Cardiopulmonary functional capacity in Taiwanese children with ventricular septal defects.

BACKGROUND: Children with ventricular septal defects (VSDs) are considered to have no difference in cardiopulmonary functional capacity with healthy children of the same age; however, studies have shown contradictory findings. The aim of this study was to assess whether Taiwanese children with VSDs exhibited cardiopulmonary deficits. METHODS: This is a retrospective cohort study with the data collected from January 2010 to December 2021. All patients and controls (age-, sex-, and body mass index -matched) underwent cardiopulmonary exercise testing (CPET) and pulmonary function test. RESULTS: In total, 157 VSD patients (80 patients with surgically closed VSDs, 77 patients with unrepaired VSDs) and 157 healthy controls were recruited. Pulmonary function test showed significant among-group differences in maximal voluntary ventilation (MVV) (p = 0.015). The surgically closed group had lower MVV compared to the control group. Regarding CPET, we found VSD patients had lower peak oxygen uptake than the controls (surgically closed group: 30.84 ± 6.27 ml/kg/min; unrepaired group: 32.00 ± 5.95 ml/kg/min; control group: 36.76 ± 6.50 ml/kg/min, p < 0.001). There was also significant among-group differences in aerobic capacity (surgically closed group: 21.20 ± 4.39 ml/kg/min; unrepaired group: 21.68 ± 4.47 ml/kg/min; control group: 26.25 ± 4.33 ml/kg/min, p < 0.001). In addition, the surgically closed group had lower heart rate average at anaerobic threshold than the control group (surgically closed group: 138.11 ± 16.42 bpm; control group: 145.78 ± 15.53 bpm, p = 0.002). CONCLUSION: Taiwanese children with VSD, whether surgically closed or not, have poorer cardiopulmonary performance than age-matched healthy children, and the results of the surgically closed group were even worse.

Long-Term Results of Serial Exercise Testing and Echocardiography Examinations in Patients with Pulmonary Stenosis.

Pulmonary stenosis (PS) affects cardiopulmonary function and exercise performance. Cardiopulmonary exercise testing (CPET) together with transthoracic echocardiography (TTE) can measure exercise performance, PS progression, and treatment effects. We assessed exercise capacity in PS patients using these methods. We enrolled 28 PS patients aged 6-35 years who received surgery, balloon pulmonary valvuloplasty, and follow-up care. The control population was selected by a 1:1 matching on age, sex, and body mass index. Baseline and follow-up peak pulmonary artery pulse wave velocity (PAV) were compared using TTE. Initial CPET revealed no significant differences in anaerobic metabolic equivalent (MET), peak oxygen consumption (VO2), and heart rate recovery between the two groups, nor were significant differences in pulmonary function identified. Within the PS group, there were no significant differences in MET, peak VO2, and heart rate recovery between the baseline and final CPET. Similarly, no significant differences were observed between the baseline and final PAV. The exercise capacity of patients with properly managed PS was comparable to that of healthy individuals. However, during the follow-up, declining trends in pulmonary function, aerobic metabolism, and peak exercise load capacity were observed among adolescents with PS. This study provides long-term data suggesting that PS patients should be encouraged to perform physical activity. Regular reevaluation should also be encouraged to limit performance deterioration.

Effectiveness of Perioperative Cardiopulmonary Rehabilitation in Patients With Lung Cancer Undergoing Video-Assisted Thoracic Surgery.

