Pathobiological Mechanisms of Endothelial Dysfunction Induced by tert-Butyl Hydroperoxide via Apoptosis, Necrosis and Senescence in a Rat Model.

Background: Endothelial dysfunction is one of the underlying causes for vascular diseases. tert-Butyl hydroperoxide (t-BHP), a short-chain lipid hydroperoxide analog, has been reported to cause adverse effects in different systems. However, the adverse actions of t-BHP on inducing endothelial dysfunction are unclear and remain under investigation. Aim of the present study was to identify the pathobiological mechanisms of t-BHP in rat aortic endothelial cells and thoracic aorta. Methods: Primary cultured cells were treated with vehicle or t-BHP (50, 100, 250, 500, and 1,000 µM). Cells were harvested and specific analyses regarding cellular apoptosis, necrosis, and senescence were conducted. Additionally, t-BHP (0.1, 0.2, and 0.4 mmol/kg body weight) or vehicle were administered to male rats (the young group at 6 weeks of age and the mature adult group at 24 weeks of age) daily through intraperitoneal injections. At 10 days after the first drug treatment apoptotic endothelial toxicity was evaluated by biochemical, histological, and immunofluorescent staining analyses. Results: Dose-dependent effects of t-BHP were observed for the reduction of cell viability, deterioration of cell toxicity, initiation of cell cycle arrest, and triggering of apoptosis and necrosis. Moreover, increase of cells stained positive for senescence-associated beta-galactosidase (SA-ß-Gal), amelioration of telomerase activity, and precipitations of necrotic, cell cycle, and apoptotic signaling regulatory proteins were also found in the in vitro model. In the in vivo study, results indicated that t-BHP at higher doses enlarged the intima-medial thickness of descending aorta in the mature adult group, but led to aortic narrowing in the young group. Increased injuries were observed by upregulating endothelial apoptosis- and senescence-positive staining, along with caspase-3 activity and down-regulating telomerase activity. Conclusion: These results confirmed that t-BHP impaired aortic endothelial cell survival at least partially by the activation of p53-mediated signaling pathways, inhibition of cell cycle regulatory proteins, and initiation of cellular senescence-related signaling pathways. In conclusion, t-BHP was found to be a major trigger for impairing aortic endothelial cell survival and deteriorating vascular dysfunction in experimental practice.

Iatrogenic Takotsubo Cardiomyopathy Following Overdose Norepinephrine Administration During Percutaneous Coronary Intervention.

Takotsubo cardiomyopathy (TTC) is characterized by reversible ventricular dysfunction induced by endogenous and, occasionally, exogenous catecholamine. We present a report on a patient who developed TTC and cardiogenic shock during percutaneous coronary intervention (PCI) secondary to inadvertent norepinephrine administration. His hemodynamic status and cardiac function were totally restored within 1 week after hemodynamic support using intra-aortic balloon pump without sequela. Thus, TTC should be considered once a patient presents with symptoms mimicking acute coronary syndrome (ACS) after catecholamine administration.

Factors causing prolonged mechanical ventilation and peri-operative morbidity after robot-assisted coronary artery bypass graft surgery.

Robot-assisted coronary artery bypass graft [robot-assisted (coronary artery bypass grafting (CABG)] surgery is the latest treatment for coronary artery disease. However, the surgery extensively affects cardiac and pulmonary function, and the risk factors associated with peri-operative morbidity, including prolong mechanical ventilation (PMV), have not been fully examined. In this retrospective cohort study, a total of 382 patients who underwent robot-assisted internal mammary artery harvesting with mini-thoracotomy direct-vision bypass grafting surgery (MIDCABG) from 2005 to 2012 at our tertiary care hospital were included. The definition of PMV was failure to wean from mechanical ventilation more than 48 h after the surgery. Risk factors for PMV, and peri-operative morbidity and mortality were analyzed with a multivariate logistic regression model. Forty-three patients (11.3%) developed PMV after the surgery, and the peri-operative morbidity and mortality rates were 38 and 2.6%, respectively. The risk factors for PMV were age, left ventricular ejection fraction (LVEF), the duration of one-lung ventilation for MIDCABG (beating time), and peak airway pressure at the end of the surgery. Furthermore, age and anesthesia time were found to be independent risk factors for peri-operative morbidity, whereas age, LVEF, and anesthesia time were the risk factors for peri-operative mortality. These findings may help physicians to properly choose patients for this procedure, and provide more attention to patients with higher risk after surgery to achieve better clinical outcomes.

