Ziprasidone triggers inflammasome signaling via PI3K-Akt-mTOR pathway to promote atrial fibrillation.

BACKGROUND: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. METHODS: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. RESULTS: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1ß, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. CONCLUSIONS: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.

The associations among peptic ulcer disease, Helicobacter pylori infection, and abdominal aortic aneurysms: A nationwide population-based cohort study.

BACKGROUND: There are overlapping risk factors and underlying molecular mechanisms for both peptic ulcer disease (PUD) and abdominal aortic aneurysm (AAA). Despite improvements in the early diagnosis and treatment of AAA, ruptured AAAs continue to cause a substantial number of deaths. Helicobacter pylori are Gram-negative, microaerophilic bacteria that are now recognized as the main cause of PUD. H. pylori infection (HPI) is associated with an increased risk of certain cardiovascular diseases. HPIs can be treated with at least two different antibiotics to prevent bacteria from developing resistance to one particular antibiotic. METHODS: We conducted a population-based cohort study using the National Health Insurance Research Database to evaluate whether associations exist among PUD, HPI, and eradication therapy for HPI and AAA. The primary outcome of this study was the cumulative incidence of AAA among patients with or without PUD and HPI during the 14-year follow-up period. RESULTS: Our analysis included 7003 patients with PUD/HPI, 7003 patients with only PUD, and another 7003 age-, sex-, and comorbidity-matched controls from the database. We found that patients with PUD/HPI had a significantly increased risk of AAA compared to those with PUD alone and matched controls. The patients who had PUD/HPI had a significantly higher cumulative risk of developing AAA than those with PUD and the comparison group (2.67 % vs. 1.41 % vs. 0.73 %, respectively, p < 0.001). Among those patients with PUD/HPI, patients who had eradication therapy had a lower incidence of AAA than those without eradication therapy (2.46 % vs. 3.88 %, p = 0.012). CONCLUSIONS: We revealed an association among PUD, HPI, and AAA, even after adjusting for age, sex, comorbidities, and annual medical follow-up visits. Notably, we found that HPI eradication therapy reduced the incidence of AAA among patients with PUD.

Electroconvulsive therapy for obsessive compulsive symptoms in a patient with schizophrenia: a brief report.

Comorbid obsessive-compulsive disorder (OCD) is common among patients with schizophrenia. The role of electroconvulsive therapy (ECT) in the treatment of OCD in schizophrenia is unclear. Herein, we present a 45-year-old man who was diagnosed with schizophrenia along with OCD and received ECT due to relapse of psychosis owing to refractive schizophrenia. Together with psychotic symptoms, obvious symptoms of OCD were observed prior to treatment, including obsessive thoughts, difficulty in starting activities, and repetitive and ritualistic behavior. After 12 sessions of ECT, symptoms of schizophrenia and OCD both improved significantly (Positive and Negative Syndrome Scale [PANSS] score decreased from 95 points to 58 points, and Yale - Brown Obsessive-Compulsive Scale [Y-BOCS] score decreased from 29 points to 11 points). Mild aggravation of OCD symptoms was noted 3 months after ECT treatment (Y-BOCS score increased from 11 points to 17 points) without obvious relapse of psychotic symptoms (PANSS score changed from 58 points to 62 points). In conclusion, ECT could be considered as an alternative therapy for patients with schizophrenia and OCD with limited response to pharmacological treatment.

Inflammatory Biomarkers and Blood Physical Property Transformations Following On-Pump Coronary Artery Bypass Graft Surgery.