Objectives: Patients with lung cancer pose a high risk of morbidity and mortality after lung resection. Those who receive perioperative cardiopulmonary rehabilitation (PRCR) have better prognosis. Peak oxygen consumption (peak VO2), VO2 at the ventilatory threshold (VO2 at VT), and slope of minute ventilation to carbon dioxide production (VE/VCO2 slope) measured during pre-surgical cardiopulmonary exercise testing (CPET) have prognostic values after lung resection. We aimed to investigate the influence of individualized PRCR on postoperative complications in patients undergoing video-assisted thoracic surgery (VATS) for lung cancer with different pre-surgical risks. Methods: This was a retrospective study. We recruited 125 patients who underwent VATS for lung cancer between 2017 and 2021. CPET was administered before surgery to evaluate the risk level and PRCR was performed based on the individual risk level defined by peak VO2, VO2 at VT, and VE/VCO2 slope, respectively. The primary outcomes were intensive care unit (ICU) and hospital lengths of stay, endotracheal intubation time (ETT), and chest tube insertion time (CTT). The secondary outcomes were postoperative complications (PPCs), including subcutaneous emphysema, pneumothorax, pleural effusion, atelectasis, infection, and empyema. Results: Three intergroup comparisons based on the risk level by peak VO2 (3 groups), VO2 at VT (2 groups), and VE/VCO2 slope (3 groups) were done. All of the comparisons showed no significant differences in both the primary and secondary outcomes (p = 0.061-0.910). Conclusion: Patients with different risk levels showed comparable prognosis and PPCs after undergoing CPET-guided PRCR. PRCR should be encouraged in patients undergoing VATS for lung cancer.

Evaluations of exercise intolerance with cardiopulmonary exercise tests in an 18-year-old adolescent with pituitary stalk interruption syndrome: a case report.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a rare disease associated with different level of anterior pituitary hormone deficiency resulting with a variety of clinical manifestations which could limit exercise capacity. Cardiopulmonary exercise test (CPET) is valuable in differential diagnosis of exercise intolerance and exercise prescription. CASE PRESENTATION: An 18-year-old male adolescent was diagnosed with PSIS at 4 years old, had undergone growth hormone supplement until puberty, and was referred to rehabilitation department due to exercise intolerance. We arranged pulmonary function test (PFT) and CPET to clarify the cause of limited capacity. The test result provided evidence of moderate functional impairment (54% of predicted maximal oxygen uptake) mainly affected by physical unfitness without significant cardiovascular or pulmonary limitations. CONCLUSION: CPET serves as a valuable tool for diagnostic purpose. Aerobic and resistance exercise training for the patient should be conducted promptly for better prognosis but under safe circumstances, with criteria which could be provided by CPET results.

Cardiopulmonary function findings of pediatric patients with patent ductus arteriosus.

ABSTRACT: Transcatheter occlusion and surgical ligation are the treatments of choice for most patent ductus arteriosus (PDA) in children. Fifty-five children who had PDA completed a pulmonary function test and a symptom-limited treadmill exercise test from 2016 to 2018 at 1 medical center in southern Taiwan. The study group was divided into surgical ligation and catheterization groups, which were compared to a healthy control group matched for age, sex, and body mass index. Data about the performance on the exercise test, including metabolic equivalent at anaerobic threshold and peak, were analyzed. No differences in the pulmonary function and ventilatory parameters were observed between the surgery, catheterization, and control groups. Heart rate at peak and at anaerobic threshold significantly differed in the investigated groups. The post hoc analysis showed that the surgery group had a lower heart rate at peak and threshold compared to the catheterization and control groups (P = .02, P < .001, respectively). No significant difference was found between the catheterization group and the control group. A larger and younger group of patients were recruited, allowing for newer data about the cardiopulmonary function to be obtained. The findings suggest that patients with PDA could undergo physical training after intervention. The imposition of restrictions to limit sports activities should be avoided.

Serial Cardiopulmonary Exercise Testing in Patients after Extracardiac Conduit Total Cavopulmonary Connection for Single-Ventricle Hearts: An Observational Study.