Efficacious and safe orotracheal intubation for laboratory mice using slim torqueable guidewire-based technique: comparisons between a modified and a conventional method.

BACKGROUND: Tracheal intubation of laboratory mice remains essential yet challenging for most researchers. The aim of this study was to investigate whether this procedure can be more efficiently and safely accomplished by a novel method using slim and torqueable guidewires to guide access to the trachea. METHODS: This study was carried out in an animal laboratory affiliated to a tertiary medical center. Mice weighing 22 to 28 g were subjected to various open-chest experiments after being anesthetized with intraperitoneal ketamine (100 mg/kg) and lidocaine hydrochloride (10 mg/kg). The oropharyngeal cavity was opened with angled tissue forceps, and the trachea was transilluminated using an external light. The vocal cords were then crossed using either the Conventional method with a 38-mm-long, end-blunted stiff needle as a guide for insertion of a 22-gauge, 25-mm-long intravenous catheter into the trachea, or the Modified method utilizing using a 0.014-inch-thin torqueable wire as the guide to introduce an identical tube over it into the trachea. The epithelial integrity of the trachea was later examined histologically when the animals were sacrificed either immediately after the surgery or at 28 days post-surgery, depending on the corresponding research protocols. RESULTS: Orotracheal intubation was successfully completed in all mice using either the Conventional (N = 42) or the Modified method (N = 50). With the Modified method, intubation took less time (1.73 vs. 2.17 min, Modified vs. Conventional, p < 0.001) and fewer attempts (1.0 vs. 1.33, p < 0.001), and there were fewer procedural difficulties (0% vs. 16.7%, p = 0.009) and complications (0% vs. 11.9%, p = 0.041) compared with the Conventional method. Histological analysis revealed a significantly lower incidence of immediate (0% vs. 39%, p < 0.001) and late (0% vs. 58%, p < 0.001) injuries to the tracheal epithelial lining with the Modified method compared to the Conventional method. CONCLUSIONS: Tracheal intubation for laboratory mice can be completed efficiently, safely and atraumatically using the proposed Modified method employing readily available inexpensive instruments.

Lower serum triglyceride level is a risk factor for in-hospital and late major adverse events in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention- a cohort study.

BACKGROUND: Whether serum triglyceride level correlates with clinical outcomes of patients with ST segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI) remains unclear. METHODS: From June 2008 to February 2012, all patients with STEMI who were treated with pPCI in this tertiary referral hospital and then had fasting lipid profiles measured within 24 hours were included and dichotomized into lower- (≦ 150 mg/dl) and higher-triglyceridemic (>150 mg/dl) groups. Baseline characteristics, in-hospital outcomes, and late major adverse cardiovascular events (MACE) were compared in-between. Independent predictors for in-hospital death and late adverse events were identified by multivariate logistic and Cox regression analyses. RESULTS: A total of 247 patients were enrolled, including 163 lower-triglyceridemic and 84 higher-triglyceridemic subjects. The angiographic characteristics, pPCI results and in-hospital outcomes were similar between the two groups. However, multivariate logistic analysis identified triglyceride level as a negative predictor for in-hospital death (OR 0.963, 95% CI 0.931-0.995, p = 0.023). At follow-up for a mean period of 1.23 to 1.40 years, compared with the high-triglyceridemic group, low-triglyceridemic patients had fewer cumulative incidences of target vessel revascularization (TVR) (21.7% vs. 9.5%, p = 0.011) and overall MACE (26.1% vs. 11.9%, p = 0.0137). Cox regression analysis confirmed serum triglyceride as a negative predictor for TVR and overall MACE. CONCLUSIONS: Serum triglyceride level inversely correlates with in-hospital death and late outcomes in patients with STEMI treated with pPCI. Thus, when managing such patients, a high serum triglyceride level can be regarded as a benign factor but not a target for aggressive therapy.

