[Comparison of 5-year follow-up outcomes between"one-stop"procedure and long-term oral anticoagulants after radiofrequency catheter ablation in patients with atrial fibrillation].

Objective: To compare the 5-year follow-up outcomes of radiofrequency catheter ablation (RFCA) combined with left atrial appendage closure (LAAC) and long-term oral anticoagulant (OAC) after RFCA in patients with atrial fibrillation. Methods: This retrospective cross-sectional study included patients with atrial fibrillation who underwent"one-stop"procedure in the First Affiliated Hospital of Ningbo University from September 2015 to December 2017 (RFCA+LAAC group). Baseline data of patients were collected. Propensity score matching at the ratio of 1∶1 was used to select patients with atrial fibrillation who took long-term OAC after RFCA (RFCA+OAC group). The maintenance rate of sinus rhythm and the incidence of adverse events during follow-up were compared between the two groups. Results: A total of 110 patients were enrolled in the RFCA+LAAC group and RFCA+OAC group, respectively. Age of patients was (67.4±8.8) years in RFCA+LAAC group, and there were 42 (38.2%) female patients. Age of patients was (67.3±7.9) years in RFCA+OAC group, and there were 47 (42.7%) female patients. The patients were followed up for mean of (5.3±1.1) years. There was no significant difference in the maintenance rate of sinus rhythm (log-rank: χ2=0.277, P=0.602) and incidence of ischemic stroke events (2.7% (3/110) vs. 4.5% (5/110), P=0.719) during follow-up between the two groups. The incidence of bleeding events (6.4% (7/110) vs. 18.2% (20/110), P=0.008) and major bleeding events (1.8% (2/110) vs. 8.2% (9/110), P=0.030) was significantly higher in the RFCA+OAC group than in the RFCA+LAAC group. Conclusion: There is no significant difference between RFCA+LAAC group and RFCA+OAC group in maintenance rate of sinus rhythm and incidence of ischemic stroke events. Patients in the RFCA+LAAC group have a lower risk of bleeding events compared to the RFCA+OAC group.

[Feasibility and safety of closing large left atrial appendage using the LAmbre device].

Objective: To evaluate the feasibility and safety of the LAmbre occluder for large-diameter left atrial appendage occlusion. Methods: This study was a retrospective cohort study. Patients with large orifice of the left atrial appendage (≥31 mm) and occlusion with the LAmbre device in the Arrhythmia Center of Ningbo First Hospital were included from June 2018 to March 2020. Baseline data were collected and major perioperative complications of left atrial appendage occlusion (including death, stroke, instrumental embolism, cardiac tamponade, and major bleeding events) were recorded. Patients were followed up 45 days, 6 months and 12 months after surgery. The shunt and device-related thrombosis were recorded by esophageal cardiac ultrasound or pulmonary vein CT, and the occurrence of postoperative thromboembolism, bleeding events, death and other serious adverse events were recorded. Results: The average age and left atrial appendage ostial dimension of 32 patients (37.5% women) included in this research were (70.4±8.4) years old and (34.4±2.9) mm. The LAmbre device was successfully implanted in 31(96.9%) patients. No major complications occurred during the perioperative period. During the 12-month follow-up, pericardial tamponade occurred in 1(3.2%) patient and was recovered after treatment. There was no occluder edge shunt>5 mm in patients followed up by esophageal echocardiography. No significant peri-device leak, device-related thrombus, thromboembolism or death event has occurred. Conclusion: The LAmbre occluder may be feasible and safe for large-diameter left atrial appendage occlusion.

[Safety and efficacy of percutaneous left atrial appendage closure in nonvalvular atrial fibrillation patients with left atrial spontaneous echocardiographic contrast].