OBJECTIVE: To analyze the aerobic fitness and evolution of exercise tolerance in patients with single-ventricle physiology after total cavopulmonary connection (TCPC) with an extracardiac conduit (ECC). STUDY DESIGN: This retrospective cohort study included patients with previous ECC-TCPC who underwent cardiopulmonary exercise testing (CPET) between September 2010 and September 2019. Patients who completed at least 2 tests (≥6 months apart) with adequate levels of effort were recruited for the serial CPET evaluation. RESULTS: We identified 70 patients (50% male) with a mean age of 6.45 ± 5.14 years at ECC-TCPC and 15.67 ± 5.03 years at the initial CPET. The peak oxygen consumption (peak VO2) to predicted value (peak PD) was 55.90 ± 16.81%. Twenty of the 70 identified patients (50% male) were recruited for serial analysis. The average number of CPETs was 2.6 per patient. The average duration from the first CPET to the last CPET was 3.64 years. The peak VO2 and PD increased slowly, with mean rates of 38.77 ± 129.01 mL/min and 1.66 ± 6.40%, respectively, during the study period. CONCLUSIONS: Although the patients had lower exercise tolerance after ECC-TCPC compared with their normal peers, exercise tolerance appears to have been preserved over the adolescent period in those who underwent serial testing after ECC-TCPC.

Exploration of Niflumic Acid's Action on Ca²âº Movement and Cell Viability in Human Osteosarcoma Cells.

Niflumic acid, a drug used for joint and muscular pain, affected Ca²âº signaling in different models. However, the effect of niflumic acid on Ca²âº homeostasis and Ca²âº-related physiology in human osteosarcoma cells is unknown. This study examined the effect of niflumic acid on cytosolic free Ca²âº concentrations ([Ca²âº]i) in MG63 human osteosarcoma cells. Intracellular Ca²âº concentrations in suspended cells were monitored by using the fluorescent Ca²âº-sensitive dye fura- 2. Cell viability was examined by using 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio- 1,3-benzene disulfonate] water soluble tetrazolium-1 (WST-1). In MG63 cells, niflumic acid at concentrations of 250-750 µM evoked [Ca²âº]i rises concentration-dependently. Niflumic acid-evoked Ca²âº entry was confirmed by Mn²âº-induced quenching of fura-2 fluorescence. This entry was inhibited by nifedipine, econazole, SKF96365, the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate (PMA), but was not affected by the PKC inhibitor GF109203X. In Ca²âº- free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin (TG) inhibited niflumic acid-evoked [Ca²âº]i rises. Conversely, treatment with niflumic acid abolished TG-evoked [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 also partly reduced niflumic acid-evoked [Ca²âº]i rises. Niflumic acid killed cells at 200-500 µM in a concentration-dependent fashion. Chelating cytosolic Ca²âº with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/ AM (BAPTA/AM) did not reverse niflumic acid-induced cytotoxicity. Collectively, our data suggest that in MG63 cells, niflumic acid induced [Ca²âº]i rises by evoking PLC-dependent Ca²âº release from the endoplasmic reticulum, and Ca²âº entry via PKC-sensitive store-operated Ca²âº entry. Niflumic acid also induced Ca²âº-independent cell death.

Effect of thymol on Ca²âº homeostasis and viability in PC3 human prostate cancer cells.

Thymol is a phenolic compound that affects physiology in different cell models. However, whether thymol affects Ca²âº homeostasis in prostate cancer cells is unknown. The action of this compound on cytosolic Ca²âº concentrations ([Ca²âº]i) and viability in PC3 human prostate cancer cells was explored. The results show that thymol at concentrations of 100-1500 µM caused [Ca²âº]i rises in a concentration-dependent manner. Removal of extracellular Ca²âº reduced thymol's effect by approximately 80%. Thymol-induced Ca²âº entry was confirmed by Mn²âº entry-induced quench of fura-2 fluorescence, and was inhibited by approximately 30% by Ca²âº entry modulators (nifedipine, econazole, SKF96365), and the protein kinase C (PKC) inhibitor GF109203X. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin abolished thymol-induced [Ca²âº]i rises. Treatment with thymol also abolished thapsigargin-induced [Ca²âº]i rises. Thymol-induced Ca²âº release from the endoplasmic reticulum was abolished by the phospholipase C (PLC) inhibitor U73122. Thymol at 100-900 µM decreased cell viability, which was not reversed by pretreatment with the Ca²âº chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in PC3 cells, thymol induced [Ca²âº]i rises by inducing PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via PKC-sensitive store-operated Ca²âº channels and other unknown channels. Thymol also induced Ca²âº-dissociated cell death.