Involving a Dedicated Epidural-Caring Nurse in Labor Ward Practice Improves Maternal Satisfaction towards Childbirth: A Retrospective Study.

The quality of healthcare is crucially linked to patient satisfaction, particularly in the provision of neuraxial analgesia for labor pain. Neuraxial analgesia for labor pain control should ideally be readily available when requested. However, in real-world practice, anesthesiologists may not always respond immediately to maternal demands, which can compromise the quality of care. To address this issue, this study aimed to evaluate the effectiveness of involving a dedicated nurse in epidural care to improve maternal satisfaction. This study was conducted in a single tertiary center. Medical records of women with singleton pregnancies above 36 gestational weeks who received neuraxial analgesia for labor pain control were reviewed (N = 354). Among them, 104 women (29%) received care from a dedicated nurse. The results showed that involving a dedicated nurse led to higher maternal satisfaction scores before (4.7 ± 0.5 versus 4.5 ± 0.6, p = 0.001), during (4.7 ± 0.6 versus 4.5 ± 0.6, p = 0.002), and at 24 h postpartum (4.7 ± 0.5 versus 4.5 ± 0.5, p = 0.001), without any adverse impact on maternal, neonatal, or epidural-related complications. These findings suggest that allocating a dedicated nurse to epidural care can effectively enhance maternal satisfaction and potentially improve overall care quality.

Transcatheter Edge-to-Edge Repair for a Patient With Severe Mitral Regurgitation of Carpentier IIIa Classification.

Whether patients diagnosed with mitral regurgitation of Carpentier class IIIa (rheumatic origin) can possibly be treated with balloon mitral commissurotomy followed by transcatheter edge-to-edge repair remains unclear. Here, we report on such a case who was successfully treated with balloon mitral commissurotomy and then transcatheter edge-to-edge repair without aggravating mitral stenosis. (Level of Difficulty: Intermediate.).

Recurrent vasodilator-refractory acute coronary syndrome as the exclusive manifestation of Graves disease.

Whether recurrent acute coronary syndrome could be the exclusive manifestation of Graves disease remains unreported. We describe a premenopausal woman who had angiographically normal coronary arteries yet had 3 episodes of acute coronary events in forms of unstable angina, ST elevation, and non-ST elevation myocardial infarction despite the active therapy of calcium-channel blockade. She was finally diagnosed as with Graves disease, treated with antithyroid medication, and free from any angina relapse for up to 18 months. Thus, recurrent coronary events might be the only manifestation of subclinical hyperthyroidism in patients with angiographically normal coronary arteries and could only be prevented by antithyroid agents instead of conventional vasodilators.

A secure and rapid method for orotracheal intubation of laboratory rats utilising handy instruments.

CONTEXT: Tracheal intubation of anaesthetised rats for laboratory experiments remains an essential yet challenging procedure. OBJECTIVE: We aimed to investigate whether tracheal intubation can be safely and securely accomplished in laboratory rats employing only handy instruments and with minimal experience. DESIGN: The feasibility and safety of a modified orotracheal intubation method was evaluated in rats undergoing open-chest surgery as part of another research protocol, and compared with an existing technique. SETTING: The study was carried out in a tertiary medical centre-affiliated animal laboratory. ANIMALS: Eighty-five rats weighing 250 to 350 g anaesthetised with intraperitoneal pentobarbital (60 mg kg(-1)). INTERVENTIONS: Orotracheal intubation was performed on 35 animals (group Jou) using a previously reported technique and then on another 50 rats (group New) using the modified method employing a 3-ml syringe-derived intubation wedge, a 0.025-inch guidewire and a 16-gauge 45-mm-long intravenous catheter. MAIN OUTCOME MEASURES: The time for completion, the number of attempts and the incidence of difficulties and complications were recorded. The intubated tracheas were subsequently examined macroscopically and microscopically to determine position of the intubation catheter and the integrity of epithelial lining. RESULTS: Compared with the previous technique, the new method was completed more rapidly (1 ± 0.2 vs. 5 ± 2.4 min; P < 0.001), more smoothly (difficulties encountered in 8 vs. 74%; P < 0.001), with greater overall success (100 vs. 86%; P=0.022) and with fewer attempts [1 (1 to 1) vs. 2 (2 to 4); P < 0.001) for the new and Jou techniques, respectively, and with a lower incidence of procedure-related complications. Postmortem analysis confirmed there was no microscopic injury to the tracheal epithelial lining with the new technique in contrast to 57% in those using the Jou technique (P < 0.001). CONCLUSION: Tracheal intubation for laboratory rats can be securely and safely completed with the modified method employing a short learning curve and easily available devices.

