, the disappearance rates of the niche are 68% in transvaginal group and 38% in hysteroscopic group, however, hysteroscopic resection had shorter operative time and hospitalization duration, less complications, and lower hospitalization costs. Conclusion: Both treatments can improve the spotting symptom and anatomical structures of uterine lower segments with niches. Transvaginal repair is better in thickening the residual myometrium than hysteroscopic resection, however, hysteroscopic resection has shorter operative time and hospitalization duration, less complications, and lower hospitalization costs.

Efficacy and Safety of Ultrasound-Guided High-Intensity Focused Ultrasound Ablation in Women With Multiple Uterine Fibroids: An Exploratory Study.

OBJECTIVE: The aim of the work described here was to explore the clinical efficacy and safety of ultrasound-guided high-intensity focused ultrasound (USg-HIFU) treatment in women with multiple fibroids and identify the characteristic parameters predicting USg-HIFU efficacy in multiple fibroids. METHODS: From February 2021 to August 2022, 138 patients with multiple fibroids (group A comprising 125 patients with two to four fibroids and 13 patients with five or more fibroids) and 149 patients with solitary fibroids (group B) were included. HIFU treatment information, efficacy comparisons and adverse events were recorded. A nomogram model of the characteristic parameters used to predict the efficacy of USg-HIFU in multiple fibroids was established. RESULTS: After USg-HIFU treatment, the statistical comparison of pre-operative versus post-operative symptom scores and fibroid volume in the two groups indicated obvious symptom relief and substantial shrinkage of fibroid volume (all p values <0.001). Nevertheless, group A required more energy and longer treatment and sonication times to achieve a 70% non-perfused volume (NPV) ratio, and had a lower energy efficiency factor than group B (all p values <0.05). No severe complications were observed in either group. The nomogram model included fibroid volume, fibroid location and signal intensity on T2-weighted imaging (T2WI). The area under the receiver operating characteristic curve and the accuracy of the model were 0.698 and 0.686, respectively. CONCLUSION: USg-HIFU appears to be an effective and safe treatment option for multiple fibroids. Knowledge of the fibroid volume, location and signal intensity on T2WI may help determine the efficacy of USg-HIFU in multiple fibroids.

Reciprocal regulation between proinflammatory cytokine-induced inducible NO synthase (iNOS) and connexin43 in bladder smooth muscle cells.

Gap junctions (GJs) play an important role in the control of bladder contractile response and in the regulation of various immune inflammatory processes. Here, we investigated the possible interaction between inflammation and GJs in bladder smooth muscle cells (BSMCs). Stimulation of BSMCs with IL1ß and TNFα increased connexin43 (Cx43) expression and function, which was associated with increased phosphorylation of vasodilator-stimulated phosphoprotein. Inhibition of PKA with H89 or down-regulation of CREB with specific siRNAs largely abolished the Cx43-elevating effect. Further analysis revealed that IL1ß/TNFα induced NFκB-dependent inducible NO synthase (iNOS) expression. Inhibition of iNOS with G-nitro-l-arginine methyl ester abrogated and an exogenous NO donor mimicked the effect of the cytokines on Cx43. Intraperitoneal injection of LPS into mice also induced bladder Cx43 expression, which was largely blocked by an iNOS inhibitor. Finally, the elevated Cx43 was found to negatively regulate iNOS expression. Dysfunction of GJs with various blockers or down-regulation of Cx43 with siRNA significantly potentiated the expression of iNOS. Fibroblasts from Cx43 knock-out (Cx43(-/-)) mice also displayed a significantly higher response to the cytokine-induced iNOS expression than cells from Cx43 wild-type (Cx43(+/+)) littermates. Collectively, our study revealed a previously unrecognized reciprocal regulation loop between cytokine-induced NO and GJs. Our findings may provide an important molecular mechanism for the symptoms of bladder infection. In addition, it may further our understanding of the roles of GJs in inflammatory diseases.

Invasive versus conservative strategy in the very elderly with non-ST-elevation acute coronary syndrome: A meta-analysis of randomized controlled trials.