Effect of protriptyline on [Ca2+]i and viability in MG63 human osteosarcoma cells.

Tricyclic antidepressants (TCA) have been clinically prescribed in the auxiliary treatment of cancer patients. Although protriptyline, a type of TCA, was used primarily in the clinical treatment of mood disorders in cancer patients, the effect of protriptyline on physiology in human osteosarcoma is unknown. This study examined the effect of protriptyline on cytosolic free Ca2+ concentrations ([Ca2+]i) and viability in MG63 human osteosarcoma cells. Protriptyline between 50 and 250 µM evoked [Ca2+]i rises concentration-dependently. Protriptyline induced influx of Mn2+, indirectly implicating Ca2+ influx. Protriptyline-evoked Ca2+ entry was inhibited by nifedipine by 20% but was not altered by econazole, SKF96365, GF109203X, and phorbol-12-myristate-13-acetate (PMA). In Ca2+-free medium, treatment with protriptyline inhibited the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin-evoked [Ca2+]i rises. Conversely, treatment with thapsigargin inhibited 45% of protriptyline-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter protriptyline-evoked [Ca2+]i rises. Protriptyline at 50-250 µM decreased cell viability, which was not reversed by pretreatment with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, our data suggest that in MG63 cells, protriptyline induced [Ca2+]i rises by evoking Ca2+ release from the endoplasmic reticulum and other stores in a PLC-independent manner, and Ca2+ entry via a nifedipine-sensitive Ca2+ pathway. Protriptyline also caused Ca2+-independent cell death.

Oxygen uptake efficiency slope and peak oxygen consumption predict prognosis in children with tetralogy of Fallot.

BACKGROUND: Oxygen uptake efficiency slope (OUES) and peak oxygen consumption (VO2peak) are exercise parameters that can predict cardiac morbidity in patients with numerous heart diseases. But the predictive value in patients with tetralogy of Fallot is still undetermined, especially in children. We evaluated the prognostic value of OUES and VO2peak in children with total repair of tetralogy of Fallot. DESIGN: Retrospective cohort study. METHODS: Forty tetralogy of Fallot patients younger than 12 years old were recruited. They underwent a cardiopulmonary exercise test during the follow-up period after total repair surgery. The results of the cardiopulmonary exercise test were used to predict the cardiac related hospitalization in the following two years after the test. RESULTS: OUES normalized by body surface area (OUES/BSA) and the percentage of predicted VO2peak appeared to be predictive for two-year cardiac related hospitalization. Receiver operating characteristic curve analysis demonstrated that the best threshold value for OUES/BSA was 1.029 (area under the curve = 0.70, p = 0.03), and for VO2peak was 74% of age prediction (area under the curve = 0.72, p = 0.02). The aforementioned findings were confirmed by Kaplan-Meier plots and log-rank test. CONCLUSIONS: OUES/BSA and VO2peak are useful predictors of cardiac-related hospitalization in children with total repair of tetralogy of Fallot.

The mechanism of protriptyline-induced Ca2+ movement and non-Ca2+-triggered cell death in PC3 human prostate cancer cells.