OBJECTIVE: This study aimed to compare the hemorheological and inflammatory changes before and after coronary artery bypass graft (CABG) surgery, as factors such as hypothermia, hemodilution, transfusion, and other variables affect blood viscosity and inflammation during the procedure. METHODS: A total of 25 patients who underwent CABG surgery were enrolled in this study. Whole blood was collected just before the CABG (D0), 2 days after surgery (D2), and 5 days after surgery (D5). The plasma viscosity (PV) and whole blood viscosity (WBV) were measured at shear rates ranging from 0.1 to 1000 s-1 using a rheometer, and the mean values were compared. Inflammatory markers were also assessed and analyzed in relation to the hemorheological changes. RESULTS: Compared with the baseline values, the PV significantly increased after 5 days. WBV showed a significant increase on day 2 and after 5 days. The WBV and fibrinogen were significantly correlated on day 2 and day 5 but not before surgery. Inflammatory markers such as CRP, WBC, platelets, and fibrinogen also demonstrated notable changes in relation to the hemorheological alterations. CONCLUSIONS: This study highlights the crucial finding that hyperviscosity, characterized by elevated PV and WBV, persists for almost one week after on-pump CABG surgery. Understanding the interplay between inflammation and hemorheological properties during the postoperative period is crucial for optimizing patient care. Future research should focus on exploring the underlying mechanisms and potential therapeutic interventions to mitigate the impact of inflammation on blood viscosity and improve patient outcomes following CABG surgery.

Bidirectional association between major depressive disorder and dementia: Two population-based cohort studies in Taiwan.

BACKGROUND: Major depressive disorder (MDD) and dementia are both major contributors to the global burden of disease. Despite existing literature on the association between MDD and dementia, there is a lack of a nationwide longitudinal cohort study that considers the competing risk of death. Therefore, this study assessed the bidirectional associations between MDD and dementia over an 11-year period in population-based settings, accounting for death as a competing risk. METHODS: We conducted two population-based retrospective cohort studies in Taiwan. We identified 80,742 patients diagnosed with MDD in 2009-2010 and matched them with patients without MDD by sex, age, and year of diagnosis to assess the relative risk of dementia. We also identified 80,108 patients diagnosed with dementia in 2009-2010 and matched them with patients without dementia by sex, age, and year of diagnosis to assess the relative risk of MDD. All patients were followed until they received a diagnosis of new onset MDD or new onset dementia, their death, or the end of 2019. Cause-specific hazards models were used to estimate adjusted hazard ratios (aHRs). RESULTS: The incidence density (ID) of dementia was higher in patients with MDD than in patients without MDD (7.63 vs. 2.99 per 1000 person-years), with an aHR of 2.71 (95% confidence interval [CI]: 2.55-2.88). The ID of MDD was higher in patients with dementia than in patients without dementia (12.77 vs. 4.69 per 1000 person-years), with an aHR of 2.47 (95% CI: 2.35-2.59). CONCLUSIONS: This population-based study found a bidirectional association between MDD and dementia. Our findings suggest the need to identify dementia in patients with MDD and vice versa.

Essence of the Giant Reduction of Power Density in Osmotic Energy Conversion in Porous Membranes: Importance of Testing Area.

Harvesting osmotic energy through nanofluidic devices with diverse materials has received considerable attention in recent years. Often, a small testing area on a membrane was chosen to assess its power performance by calculating power density as output power per effective area. Since the choice of this testing area is arbitrary, and it is usually quite small, the result obtained can be too optimistic. There is a need to come up with a common standard so that the performance of a device/membrane can be assessed reasonably. In this study, we systematically investigate the power density as a function of testing area in nanoporous anodic-aluminum-oxide membranes. Through changing the aperture size of substrates, we clearly show that the obtained power density decreases drastically with increasing testing area. For instance, the power density acquired from the testing area of µm2-scale can be five orders of magnitude larger than that from the pristine membrane of cm2-scale. We also advance simulations by building a 3D model to simulate osmotic-driven ion transport in the multichannel system. The result of modeling agrees with our experimental observation that the power density decreases with increasing number of channels, and the ionic concentration profile reveals that the concentration polarization becomes serious as the number of channels increases. Our result highlights the importance of effective area on testing the power performance in nanofluidic devices.

Developing an AI-assisted planning pipeline for hippocampal avoidance whole brain radiotherapy.