Objective: To investigate the safety and efficacy of percutaneous left atrial appendage closure (LAAC) in nonvalvular atrial fibrillation patients (NVAF) with left atrial spontaneous echocardiographic contrast (LA SEC). Methods: A total of 95 NVAF patients treated in the Department of Cardiology of Ningbo First Hospital from July 2018 to June 2019 were enrolled in this study. The study population was divided into two group according to the presence or absence of LA SEC detected by transesophageal echocardiography (TEE). TEE was scheduled 45 days post-procedure to detect device-related thrombus (DRT). Stroke and bleeding events were recorded during follow-up. Periprocedural complications and follow-up results were compared between the two groups. Results: LA diameters were smaller in non-LA SEC group than LA SEC group ((44.0±7.4)mm vs (47.3±6.6)mm, P=0.033). Watchman device was successfully implanted into all the enrolled patients. No death, transient ischemic attack (TIA)/stroke, device embolization and major bleeding events occurred. Fifty patients (90.2%) in LA SEC group and 31 patients (91.2%) in non-LA SEC group finished TEE follow-up 45 days post-procedure. No device-related thrombus was detected in non-LA SEC group, while 2 cases (6.5%) were detected in LA SEC group, but there was no significant differences in the incidence between the two groups (P=0.127). The LA SEC group and non-LA SEC group were followed-up for (12.3±3.8) months and (12.9±3.3) months, respectively; and there was no significant differences in the incidence of death, TIA/stroke, major and minor bleeding events between two groups during the follow-up (all P>0.05). Conclusion: LAAC in NVAF patients with LA SEC was safe and effective. However, the incidence of DRT was slightly higher.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Management of hyperparathyroid-induced hypercalcaemic crisis with intracardiac thrombi.

A 29-year-old previously healthy patient presented with a hyperparathyroid-induced hypercalcaemic crisis refractory to conventional therapy. The patient developed ventricular fibrillation and subsequently required emergency parathyroidectomy and extracorporeal membrane oxygenation support. Extensive intracardiac and pulmonary trunk thrombi were identified soon after the commencement of extracorporeal membrane oxygenation, despite full anticoagulation. In this report we highlight the non-specific presentations of hypercalcaemia which may lead to delayed diagnosis, and discuss the incidence, risk factors and treatment of a hyperparathyroid-induced hypercalcaemic crisis. We emphasise the role of emergency parathyroidectomy as a salvage therapy in medically refractory We consider the likely factors leading to intracardiac thrombi formation in this case, including how hypercalcaemia may have been a contributing factor.

Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element.

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax. Chimeric fusion proteins consisting of the DNA-binding domain of the yeast transcription factor Gal4 and the amino-terminal domain (residues 1 to 66) of ATF3 were able to mediate Tax-dependent transactivation of a Gal4-responsive promoter, which suggests a direct involvement of this region of ATF3. Recombinant fusion proteins of glutathione S-transferase with either the amino- or carboxy-terminal (residues 139 to 181) domain of ATF3 were able to specifically interact with Tax. Furthermore, specific antisera directed against Tax coimmunoprecipitated ATF3 only in the presence of Tax.

Activating transcription factor-3 stimulates 3',5'-cyclic adenosine monophosphate-dependent gene expression.

Activating transcription factor-3 (ATF-3) is one member of a large family of leucine zipper transcription factors which bind to promoters responsive to cAMP and phorbol ester at the related cAMP (CRE) and phorbol ester response elements. We report here that ATF-3 is coexpressed with the neuropeptide precursor proenkephalin in human neuroblastoma SK-N-MC cells. Cotransfection experiments indicate that activation of proenkephalin gene expression by ATF-3 is dependent upon both the catalytic subunit of the cAMP-dependent protein kinase and the CRE-2 element. The CRE-2 element is essential for second messenger-inducible expression and is known to bind AP-1-like transcription factors. ATF-3 expressed in bacteria or from rabbit reticulocyte lysates binds to the proenkephalin CRE-2 element as a homodimer and as a heterodimer with Jun-D, another activator of proenkephalin transcription. ATF-3 stimulates binding of Jun-D to the proenkephalin CRE-2 element and acts synergistically with Jun-D to induce proenkephalin gene expression. Sequential immunoprecipitations of ATF-3 from SK-N-MC cells expressing proenkephalin indicate that ATF-3 is complexed with Jun-D in vivo and that both proteins are highly phosphorylated. Together, our results suggest that ATF-3 may play an important role in the regulation of gene expression by cAMP-dependent intracellular signaling pathways.

Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs.