The Distribution of Skull Score and Skull Density Ratio in Tremor Patients for MR-Guided Focused Ultrasound Thalamotomy.

OBJECTIVE: Magnetic resonance-guided focused ultrasound (MRgFUS) is a minimum-invasive surgical approach to non-incisionally cause the thermos-coagulation inside the human brain. The skull score (SS) has already been approved as one of the most dominant factors related to a successful MRgFUS treatment. In this study, we first reveal the SS distribution of the tremor patients, and correlate the SS with the image feature from customized skull density ratio (cSDR). This correlation might give a direction to future clinical studies for improving the SS. METHODS: Two hundred and forty-six patients received a computed tomography (CT) scan of the brain, and a bone-enhanced filter was applied and reconstructed to a high spatial resolution CT images. The SS of all patients would be estimated by the MRgFUS system after importing the reconstructed CT images into the MRgFUS system. The histogram and the cumulative distribution of the SS from all the patients were calculated to show the percentage of the patients whose SS lower than 0.3 and 0.4. The same CT images of all patients were utilized to calculated the cSDR by first segmented the trabecular bone and the cortical bone from the CT images and divided the average trabecular bone intensity (aTBI) by the average cortical bone intensity (aCBI). The Pearson's correlations between the SS and the cSDR, aTBI, and the aCBI were calculated, respectively. RESULTS: There were 19.19 and 50% of the patient who had the SS lower than the empirical threshold 0.3 and 0.4, respectively. The Pearson's correlation between the SS and the cSDR, aCBI, and the aTBI were R = 0.8145, 0.5723, and 0.8842. CONCLUSION: Half of the patients were eligible for the MRgFUS thalamotomy based on the SS, and nearly 20% of patients were empirically difficult to achieve a therapeutic temperature during MRgFUS. The SS and our cSDR are highly correlated, and the SS had a higher correlation with aTBI than with aCBI. This is the first report to explicitly reveal the SS population and indicate a potential way to increase the chance to achieve a therapeutic temperature for those who originally have low SS.

Case reports of one-lung ventilation using Fuji Uniblocker bronchial blockers for infants under one-year-old in uniportal video-assisted thoracoscopic surgery.

INTRODUCTION: Uniportal video-assisted thoracoscopic surgery (VATS) for various pulmonary diseases provides advantages of less postoperative pain and earlier post-operative recovery over traditional open surgery. The inherent limitation of this surgical modality in manipulation of surgical instruments renders intra-operative one-lung ventilation a requisite to increase the substantially restricted working space and thus visibility of the surgical filed. PATIENT CONCERNS: Patient 1, an 8-month-old, 9-kg, and 70 cm-in-height male infant was diagnosed as congenital pulmonary airway malformation (CPAM) over left lower lobe.Patient 2, a 9-month-old, 8-kg and 72 cm-in-height male infant was diagnosed as CPAM over right lower lobe.Patient 3, an 8-month-old, 8-kg and 67 cm-in-height female infant was diagnosed as CPAM over left lower lobe.This facilitating one-lung ventilation yet was rarely conducted in infants under one year of age for the extremely small body size, the unavailability of dedicated tools, and therein the very tough techniques demanded. DIAGNOSIS: Infants with congenital cystic adenomatoid malformation. INTERVENTIONS: Here we report three infants of less than one year of age in whom one-lung ventilation was successfully achieved by intraluminal use of 5-Fr Fuji Uniblocker Bronchial Blocker devices and in turn assisted the completion of uniportal VATS for congenital cystic adenomatoid malformation in unilateral lungs. OUTCOMES: Three infants received VATS under uniblocker smoothly. Patient 1 had two episode of balloon dislodgement and desaturation and solved by re-insertion. And he had subglottic tracheal stenosis which treatment with laser coagulation. Patient 2 had overall blood loss 80 ml. Patient 3 had one episode of desaturation after stapling the bronchus and fiberoptic bronchoscope revealed obstruction by blood and secretion which solved by suction. CONCLUSION: In conclusion, OLV in infants undergoing uniportal VATs could be successfully achieved by Fuji 5 Fr Uniblocker bronchial blockers for as long as 4 hours, as exemplified by our three cases, and balloon poor sealing and dislodgment can be immediately solved by bronchoscope-guided re-positioning without compromising surgical proceeding or outcome.