Protriptyline, a tricyclic anti-depressant, is used primarily to treat the combination of symptoms of anxiety and depression. However, the effect of protriptyline on prostate caner is unknown. This study examined whether the anti-depressant protriptyline altered Ca(2+) movement and cell viability in PC3 human prostate cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)](i). Protriptyline evoked [Ca(2+)](i) rises concentration-dependently. The response was reduced by removing extracellular Ca(2+). Protriptyline-evoked Ca(2+) entry was inhibited by store-operated channel inhibitors (nifedipine, econazole and SKF96365), protein kinase C activator (phorbol 12-myristate 13 acetate, PMA) and protein kinase C inhibitor (GF109203X). Treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5-di-tert-butylhydr-oquinone (BHQ) in Ca(2+)-free medium inhibited 60% of protriptyline-evoked [Ca(2+)](i) rises. Conversely, treatment with protriptyline abolished BHQ-evoked [Ca(2+)](i) rises. Inhibition of phospholipase C with U73122 suppressed 50% of protriptyline-evoked [Ca(2+)](i) rises. At concentrations of 50-70 µM, protriptyline decreased cell viability in a concentration-dependent manner; which were not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, in PC3 cells, protriptyline evoked [Ca(2+)](i) rises by inducing phospholipase C-associated Ca(2+) release from the endoplasmic reticulum and other stores, and Ca(2+) influx via protein kinase C-sensitive store-operated Ca(2+) channels. Protriptyline caused cell death that was independent of [Ca(2+)](i) rises.

Effect of fluoxetine on [Ca²âº]i and cell viability in OC2 human oral cancer cells.

Fluoxetine is a serotonin-specific reuptake inhibitor that has been used as an antidepressant. This study examined the effect of fluoxetine on cytosolic free Ca²âº concentrations ([Ca2⁺]i) and viability in OC2 human oral cancer cells. The Ca²âº-sensitive fluorescent dye fura-2 was used to measure [Ca²âº]i, and the water soluble tetrazolium (WST-1) regent was used to measure viability. Fluoxetine induced [Ca²âº]i rises concentration-dependently. The response was reduced by half by removing extracellular Ca²âº. Fluoxetine-induced Ca²âº entry was enhanced by activation of protein kinase C (PKC) with phorbol 12-myristate 13 acetate (PMA) but was inhibited by inhibition of the enzyme with GF109203X. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or thapsigargin abolished fluoxetine-evoked [Ca²âº]i rise. Conversely, treatment with fluoxetine inhibited BHQ/thapsigargin-evoked [Ca²âº]i rise. Inhibition of phospholipase C (PLC) with U73122 abolished fluoxetine-induced [Ca²âº]i rise. At 20-80 µM, fluoxetine decreased cell viability concentration-dependently, which was not altered by chelating cytosolic Ca²âº with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). At 20-60 µM, fluoxetine induced apoptosis as detected by annexin V/propidium iodide (PI) staining. Together, in OC2 cells, fluoxetine induced [Ca²âº]i rises by evoking PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via PKC-regulated mechanisms. Fluoxetine also caused Ca²âº-independent apoptosis.

Rise of [Ca²âº]i and apoptosis induced by M-3M3FBS in SCM1 human gastric cancer cells.

M-3M3FBS (2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide is a presumed phospholipase C activator which induced Ca²âº movement and apoptosis in different cell models. How- ever, the effect of m-3M3FBS on cytosolic free Ca²âº concentrations ([Ca²âº]i) and apoptosis in SCM1 human gastric cancer cells is unclear. This study explored whether m-3M3FBS elevated basal [Ca²âº]i levels in suspended cells by using fura-2 as a Ca²âº-sensitive fluorescent dye. M-3M3FBS at concentrations between 5-50 µM increased [Ca²âº]i in a concentration-dependent manner. The Ca²âº signal was reduced by half by removing extracellular Ca²âº. M-3M3FBS-induced Ca²âº influx was inhibited by nifedipine, econazole, SK&F96365, aristolochic acid, and GF109203X. In Ca²âº-free medium, 50 µM m-3M3FBS pretreatment inhibited the [Ca²âº]i rise induced by the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin. Conversely, pretreatment with thapsigargin partly reduced m-3M3FBS-induced [Ca²âº]i rise. Suppression of inositol 1,4,5-trisphosphate production with U73122 did not change m-3M3FBS- induced [Ca²âº]i rise. At concentrations between 25 and 50 µM m-3M3FBS killed cells in a concentration- dependent manner. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca²âº with acetoxy-methyl ester of bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM). Annexin V/propidium iodide staining data suggest that m-3M3FBS induced apoptosis at 25 and 50 µM. M-3M3FBS also increased levels of superoxide. Together, in human gastric cancer cells, m-3M3FBS induced a [Ca²âº]i rise by inducing phospholipase C-independent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via protein kinase C-sensitive store-operated Ca²âº channels. M-3M3FBS induced cell death that might involve apoptosis via reactive oxygen species production.