AIM: To investigate the optimal treatment strategy in patients older than 80 years with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: All published randomized, placebo-controlled trials (RCTs) reporting on comparisons between invasive and conservative strategies for patients aged 80 years or older with NSTE-ACS were identified. The literature search was performed using PubMed, EMBASE, Cochrane Library, and the ISI Web of Science, from their establishment to July 2021 with no language restriction. The pooled risk ratios (RRs) with 95% confidence intervals (CI) for dichotomous outcomes were calculated. RESULTS: Three RCTs involving a total of 893 cases met the inclusion criteria. Compared with the conservative group, the invasive strategy could significantly improve the incidence rate of composite endpoint (I2  = 21.9%; RR 0.727, 95% CI 0.619 to 0.855, P < 0.001), recurrent myocardial infarction (MI) (I2  = 0.0%; RR 0.585, 95% CI 0.441 to 0.776, P < 0.001) and revascularization (I2  = 0.0%; RR 0.239, 95% CI 0.126 to 0.455, P < 0.001). However, no benefits were observed on outcomes of all-cause death (I2  = 0.0%; RR 0.888, 95% CI 0.681 to 1.160, P = 0.384), cardiac death (I2  = 0.0%; RR 0.769, 95% CI 0.412 to 1.433, P = 0.408) and stroke (I2  = 0.0%; RR 0.778, 95% CI 0.392 to 1.543, P = 0.473). The major bleeding events were comparable between the two groups (I2  = 0.0%; RR 1.582, 95% CI 0.622 to 4.025, P = 0.336). CONCLUSIONS: Compared with a conservative strategy, the invasive treatment could reduce the incidence of composite endpoint, recurrent MI, and revascularization in the very elderly with NSTE-ACS. However, no benefits were observed on mortality. Geriatr Gerontol Int 2022; 22: 36-41.

Nonsteroidal anti-inflammatory drug flufenamic acid is a potent activator of AMP-activated protein kinase.

Flufenamic acid (FFA) is a nonsteroidal anti-inflammatory drug (NSAID). It has anti-inflammatory and antipyretic properties. In addition, it modulates multiple channel activities. The mechanisms underlying the pharmacological actions of FFA are presently unclear. Given that AMP-activated protein kinase (AMPK) has both anti-inflammatory and channel-regulating functions, we examined whether FFA induces AMPK activation. 1) Exposure of several different types of cells to FFA resulted in an elevation of AMPKα phosphorylation at Thr172. This effect of FFA was reproduced by functionally and structurally similar mefenamic acid, tolfenamic acid, niflumic acid, and meclofenamic acid. 2) FFA-induced activation of AMPK was largely abolished by the treatment of cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (an intracellular Ca(2+) chelator) or depletion of extracellular Ca(2+), whereas it was mimicked by stimulation of cells with the Ca(2+) ionophore 5-(methylamino)-2-({(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl}methyl)-1,3-benzoxazole-4-carboxylic acid (A23187) or ionomycin. 3) FFA triggered a rise in intracellular Ca(2+), which was abolished by cyclosporine, a blocker of mitochondrial permeability transition pore. Cyclosporine also abolished FFA-induced activation of AMPK. 4) Inhibition of Ca(2+)/calmodulin-dependent kinase kinase ß (CaMKKß) with 7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid acetate (STO-609) or down-regulation of CaMKKß with short interfering RNA largely abrogated FFA-induced activation of AMPK. 5) FFA significantly suppressed nuclear factor-κB activity and inducible nitric-oxide synthase expression triggered by interleukin-1ß and tumor necrosis factor α. This suppression was also largely abrogated by STO-609. Taken together, we conclude that FFA induces AMPK activation through the Ca(2+)-CaMKKß pathway. Activation of AMPK is a presently unrecognized important mechanism underlying the pharmacological effects of FFA.

Immunohistochemical distribution of serum proteins in living mouse heart with In vivo cryotechnique.