BACKGROUND AND PURPOSE: Hippocampal avoidance whole brain radiotherapy (HA-WBRT) is effective for controlling disease and preserving neuro-cognitive function for brain metastases. However, contouring and planning of HA-WBRT is complex and time-consuming. We designed and evaluated a pipeline using deep learning tools for a fully automated treatment planning workflow to generate HA-WBRT radiotherapy plans. MATERIALS AND METHODS: We retrospectively collected 50 adult patients who received HA-WBRT. Using RTOG- 0933 clinical trial protocol guidelines, all organs-at-risk (OARs) and the clinical target volume (CTV) were contoured by experienced radiation oncologists. A deep-learning segmentation model was designed and trained. Next, we developed a volumetric-modulated arc therapy (VMAT) auto-planning algorithm for 30 Gy in 10 fractions. Automated segmentations were evaluated using the Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95 % HD). Auto-plans were evaluated by the percentage of PTV volume that receives 30 Gy (V30Gy), conformity index (CI), and homogeneity index (HI) of planning target volume (PTV) and the minimum dose (D100%) and maximum dose (Dmax) for the hippocampus, Dmax for the lens, eyes, optic nerve, brain stem, and chiasm. RESULTS: We developed a deep-learning segmentation model and an auto-planning script. For the 10 cases in the independent test set, the overall average DSC and 95 % HD of contours were greater than 0.8 and less than 7 mm, respectively. All auto-plans met the RTOG- 0933 criteria. The HA-WBRT plan automatically created time was about 10 min. CONCLUSIONS: An artificial intelligence (AI)-assisted pipeline using deep learning tools can rapidly and accurately generate clinically acceptable HA-WBRT plans with minimal manual intervention and increase efficiency of this treatment for brain metastases.

Supercritical carbon dioxide-decellularized arteries exhibit physiologic-like vessel regeneration following xenotransplantation in rats.

Currently, many techniques are used for decellularization of grafts, including physical, enzymatic, and chemical treatments. Indeed, decellularized xenogenic grafts provide superior outcomes than alternative synthetic conduits. However, vascular grafts produced by these methods are not perfect; their defects include defective vessel wall structures, detergent residues, and the development of aneurysms after grafting. Therefore, it is essential to develop a more appropriate process to produce decellularized vascular grafts. Supercritical carbon dioxide (ScCO2) has been used in decellularization technologies in recent years. It is beneficial for the long-term preservation of tissues and regeneration of new vessels. We have previously reported that ScCO2-produced acellular porcine corneas show excellent biocompatibility following lamellar corneal transplantation in rabbits. In this study, we wanted to use this method to fabricate vascular grafts (ScCO2-decellularized rabbit femoral artery (DFA)) and analyze their efficacy, parameters regarding rejection by the recipient's (ACI/NKyo rats) immune system and biocompatibility, structural regeneration, and functionality in vivo. The results indicated that the ScCO2-DFA showed higher biocompatibility, enhanced chemotactic migration of endothelial progenitor cells, lower risk of vasculopathy, lower inflammatory and splenic immune responses, and better physiological-like tension responses after xenotransplantation (XTP) in ACI/NKyo rats compared with the results obtained after XTP using detergent decellularized vascular grafts (SDS-DFA). In conclusion, ScCO2 is an excellent decellularization technique in the fabrication of biocompatible vascular grafts and has tremendous application in vascular regenerative medicine.

Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis.

BACKGROUND AND AIMS: Atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed flow. In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to therapeutic application in atherogenesis were elucidated. METHODS: Porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs). RESULTS: A large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE-/-) mice overexpressing S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE-/- mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis. CONCLUSIONS: The findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis.

Extracorporeal Life Support for Severely Burned Patients with Concurrent Inhalation Injury and Acute Respiratory Distress Syndrome: Experience from a Military Medical Burn Center.