M-3M3FBS-induced Ca² ⁺ movement and apoptosis in HA59T human hepatoma cells.

The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide (m-3M3FBS), a presumed phospholipase C activator, on cytosolic free Ca² ⁺ concentrations ([Ca² ⁺ ]i ) in HA59T human hepatoma cells is unclear. This study explored whether m-3M3FBS elevated basal [Ca² ⁺ ]i levels in suspended cells by using fura-2 as a Ca² ⁺ -sensitive fluorescent dye. M-3M3FBS at concentrations of 10- 50 µM increased [Ca² ⁺ ]i in a concentration-dependent fashion. The Ca² ⁺ signal was reduced partly by removing extracellular Ca² ⁺ . M-3M3FBS-induced Ca² ⁺ influx was inhibited by nifedipine, econazole, SK&F96365, aristolochic acid, and GF109203X. In Ca² ⁺ -free medium, 50 µM m-3M3FBS pretreatment inhibited the [Ca² ⁺ ]i rise induced by the endoplasmic reticulum Ca² ⁺ pump inhibitor thapsigargin. Conversely, pretreatment with thapsigargin partly reduced m-3M3FBS-induced [Ca² ⁺ ]i rise. Inhibition of inositol 1,4,5-trisphosphate formation with U73122 did not alter m-3M3FBS-induced [Ca² ⁺ ]i rise. At concentrations between 10 and 40 µM m-3M3FBS killed cells in a concentration-dependent manner. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca² ⁺ with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data suggest that m-3M3FBS induced apoptosis in a concentration-dependent manner. M-3M3FBS also increased levels of reactive oxygen species. Together, in human hepatoma cells, m-3M3FBS induced a [Ca² ⁺ ]i rise by inducing phospholipase C-independent Ca² ⁺ release from the endoplasmic reticulum and Ca² ⁺ entry via protein kinase C-sensitive store-operated Ca² ⁺ channels. M-3M3FBS induced cell death that might involve apoptosis via mitochondrial pathways.

Effect of sertraline on [Ca2+](i) and viability of human MG63 osteosarcoma cells.

The antidepressant, sertraline, has been shown to have diverse in vitro effects. This study examined whether sertraline altered [Ca(2+)](i) in MG63 human osteosarcoma cells by using fura-2 as a Ca(2+)-sensitive fluorescent dye. At 50-200 µM, sertraline induced a [Ca(2+)](i) rise in a concentration-dependent manner. Ca(2+) response was decreased by removing extracellular Ca(2+), suggesting that Ca(2+) entry and release contributed to the [Ca(2+)](i) signal. Sertraline-induced Ca(2+) entry was inhibited by nifedipine, La(3+), Gd(3+), and SK&F96365. When extracellular Ca(2+) was removed, pretreatment with the endoplasmic reticulum (ER) Ca(2+) pump inhibitor, thapsigargin, or 2,5-di-tert-butylhydroquinone (BHQ) abolished the sertraline-evoked [Ca(2+)](i) rise. Incubation with sertraline also abolished the thapsigargin or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C (PLC) with U73122 abolished the sertraline-induced [Ca(2+)](i) rise. At 20-30 µM, overnight treatment with sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data demonstrate that sertraline (30 µM) evoked apoptosis. Sertraline (20 and 30 µM) also increased levels of reactive oxygen species. Together, in human osteosarcoma cells, sertraline evoked a [Ca(2+)](i) rise by inducing PLC-dependent Ca(2+) release from the ER and Ca(2+) entry by L-type Ca(2+) channels and store-operated Ca(2+) channels. Sertraline induced cell death that may involve apoptosis by mitochondrial pathways.