Focused Ultrasound Thalamotomy for the Treatment of Essential Tremor: A 2-Year Outcome Study of Chinese People.

Background: Essential tremor (ET) is a common movement disorder among elderly individuals worldwide and is occasionally associated with a high risk for mild cognitive impairment and dementia. This retrospective study aimed to determine the clinical outcome of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET. Methods: In total, 31 male and 17 female patients with drug-refractory ET were enrolled in this research study from January 2017 to September 2019. The severity of tremor and disability were assessed using the Clinical Rating Scale for Tremor (CRST) within a 2-year follow-up period. Results: The mean age of the participants was 59.14 ± 13.5 years. The mean skull density ratio (SDR) was 0.5 ± 0.1. The mean highest temperature was 57.0 ± 2.4°C. The mean number of sonications was 10.0 ± 2.6. The average maximum energy was 19,710.5 ± 8,624.9 J. The total CRST scores and sub-scores after MRgFUS thalamotomy significantly reduced during each follow-up (p < 0.001). All but four (8.3%) of the patients had reversible adverse events (AEs) after the procedure. Conclusions: MRgFUS had sustained clinical efficacy 2 years after treatment for intractable ET. Only few patients presented with thalamotomy-related AEs including numbness, weakness, and ataxia for an extended period. Most Chinese patients were treated safely and effectively despite their low SDR.

Insulin ameliorates hypoxia-induced autophagy, endoplasmic reticular stress and apoptosis of myocardial cells: In vitro and ex vivo models.

Whether and how insulin counteracts the cytotoxic effects of hypoxia and improves cardiomyocyte viability remains unclear. To achieve this aim, cultured neonatal rat cardiomyocytes pretreated with vehicle or 1 µM insulin were exposed to either normoxic or hypoxia environment for up to 24 h. Cell viability was monitored and cellular apoptosis as well as necrosis, indexes of autophagy, endoplasmic reticular (ER) stress, and expressions of specific relevant mediators of the signaling pathways of autophagy were also assessed. Hypoxia impaired cell viability, induced autophagy, triggered apoptosis, activated ER stress pathway-associated apoptotic responses along with downstream pro-apoptotic transcriptional factor C/EBP homologous protein (CHOP), and increased apoptosis of myocardial cells. On the other hand, insulin pretreatment effectively ameliorated autophagy via PI3-K/Akt signaling pathway, suppressed ER stress, and prevented hypoxia-induced cellular apoptosis. In an ex vivo study, isolated rat hearts were pre-treated in some cases with insulin and subjected to proximal left coronary artery ligation to induce acute myocardial ischemia. Coronary ligation-induced acute ischemia upregulated glucose-related protein 78 (GRP78) and triggered cellular apoptosis in the jeopardized myocardium. Conversely, insulin pretreatment suppressed these hypoxia-related cytotoxic events and reduced myocardial infarct size by up to 15.2%. In conclusion, hypoxia impedes cell viability through triggering autophagy, ER stress and apoptosis, whereas insulin pretreatment effectively prevents these cytotoxic actions of hypoxia, preserves myocardial cell viability and reduces myocardial infarct size. These results indicated the cytoprotective mechanism of insulin against the insult of hypoxia may justify insulin as a therapeutic option for patients with acute myocardial infarction.

Ginkgo biloba extract 761 reduces doxorubicin-induced apoptotic damage in rat hearts and neonatal cardiomyocytes.