BACKGROUND: Both inhalation injury and acute respiratory distress syndrome (ARDS) are risk factors that predict mortality in severely burned patients. Extracorporeal life support (ECLS) is widely used to rescue these patients; however, its efficacy and safety in this critical population have not been well defined. We report our experience of using ECLS for the treatment of severely burned patients with concurrent inhalation injury and ARDS. METHODS: This was a retrospective analysis of 14 patients collected from a single medical burn center from 2012 to 2019. All patients suffered from major burns with inhalation injury and ARDS, and were treated with ECLS. RESULTS: The median total body surface area of deep dermal or full thickness burns was 94.5%, ranging 47.7-99.0 %. The median revised Baux score was 122.0, ranging 90.0-155.0. All patients developed ARDS with a median partial pressure of arterial oxygen to a fraction of inspired oxygen ratio of 61.5, ranging 49.0-99.0. Indications for ECLS included sustained hypoxemia and unstable hemodynamics. The median interval for initiating ECLS was 2.5 days, ranging 1.0-156.0 days. The median duration of ECLS was 2.9 days, ranging 0.3-16.7 days. The overall survival to discharge was 42.8%. Causes of death included sepsis and multiple organ failure. ECLS-related complications included cannulation bleeding, catheter-related infection, and hemolysis. The incidence of risk factors reported in literature were higher in non-survivors, including Baux>120, albumin < 3.0 g/dL, and lactate > 8 mmol/L. CONCLUSIONS: For severely burned patients with concurrent inhalation injury and ARDS, ECLS could be a salvage treatment to improve sustained hypoxemia. However, the efficacy of hemodynamic support was limited. Identifying definite ECLS indications and rigorous patient selection would contribute to better clinical outcomes.

Gating with Charge Inversion to Control Ionic Transport in Nanopores.

Multivalent ions modify the properties of the solid/liquid interfaces, and in some cases, they can even invert the polarity of surface charge, having large consequences for separation processes based on charge. The so-called charge inversion is observed as a switch from negative surface charge in monovalent salts, e.g., KCl, to effective positive surface charge in multivalent salts that is possible through a strong accumulation and correlation of the multivalent ions at the surface. It is not known yet, however, whether the density of the positive charge induced by charge inversion depends on the pore opening diameter, especially in extreme nanoconfinement. Here, we probe how the effective surface charge induced by charge inversion is influenced by the pore opening diameter using a series of nanopores with an opening between 4 and 25 nm placed in contact with trivalent chromium ions in tris(ethylenediamine)chromium(III) sulfate at different concentrations. Our results suggest that the effective positive charge density can indeed be modified by nanoconfinement to the extent that is dependent on the pore diameter, salt concentration, and applied voltage. In addition, the correlated ions can increase the transmembrane current in nanopores with an opening diameter down to 10 nm and cause a significant blockage of the current for narrower pores. The results provide guidelines to control ionic transport at the nanoscale with multivalent ions and demonstrate that in the same experimental conditions, differently sized pores in the same porous material can feature different surface charge density and possibly ion selectivity.

Ultrafast Polymer Dynamics through a Nanopore.

Ultrathin nanopore sensors allow single-molecule and polymer measurements at sub-microsecond time resolution enabled by high current signals (∼10-30 nA). We demonstrate for the first time the experimental probing of the ultrafast translocation and folded dynamics of double-stranded DNA (dsDNA) through a nanopore at 10 MHz bandwidth with acquisition of data points per 25 ns (150 MB/s). By introducing a rigorous algorithm, we are able to accurately identify each current level present within translocation events and elucidate the dynamic folded and unfolded behaviors. The remarkable sensitivity of this system reveals distortions of short-lived folded states at a lower bandwidth. This work revisits probing of dsDNA as a model polymer and develops broadly applicable methods. The combined improvements in sensor signals, instrumentation, and large data analysis methods uncover biomolecular dynamics at unprecedentedly small time scales.

Extracorporeal Life Support and Temporary CentriMag Ventricular Assist Device to Salvage Cardiogenic-Shock Patients Suffering from Prolonged Cardiopulmonary Resuscitation.