The mechanism of carvacrol-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in OC2 human oral cancer cells.

Carvacrol is one of the main substances of essential oil which triggers intracellular Ca(2+) mobilization and causes cytotoxicity in diverse cell models. However, the mechanism of carvacrol-induced Ca(2+) movement and cytotoxicity is not fully understood. This study examined the effect of carvacrol on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)), cell viability and apoptosis in OC2 human oral cancer cells. Carvacrol induced a [Ca(2+)](i) rise and the signal was reduced by removal of extracellular Ca(2+). Carvacrol-induced Ca(2+) entry was not altered by store-operated Ca(2+) channel inhibitors and protein kinase C (PKC) activator, but was inhibited by a PKC inhibitor. In Ca(2+) -free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) inhibited carvacrol-induced [Ca(2+)](i) rise. Conversely, incubation with carvacrol inhibited TG or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C (PLC) with U73122 abolished carvacrol-induced [Ca(2+)](i) rise. Carvacrol decreased cell viability, which was not reversed when cytosolic Ca(2+) was chelated with BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester). Carvacrol-induced apoptosis and activation of reactive oxygen species (ROS) and caspase-3. Together, carvacrol induced a [Ca(2+)](i) rise by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive, non store-operated Ca(2+) channels. Carvacrol-induced ROS- and caspase-3-associated apoptosis.

Effect of diindolylmethane on Ca2+ homeostasis and viability in PC3 human prostate cancer cells.

The effect of the natural product diindolylmethane on cytosolic Ca(2+) concentrations ([Ca(2+)](i)) and viability in PC3 human prostate cancer cells was explored. The Ca(2+)-sensitive fluorescent dye fura-2 was applied to measure [Ca(2+)](i). Diindolylmethane at concentrations of 20-50 µM induced [Ca(2+)](i) rise in a concentration-dependent manner. The response was reduced partly by removing Ca(2+). Diindolylmethane-evoked Ca(2+) entry was suppressed by nifedipine, econazole, SK&F96365, protein kinase C modulators and aristolochic acid. In the absence of extracellular Ca(2+), incubation with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited or abolished diindolylmethane-induced [Ca(2+)](i) rise. Incubation with diindolylmethane also inhibited thapsigargin or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C with U73122 reduced diindolylmethane-induced [Ca(2+)](i) rise. At concentrations of 50-100 µM, diindolylmethane killed cells in a concentration-dependent manner. This cytotoxic effect was not altered by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/PI staining data implicate that diindolylmethane (50 and 100 µM) induced apoptosis in a concentration-dependent manner. In conclusion, diindolylmethane induced a [Ca(2+)](i) rise in PC3 cells by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via phospholipase A(2)-sensitive store-operated Ca(2+) channels. Diindolylmethane caused cell death in which apoptosis may participate.

Treatment strategies for acute coronary syndrome with severe mitral regurgitation and their effects on short- and long-term prognosis.

Mitral regurgitation (MR) of even mild severity affects the prognosis of patients with acute coronary syndrome (ACS). The present study retrospectively analyzed 1,142 patients with ACS and MR of varying severity. Of the 95 patients with severe MR, 57 (60%) underwent primary percutaneous coronary intervention only and 38 (40%) underwent coronary artery bypass grafting (CABG) and mitral valve replacement (MVR). The severity of MR was significantly associated with the risk of heart failure but not with in-hospital or long-term mortality. In patients with severe MR, in-hospital mortality was no greater in those treated with CABG and MVR than in those treated with percutaneous coronary intervention alone. However, the incidence of long-term hard events (heart failure and all-cause mortality) was lower in those who had received the combined treatment. Multivariate analysis showed that, compared to percutaneous coronary intervention alone, CABG combined with MVR at the acute phase of ACS resulted in a significantly improved prognosis (odds ratio 0.172, 95% confidence interval 0.046 to 0.649, p = 0.009), even after adjusting for age, left ventricular filling pressure, and ejection fraction. In conclusion, the severity of MR in patients with ACS is associated with long-term heart failure events. Even at the acute phase of ACS, CABG combined with MVR results in an acceptable in-hospital mortality rate. The combined strategy also reduced the long-term hard events.