In vivo cryotechnique (IVCT), which immediately cryofixes target organs in situ, was used to clarify the morphological features of beating heart tissue of living mice. IVCT was performed for diastolic heart tissue under the condition of monitoring with electrocardiogram (ECG). Other mouse hearts were prepared with conventional perfusion-fixation (PF-DH) or immersion-fixation followed by dehydration (IM-DH), and quick-freezing of resected heart tissues (FQF). Immunolocalizations of albumin, immunoglobulin G1 (IgG1), intravenously injected bovine serum albumin (BSA), and connexin 43 were examined after different intervals of BSA injection. In the case of IVCT, the exact stop time of beating mouse hearts was recorded by ECG, and open blood vessels with flowing erythrocytes were observed with less artificial tissue shrinkage than with conventional preparation methods. Both albumin and BSA were well preserved in intercalated discs and t-tubules of cardiomyocytes in addition to blood vessels and interstitial matrices. IgG1 was immunolocalized in interstitial matrices of heart tissues in addition to their blood vessels. At 4 hr after BSA injection, it was immunolocalized in the intercalated discs of cardiomyocytes and lost later at 8 hr. IVCT should prove to be more useful for the morphofunctional examination of dynamically changing heart tissue than conventional preparation methods.

Intracoronary Thrombolysis in Patients With ST-Segment Elevation Myocardial Infarction: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The effects of intracoronary (IC) thrombolysis therapy in patients with ST-segment elevation myocardial infarction (STEMI) receiving primary percutaneous coronary intervention (PPCI) remain unclear. METHODS: The meta-analysis was conducted according to the PRISMA statement. All relevant studies were identified by searching the PubMed, EMBASE, Cochrane Library, and Web of Science, with no time or language limitation. The pooled risk ratio (RR) and weighted mean difference (WMD) with a 95% CI were calculated. RESULTS: Nine randomized controlled trials involving a total of 1341 patients were included. Compared with the control group, IC thrombolysis in patients with STEMI could reduce the incidence of major adverse cardiac events (MACE; RR 0.632, 95% CI, 0.474-0.843, P = .002) and improve left ventricular ejection fraction (RR 0.343, 95% CI, 0.178-0.509, P < .001) and myocardial microcirculation. However, there was no difference noted in the mortality (RR 0.759, 95% CI, 0.347-1.661, P = .490). The incidence rate of major bleeding and minor bleeding was comparable between the 2 groups. CONCLUSIONS: Intracoronary thrombolysis was associated with improved MACE and myocardial microcirculation in patients with STEMI having PPCI, though it failed to improve mortality.

Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury: Insights Into the SENECA Trial.

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification. OBJECTIVES: The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients. METHODS: Patient-specific iCMs were injured with 1 µmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system. RESULTS: iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy. CONCLUSIONS: L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs.

Effects of Intracoronary Nicorandil on Myocardial Microcirculation and Clinical Outcomes in Patients with Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The amelioration of myocardial reperfusion in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PPCI) remains a significant issue. OBJECTIVE: We conducted a meta-analysis of randomized controlled trials (RCTs) to better assess the effects of intracoronary nicorandil administration on myocardial microcirculation and clinical outcomes in these patients. METHODS: The meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. A literature search was performed in the PubMed, Embase, Cochrane Library, and Web of Science databases up to April 2019, with no time or language limitations. Pooled risk ratios (RRs) were calculated to evaluate the treatment effects. RESULTS: Seven RCTs involving a total of 562 patients were included. Compared with control, intracoronary nicorandil significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) grade ≤ 2 (RR 0.349; 95% confidence interval [CI] 0.199-0.611; P < 0.001) and TIMI myocardial perfusion grade ≤ 2 (RR 0.611; 95% CI 0.438-0.852; P = 0.004) and was associated with higher complete ST-segment resolution rates (RR 1.326; 95% CI 1.090-1.614; P = 0.005). However, no significant benefits were observed on clinical outcomes, including death (RR 0.370; 95% CI 0.085-1.618; P = 0.187), recurrent myocardial infarction (RR 0.507; 95% CI 0.156-1.655; P = 0.261), heart failure (RR 0.528; 95% CI 0.224-1.247; P = 0.145), and target lesion/vessel revascularization (RR 1.109; 95% CI 0.553-2.224; P = 0.770). CONCLUSIONS: Intracoronary nicorandil can significantly improve myocardial microcirculation in patients with AMI undergoing PPCI, but it failed to offer clinically significant benefits.