Background: The extracorporeal life support (ECLS) and temporary bilateral ventricular assist device (t-BiVAD) are commonly applied in patients with cardiogenic shock. Prolonged cardiopulmonary resuscitation (CPR) has poor prognosis. Herein, we report our findings on a combined ECLS and t-BiVAD approach to salvage cardiogenic-shock patients with CPR for more than one hour. Methods: Fifty-nine patients with prolonged CPR and rescued by ECLS and subsequent t-BiVAD were retrospectively collected between January 2015 and December 2019. Primary diagnoses included ischemic, dilated cardiomyopathy, acute myocardial infarction, post-cardiotomy syndrome, and fulminant myocarditis. The mean LVEF was 16.9% ± 6.56% before t-BiVAD. The median ECLS-to-VAD interval is 26 h. Results: A total of 26 patients (44%) survived to weaning, including 13 (22%) bridged to recovery, and 13 (22%) bridged to transplantation. Survivors to discharge demonstrated better systemic perfusion and hemodynamics than non-survivors. The CentriMag-related complications included bleeding (n = 22, 37.2%), thromboembolism (n = 5, 8.4%), and infection (n = 4, 6.7%). The risk factors of mortality included Glasgow Coma Scale (Motor + Eye) ≤ 5, and lactate ≥ 8 mmol/L at POD-1, persistent ventricular rhythm or asystole, and total bilirubin ≥ 6 mg/dL at POD-3. Mortality factors included septic shock (n = 11, 18.6%), central failure (n = 10, 16.9%), and multiple organ failure (n = 12, 20.3%). Conclusions: Combined ECLS and t-BiVAD could be a salvage treatment for patients with severe cardiogenic shock, especially for those already having prolonged CPR. This combination can correct organ malperfusion and allow sufficient time to bridge patients to recovery and heart transplantation, especially in Asia, where donation rates are low, as well as intracorporeal VAD or total artificial heart being seldom available.

Hypothyroidism Is Correlated with Ventilator Complications and Longer Hospital Days after Coronary Artery Bypass Grafting Surgery in a Relatively Young Population: A Nationwide, Population-Based Study.

Background: Some research indicated that hypothyroidism has huge adverse effects for the metabolic, cardiovascular, respiratory, and immune systems. However, there is no confirmed conclusion for the effect of cardiovascular surgery. This cohort study aims to investigate the prognosis of hypothyroidism patient at the age under 65-year-old after coronary artery bypass grafting (CABG) surgery. Method: From the National Health Insurance Research Database of Taiwan, 1586 patients with hypothyroidism who underwent elective CABG surgery were selected, along with 6334 patients who underwent surgery in a ratio of 1:4 sex-, age- and index year-matched controls, who were out of hypothyroidism. We used Cox proportional hazard analysis to compare the rate of 30-day, 5-year mortality, post-operative atrial fibrillation, respiratory complication during an average of 10-year follow-up. Result: Post-CABG patients had more hospital days, which was associated with hypothyroidism, male, DM and higher CCI_R (p < 0.001). Post-CABG patients had more inpatient respiratory complications, which was associated with hypothyroidism (p = 0.041), DM and CCI_R (p < 0.001, p = 0.046), and there was no difference in 1-year respiratory complication, tracheostomy in the same hospital course and within 1 year, repeated PCI, Af, CVVH, cerebral infarction, 30-day and 5-year mortality rate. Conclusions: Hypothyroidism correlates to post-CABG ventilator-related complications and pneumonia, and prolonged hospital days, but no effect on 30-day, 5-year mortality, post-operative atrial fibrillation and cerebral infarction rate. Thyroid function survey might include routinely preoperative survey for CABG outcome prognosis.

Tumor Volume Reduction Rate to Induction Chemotherapy is a Prognostic Factor for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Retrospective Cohort Study.