AIMS: The objective of this study was to investigate whether a cytoprotective herb-derived agent, Ginkgo biloba extract (EGb) 761, could have a beneficial effect on doxorubicin-induced cardiac toxicity in vitro and in vivo. METHODS AND RESULTS: Primary cultured neonatal rat cardiomyocytes were treated with the vehicle, doxorubicin (1 microM), EGb761 (25 microg/mL), or EGb761 plus doxorubicin. After 24 h, doxorubicin upregulated p53 mRNA expression, disturbed Bcl-2 family protein balance, disrupted mitochondrial membrane potential, precipitated mitochondrion-dependent apoptotic signalling, induced apoptotic cell death, and reduced viability of cardiomyocytes, whereas EGb761 pretreatment suppressed all the actions of doxorubicin. Similarly, rats treated with doxorubicin [3 mg/kg intraperitoneally (i.p.) three doses every other day] displayed retarded growth of body and heart as well as elevated apoptotic indexes in heart tissue at both 7 and 28 days after exposure, whereas EGb761 pretreatment (5 mg/kg i.p. 1 day before each dose of doxorubicin) effectively neutralized the aforementioned gross and cellular adverse effects of doxorubicin. CONCLUSION: Doxorubicin impairs viability of cardiomyocytes at least partially by activating the p53-mediated, mitochondrion-dependent apoptotic signalling. EGb761 can effectively and extensively counteract this action of doxorubicin, and may potentially protect the heart from the severe toxicity of doxorubicin.

[Risk factors for intraoperative hypoxemia during monopulmonary ventilation: an observational study]. / Fatores de risco para hipoxemia intraoperatória durante ventilação monopulmonar: estudo observacional.

BACKGROUND: Left double-lumen endotracheal tubes have been widely used in thoracic, esophageal, vascular, and mediastinal procedures to provide lung separation. Lacking clear objective guidelines, anesthesiologists usually select appropriately sized double-lumen endotracheal tubes based on their experience with 35 and 37Fr double-lumen endotracheal tubes, which are the most commonly used. We hypothesized the patients with a left main bronchus of shorter length (<40mm) had a greater chance of experiencing desaturation during one lung ventilation, due to obstruction in the orifice of the left upper lobe with the bronchial tube. METHODS: We included 360 patients with a left double-lumen intubated between September 2014 and August 2015. The patient's age, sex, height, weight, and underlying disease were recorded along with type of surgical procedure and the desaturation episodes. In addition, the width of the trachea and the width and length of the left bronchus were measured using computed tomography. RESULT: Patients with a left main bronchus length of less than 40mm who underwent intubation with a left double-lumen endotracheal tubes had significantly higher incidence of desaturation (Odds Ratio (OR: 8.087)) during one-lung ventilation. Other related factors of patients identified to be at risk of developing hypoxia were diabetes mellitus (OR: 5.368), right side collapse surgery (OR: 4.933), and BMI (OR: 1.105). CONCLUSIONS: We identified that patients with a left main bronchus length of less than 40mm have a great chance of desaturation, especially if other desaturation risk factors are present.

Obstetric and Neonatal Outcomes Associated With Implementation of a COVID-19 Predelivery Screening Policy in a Taiwan Hospital.

This cohort study examines obstetric and neonatal outcomes associated with predelivery screening policy implementation aimed to prevent COVID-19 in a Taiwan hospital.

Mitral regurgitation complicates postoperative outcome of noncardiac surgery.

BACKGROUND: Whether and how mitral regurgitation impacts perioperative outcome of noncardiac surgery remains unclear. METHODS: From November 1999 to August 2004, all patients undergoing noncardiac operations and ever examined by echocardiography within prior 12 months were screened. Those with moderate-severe or severe mitral regurgitation were enrolled provided they were not already trachea-intubated and the surgery was not performed under local anesthesia. The perioperative outcomes of these patients were analyzed, and related prognostic predictors were investigated by multivariate logistic regression analysis. RESULTS: A total of 84 patients (43 men, mean age of 66 years, low surgical risk in 28 and intermediate in 56) complying with the inclusion criteria were included. Their surgery was complicated by frequent (31%) yet minor intraoperative adverse events of controllable hypotension and bradycardia. In contrast, the postoperative outcomes were seriously complicated with high morbidity (27.4%, mostly pulmonary edema and prolonged tracheal intubation) and mortality (11.9%). Atrial fibrillation was identified by multivariate logistic regression analysis as the predictor of inhospital death (OD 11.579, P = .003), whereas surgical risk level (OD 5.118, P = .021), left ventricular ejection fraction (OD 0.958, P = .026), and atrial fibrillation (OD 3.058, P = .045), as independent predictors of postoperative morbidity. CONCLUSIONS: Under current anesthetic management, patients with advanced mitral regurgitation could go through fairly safe intraoperative course of noncardiac surgery despite minor complications. Their postoperative outcome was, however, complicated by extraordinarily high morbidity and mortality, especially in those with preexisting atrial fibrillation, higher surgical risk level, and lower left ventricular ejection fraction.

Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes.

Signaling pathways of IGF-I and insulin receptors play important roles in the regulation of myocardial function. FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. Prolonged incubation with IGF-I increased ubiquitination of FOXO1 and down-regulated the abundance of FOXO1 proteins, which suggested that IGF-I might modulate FOXO1 degradation. To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling.

Protection by doxycycline against doxorubicin-induced oxidative stress and apoptosis in mouse testes.

Spermatogenic cells constitute one of the body tissues that are susceptible to doxorubicin-induced oxidative stress and apoptosis. To explore whether doxorubicin toxicity to these male germ cells could be prevented by adjuvant medication, this study was designed to examine the possible ameliorating action of doxycycline, an antibiotic with anti-oxidant property, on doxorubicin-induced oxidative and apoptotic effects in mouse testes. Male mice at 5-week of age were treated with vehicles, doxorubicin alone (3 mg/kg, i.p. every other day for 3 doses), doxycycline alone (2.5 mg/kg, i.p. every other day for 3 doses), or doxycycline plus doxorubicin (each dose given 1 day post-doxycycline). After 28 days, mice treated with doxorubicin alone displayed smaller body and testicular weights, reduced sperm counts, impaired spermatogenic capability (scarcer spermatids and spermatocytes), increased oxidative stress (malondialdehyde levels), decreased anti-oxidant activity (superoxide dismutase and glutathione peroxidase), and elevated apoptotic indexes (upregulation of Bax and Bad, downregulation of Bcl-2 and Bcl-xL, release of cytochrome c from mitochondria to cytosol, activation of caspase-3, and increase of cleaved caspase-3 abundance and TUNEL positive cells), while doxycycline pretreatment could effectively prevent nearly all of these abnormalities. These results provide firm evidence that doxycycline pretreatment would offset the oxidative and apoptotic impact imposed by doxorubicin, and imply doxycycline to be a promising adjuvant agent that may attenuate the toxicity of doxorubicin on testicular tissues in clinical practice.

Immediate and late outcomes of patients undergoing transseptal left-sided heart catheterization for symptomatic valvular and arrhythmic diseases.

BACKGROUND: The transseptal technique has been widely used for diagnostic and therapeutic left-sided heart catheterization. However, its differential immediate and late outcomes among patients with various valvular and arrhythmic diseases are not yet determined. METHODS: Beginning from 1993, all patients undergoing transseptal procedures were screened and categorized into diagnosis, arrhythmia, and valvuloplasty groups according to the purposes of the catheterization. Incidences of transseptum-related acute major events (cardiac perforation, embolic stroke, and bradyarrhythmia during the procedure) and late complications (residual atrial septal defect [ASD], embolic stroke, bradyarrhythmia, and death up to 18 months) were analyzed and compared between groups. RESULTS: From January 1993 to May 2003, a total of 176 patients underwent 184 transseptal procedures for diagnosis of valvular heart diseases (n = 8), catheter ablation of arrhythmogenic foci (n = 29), and mitral valvuloplasty (n = 147). The immediate outcome was similar among the 3 groups, with an overall acute complication incidence of 3.8%. At follow-up, the incidences of bradyarrhythmia, embolic stroke, and death were not different among the 3 groups. Patients undergoing valvuloplasty had a significantly higher prevalence of residual ASD, especially for those with more severe mitral stenosis and less valvuloplasty success. However, presence of ASD did not impose disadvantage over the 1.5-year prognosis. CONCLUSION: Transseptal left-sided heart catheterization can be safely applied to patients with different categories of cardiac diseases with comparably good immediate and late outcomes. Although patients undergoing percutaneous valvuloplasty have a higher chance of permanent ASD creation, their prognosis is not influenced.