Left atrial expansion index for predicting atrial fibrillation and in-hospital mortality after coronary artery bypass graft surgery.

BACKGROUND: Atrial fibrillation (AF), a common complication after coronary artery bypass graft surgery (CABG), is associated with prolonged hospital stay. This prospective study assessed the accuracy of left atrial parameters and additional preoperative characteristics for predicting post-CABG AF and in-hospital mortality. METHODS: A total of 197 patients without hemodynamic-significant valvular problems, who received isolated CABG, were enrolled. Echocardiography was performed before CABG. RESULTS: Compared with patients without post-CABG AF, those with post-CABG AF were older (71 vs 64 years, p<0.0001), had a higher incidence of CABG during index hospitalization of acute myocardial infarction and preoperative respiratory failure requiring ventilator support, lower left ventricular ejection fraction (0.41 vs 0.48, p<0.0001), lower left atrial expansion index (52.2% vs 93.3%, p<0.0001), and higher left ventricular filling pressure (24.2 vs 19.1 mm Hg, p<0.0001). Multivariate analysis of preoperative variables showed that independent predictors of AF included age (odds ratio [OR], 1.064; 95% confidence interval [CI], 1.022 to 1.107 per 1-year increase; p 0.002), maximal indexed left atrial volume (OR, 1.026; 95% CI, 1.002 to 1.051 per 1 mL/m2 increase; p 0.037) and left atrial expansion index (OR, 0.981; 95% CI, 0.962 to 0.998 per 1% increase; p 0.029). The left atrial expansion index was also significantly associated with in-hospital mortality (OR, 0.982; 95% CI, 0.951 to 0.996 per 1% increase; p 0.042). Incidence of post-CABG AF in patients with left atrial expansion index less than 120% progressively increased as left atrial expansion index decreased. CONCLUSIONS: Left atrial expansion index independently predicts post-CABG AF and in-hospital mortality.

Effect of celecoxib on Ca(2+) handling and viability in human prostate cancer cells (PC3).

Celecoxib has been shown to have an antitumor effect in previous studies, but the mechanisms are unclear. Ca(2+) is a key second messenger in most cells. The effect of celecoxib on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) in human suspended PC3 prostate cancer cells was explored by using fura-2 as a fluorescent dye. Celecoxib at concentrations between 5 and 30 µM increased [Ca(2+)](i) in a concentration-dependent manner. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+). Celecoxib-induced Ca(2+) influx was not blocked by L-type Ca(2+) entry inhibitors or protein kinase C/A modulators [phorbol 12-myristate 13-acetate (PMA), GF109203X, H-89], but was inhibited by the phospholipase A(2) inhibitor, aristolochic acid. In Ca(2+)-free medium, 30 µM of celecoxib failed to induce a [Ca(2+)](i) rise after pretreatment with thapsigargin (an endoplasmic reticulum [ER] Ca(2+) pump inhibitor). Conversely, pretreatment with celecoxib inhibited thapsigargin-induced Ca(2+) release. Inhibition of phospholipase C with U73122 did not change celecoxib-induced [Ca(2+)](i) rises. Celecoxib induced slight cell death in a concentration-dependent manner, which was enhanced by chelating cytosolic Ca(2+) with BAPTA. Collectively, in PC3 cells, celecoxib induced [Ca(2+)](i) rises by causing phospholipase C-independent Ca(2+) release from the ER and Ca(2+) influx via non-L-type, phospholipase A(2)-regulated Ca(2+) channels. These data may contribute to the understanding of the effect of celecoxib on prostate cancer cells.