Introduction: Aim of this retrospective cohort study is to evaluate the prognostic value of tumor volume reduction rate status post-induction chemotherapy in locally advanced head and neck squamous cell carcinoma. Methods: Patients newly diagnosed from year 2007 to 2016 at a single center were included in this retrospective study. All patients had received induction Taxotere, Platinum, Fluorouracil followed by daily definitive intensity-modulated radiotherapy for 70 Gy in 35 fractions concurrent with or without cisplatin-based chemotherapy. Tumor volume reduction rate was measured and calculated by contrast-enhanced computed tomography images at diagnosis, and after at least 1 cycle of induction chemotherapy, and analyzed though a univariate and multivariate Cox regression model. Results: Ninety patients of the primary cancer sites at hypopharynx (31/90, 34.4%), oropharynx (29/90, 32.2%), oral cavity (19/90, 21.1%), and larynx (11/90, 12.2%) were included in this study, with a median follow-up time interval of 3.9 years. In multivariate Cox regression analysis, the tumor volume reduction rate of the primary tumor (TVRR-T) was also an independently significant prognostic factor for disease-free survival (DFS) (hazard ratio 0.77, 95% confidence interval 0.62-0.97; P-value = .02). Other factors including patient's age at diagnosis, the primary cancer site, and RECIST (Response Evaluation Criteria in Solid Tumors), were not significantly related. At a cutoff value using 50% in Kaplan-Meier survival analysis, the DFS was higher with TVRR-T ≥ 50% group (log-rank test, P = .024), and a trend of improved overall survival. (log-rank test, P = .069). Conclusion: TVRR-T is a probable prognostic factor for DFS. With a cut-off point of 50%, TVRR-T may indicate better DFS.

Ziprasidone Induces Rabbit Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis.

BACKGROUND: Atypical antipsychotics increase the risk of atrial arrhythmias and sudden cardiac death. This study investigated whether ziprasidone, a second-generation antipsychotic, affected intracellular Ca2+ and Na+ regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. METHODS: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca2+ monitoring using Fluo-3, the patch-clamp method for ionic current recordings, and a fluorescence study for the detection of reactive oxygen species and intracellular Na+ levels were conducted in enzymatically dissociated atrial myocytes. RESULTS: Ziprasidone-treated atriums showed sustained triggered activities after rapid pacing, which were inhibited by KN-93 and ranolazine. A reduced peak L-type Ca2+ channel current and enhanced late Na+ current were observed in ziprasidone-treated atrial myocytes, together with an increased cytosolic Na+ level. KN-93 suppressed the enhanced late Na+ current in ziprasidone-treated atrial myocytes. Atrial myocytes treated with ziprasidone showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leakage. Cytosolic and mitochondrial reactive oxygen species production was increased in atrial myocytes treated with ziprasidone. TNF-α and NLRP3 were upregulated in ziprasidone-treated myocytes, and the level of phosphorylated calcium/calmodulin-dependent protein kinase II protein was increased. CONCLUSIONS: Our results suggest that ziprasidone increases the occurrence of atrial triggered activity and causes intracellular Ca2+ and Na+ dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.

Association between long-term usage of acetylcholinesterase inhibitors and lung cancer in the elderly: a nationwide cohort study.

This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval [CI] = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.

Cerebral Oximetry-Monitored Nitroglycerin Infusion and Tissue Perfusion during Rewarming of Cardiopulmonary Bypass in Cardiac Surgery: A Prospective Randomized Trial.

BACKGROUND: Nitroglycerin facilitates microcirculation and oxygen delivery through vasodilation. The purpose of this study was to clarify the effects of nitroglycerin-induced vasodilation and potential hypotension on tissue perfusion under cerebral oximetry monitoring during rewarming in cardiopulmonary bypass. METHODS: Elective cardiac surgical patients were randomly assigned to either a nitroglycerin group (n = 32) with an intravenous infusion of 1-5 mcg/kg/min or a control group (n = 31) with 0-0.1 mcg/kg/min infusion, since the initiation of rewarming. Perioperative arterial blood gas data were collected in addition to hemodynamic variables, cerebral oximetry values, urine output, and postoperative outcomes. RESULTS: Nearly one-fifth (6/32) of patients in the nitroglycerin group experienced transient (≤5 min) profound hypotension (mean arterial blood pressure ≤40 mmHg) after the initiation of infusion. There were no significant differences between groups in terms of perioperative levels of cerebral oximetry, cardiac index, plasma glucose, lactate, bicarbonate, base excess, or post-bypass activated coagulation time. In the nitroglycerin group, urine output was nonsignificantly higher during cardiopulmonary bypass (p = 0.099) and within 8 h after surgery (p = 0.157). Perioperative transfused blood products, postoperative inotropic doses, extubation time, and intensive care unit stay were comparable for the two groups. CONCLUSIONS: Initiation of intravenous nitroglycerin infusion (at 1-5 mcg/kg/min) during rewarming in hypothermic cardiopulmonary bypass resulted in transient profound hypotension in one-fifth of patients and did not improve perioperative cerebral oxygenation, tissue perfusion, and coagulation in cardiac surgery.