The dopamine D4 receptor may be a site through which the clinical effects of antipsychotic drugs are mediated. Polymorphisms of a 48 base pair repeat in the third exon of the DRD4 gene code for different length segments in the third intracytoplasmic loop of the D4 receptor. The most common long (seven repeat) form of the D4 receptor has been shown in both physiologic and pharmacologic experiments to respond differently to dopamine agonists and antagonists than do shorter forms of D4. Thus, variants of D4 may partly determine patient response to antipsychotic drugs and, in particular, response to typical neuroleptics, which have a relatively low affinity for the D4 receptor, as compared to clozapine, which has a relatively high affinity for D4. DRD4 polymorphisms in the third intron were characterized in 28 patients with chronic psychosis who responded well to typical neuroleptics, 32 patients who responded well to clozapine, and 57 healthy comparison subjects. Patients responding to typical neuroleptics carried the allele for the long (seven repeat) form of the D4 receptor (allele frequency 8.9%) less frequently than patients responding to clozapine (allele frequency 23.4%, P = 0.046) or healthy comparison subjects (allele frequency 26.3%, P = 0.004). The results of this study suggest that inherited variants of D4 may explain some of the interindividual variation seen in patient response to different classes of antipsychotic medication.

Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice.

Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake.

Changes in ovarian ultrastructure and ecdysteroid titer during the aging process of female Xyleborus ferrugineus (Coleoptera: Scolytidae).

Striking ultrastructural and hormonal parameters of premature menopause and aging are reported in female Xyleborus ferrugineus fed cholesterol, rather than 7-dehydrocholesterol, as a sole dietary sterol. The titer of free ecdysteroids in such 63-day-old females remained abnormally elevated through the period of the ovarian cycle. A similar plateauing of such elevated titer also occurred in 147-day-old, irregularly cycling females fed only cholesterol as the dietary sterol. These hormonal changes in menopausing X. ferrugineus females seem especially analogous to the maintenance of an elevated concentration of 17-beta-estradiol through the estrous, as well as the proestrous, ovary of aged irregularly cycling rats. The highly abnormal ultrastructure of ovaries of X. ferrugineus females aged 216 days on a diet containing cholesterol as the sole sterol seems quite analogous to that of the nonovulatory follicles in older, irregularly cycling rats. Our new findings involving aging X. ferrugineus females indicate further the usefulness of an insect model to study aging processes.

Ultrastructure of the compound eye of the haploid male beetle, Xyleborus ferrugineus.

The compound eye of male (haploid) Xyleborus ferrugineus beetles was examined with scanning and transmission electron microscopy. The eye externally consists of ca. 19 to 33 facets. Each ommatidium is composed of a thickly biconvex lenslet with about 50 electron dense and rare layers, but at the junction area between two lenslets there are only about 35 to 37 layers that can be distinguished. A very short (3.4-4.0 mum) acone type crystalline cone is located directly beneath the lenslet. Each ommatidium is surrounded by pigment cells, and pigment granules also appear throughout the cytoplasm of the retinular cells. Some pigment granules are even present below the basement membrane. there are 8 retinular cells. The rhabdomeres of 2 centrally situated photoreceptor cells fuse into a rhabdom which is enveloped by the rhabdomeres of 6 peripheral retinular cells. The rhabdomeres of the 6 peripheral retinular cells join laterally to form a rhabdomeric ring around the central rhabdom. No tracheation was observed among the retinular cells. Virus-like particles are evident near the nucleus in each Semper cell of the crystalline cone.

Ultrastructure of the prothoracic gland of variously aged female pupae of Xyleborus ferrugineus and associated ecdysteroid titers.

The prothoracic glands of female pupae of Xyleborus ferrugineus at three ages (0-h, 48-h, and 72-h-old) were examined for ultrastructural changes that correlate with high titers of ecdysteroids in the entire pupa. In all three ages, the prothoracic gland cells appear compact with a prominent nucleus. Lysosome-like structures with concentrically oriented internal membrane are observed in both 0-h and 72-h-old gland cells. Mitochondria are abundant in the glands of both ages, and rough endoplasmic reticulum is relatively sparse. Numerous microtubules are present in the prothoracic gland cells of 48-h-old female pupae that contain relatively high titers of ecdysteroids. Rough endoplasmic reticulum also is especially abundant at this age of the pupa. Ecdysone titers, estimated by the radioimmunoassay method (RIA), were 161.04 +/- 26.80 pg/mg, 704.25 +/- 69.02pg/mg and 298.72 +/- 26.80pg/mg body weight in 0-h, 48-h and 72-h-old female pupae, respectively.