The Role of Sirtuin 1 in Palmitic Acid-Induced Endoplasmic Reticulum Stress in Cardiac Myoblasts.

BACKGROUND: Lipotoxicity causes endoplasmic reticulum (ER) stress, leading to cell apoptosis. Sirtuin 1 (Sirt1) regulates gene transcription and cellular metabolism. In this study, we investigated the role of Sirt1 in palmitate-induced ER stress. METHODS: Both H9c2 myoblasts and heart-specific Sirt1 knockout mice fed a palmitate-enriched high-fat diet were used. RESULTS: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt1 knockout mice and controls. The Sirt1 knockout mice showed higher CHOP and ATF4 expression compared to those in the control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. PA-treated H9c2 cells showed decreased cytosolic NAD+/NADH alongside reduced Sirt1's activity. The H9c2 cells showed increased ATF4 and CHOP expression when transfected with plasmid encoding dominant negative mutant Sirt1. Sirt1 activator SRT1720 did not affect CHOP and ATF4 expression. Although SRT1720 enhanced the nuclear translocation of ATF4, the extent of the binding of ATF4 to the CHOP promoter did not increase in PA treated-H9c2 cells. CONCLUSION: PA-induced ER stress is mediated through the upregulation of ATF4 and CHOP. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt1 activity. The Sirt1 activator SRT1720 promotes the nuclear translocation of ATF4 in PA-treated H9c2 cells.

Efficacy of a temporary CentriMag ventricular assist device in acute fulminant myocarditis patients revived with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Although extracorporeal life support (ECLS) can provide emergency systemic perfusion for acute fulminant myocarditis (AFM), the mortality rate remains extremely high, especially in those undergoing extracorporeal cardiopulmonary resuscitation (ECPR). Temporary ventricular assist device (VAD) can provide a more physiological blood flow direction and better subsequent organ perfusion than ECLS. We investigated temporary VAD efficacy in ECPR-revived AFM patients. METHODS: During January 2012-May 2019, we retrospectively recruited 22 AFM patients with hemodynamic collapse and ECPR; 11 underwent ECLS only and 11 underwent additional VAD support after ECLS. Systemic perfusion was compared via laboratory biochemistry at post-ECPR days 2 (D2) and 4 (D4). Consciousness and cardiac function were assessed through the Glasgow Coma Scale (GCS) and echocardiography, respectively. All major complications and causes of mortality were recorded; 30-day survival was analyzed and risk factors were predicted. RESULTS: The VAD group had significantly better hemodynamic improvement; more inotropes being tapered at D2 and D4; better data representative of systemic perfusion, including albumin, pH, bicarbonate, and lactate levels at D4; and better 30-day survival (72.7% vs. 27.2%, p = 0.033). The causes of mortality included central failure, multiple organ failure, and bacteremia with sepsis. The risk factors included lethal dysrhythmia before ECLS, GCS <5 at D2, and elevated cardiac enzymes at D4. CONCLUSION: For AFM patients, temporary VAD could provide better systemic perfusion and organ preservation than ECLS. VAD had better survival, including improved recovery and successful transplantation. Hence, temporary VAD should be considered if ECLS cannot revive the sustained cardiogenic shock.