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Background: Despite improvements in outcomes of ST elevation myocardial infarction (STEMI), ventricular septal rupture (VSR) remains a known complication, carrying high mortality. The contemporary incidence, mortality, and management of post-STEMI VSR remains unclear., Methods: The National Inpatient Sample database (2009-2020) was used to study trends in admissions and outcomes of post-STEMI VSR over time. Survey estimation commands were used to determine weighted national estimates., Results: There were 2 315 186 ± 22 888 visits for STEMI with 0.194 ± 0.01% experiencing VSR during 2009-2020 in the USA. Patients with VSR were more often older, white, female, and presented with an anterior STEMI; there was no difference in the rates of fibrinolysis. In-hospital mortality was 73.6 ± 1.8%, but only 29.2 ± 1.9 and 10 ± 1.2% received surgical repair and transcatheter repair (TCR), respectively. TCR was associated with higher and surgical repair with lower mortality. Days to surgery were longer for those who survived (5.9 ± 2.75) compared with those who died (2.44 ± 1). In a multivariable analysis, surgical repair at greater than or equal to day 4 was associated with lower in-hospital mortality (odds ratio = 0.39, 95% confidence interval: 0.17-0.88)., Conclusion: Mortality in post-STEMI VSR remains high with no improvement over time. Most patients are managed conservatively, and the frequency of surgical repair has decreased, while TCR has increased over the study period. Despite design limitations and survival bias, surgical repair at greater than or equal to 4 days was associated with a lower mortality., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Despite key differences in pathological processes, both Intramural Hematomas and Aortic Dissections are Acute Aortic Syndromes repaired with similar surgical technique. The objective of this study was to determine differences in surgical outcomes between patients with Intramural Hematoma versus Type A Aortic Dissection undergoing Ascending Aortic Arch repair., Methods: This retrospective review of prospectively collected data included all patients with acute Intramural Hematoma or Type A Aortic Dissection who underwent emergent Ascending- or Arch Repair from January 2018 to May 2023 at a single academic institution. Primary outcomes included intraoperative mortality, 30-Day mortality, and postoperative stay. Secondary outcomes included postoperative complications. Outcomes were analyzed using Chi-squared, Fisher's Exact, and t-tests, with significance set at p < 0.05., Results: A total of 107 patients were included, 27 of whom (25%) had Intramural Hematoma and 80 (75%) had Type A Aortic Dissection. There were no differences in preoperative characteristics such as age, gender, and comorbidities, and no differences in perioperative characteristics such as case length, cardiopulmonary bypass, aortic cross-clamp, and circulatory arrest times. When comparing postoperative outcomes, there was a higher rate of postoperative pericardial effusions requiring pericardial window in the Intramural Hematoma cohort compared to the Aortic Dissection cohort (15% [n = 4] vs. 3% [n = 2]; p = 0.02). There were no differences in other primary outcomes such as intraoperative mortality, 30-Day mortality, and postoperative length of stay. There were also no differences in the rates of postoperative complications such as bleeding requiring reoperation, cerebrovascular accident, atrial fibrillation, pleural effusion requiring thoracentesis, and surgery-related Emergency Department visits., Conclusions: Our analysis demonstrates similar outcomes for patients undergoing Ascending Aortic Arch repair between patients with Intramural Hematoma and Type A Aortic Dissection. Despite the higher rate of required postoperative pericardial windows in the Intramural Hematoma cohort, the overall primary outcomes remained comparable. These findings better elucidate the standard of care for patients with acute Intramural Hematoma undergoing Ascending Aortic Arch repair., (© 2024. The Author(s).)

We describe a rare complication of intraprocedural spontaneous thrombus formation on a transcatheter edge-to-edge repair (MitraClip; Abbott Laboratories) device in a hypercoagulable yet adequately anticoagulated patient. We also outline the novel use of a vacuum (Penumbra) aspiration system, which resulted in rapid and effective thrombus elimination., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Dishcook is a new cooking system that allows individual cooking using a dedicated induction heater. This study investigated whether Dishcook use affects the nutritional value of individuals with intellectual disabilities. This study was conducted on users receiving support from a continuous-employment office in Obama City, Fukui Prefecture, in 2022. Of these participants, 18 (seven women and 11 men) who requested the use of the Dishcook were included in the analysis. The study period was from January to August 2023. The mean age was 48.72±16.24 y. A significant increase in the overall phase angles of the limbs was observed. Triglyceride, LDL cholesterol, HbA1c, and serum zinc levels improved in patients who used the Dishcook. The phase angle obtained using Bioelectrical Impedance Analysis also improved, indicating the usefulness of the Dishcook in treating metabolic diseases and the possibility of individualized nutritional management.

Introduction: We sought to compare outcomes after early discharge in patients with and without predischarge diagnosis of arrhythmia following minimally invasive valve surgery (MIVS)., Materials and Methods: We retrospectively reviewed ambulatory electrocardiography (AECG) datasheets and medical records of patients discharged with 14-d AECG monitoring from our facility between October 2019 and March 2022 ≤ 3 d after MIVS. Baseline and clinical characteristics, arrhythmias during AECG monitoring, and 30-d adverse outcomes were reported for the population and stratified by presence or absence of predischarge arrhythmia., Results: Of 41 patients discharged ≤3 d postoperatively of MIVS, 17 (41.5%) experienced predischarge arrhythmias and 24 (58.5%) did not. The population was predominantly male and White with a median age of 62 y [57, 70]. Baseline and clinical characteristics did not differ between subgroups. Most patients (92.7% [n = 38]) experienced one or more tachyarrhythmias during the AECG monitoring period. There were similar proportions of patients experiencing atrial fibrillation in both groups, but patients with predischarge arrhythmias had higher burden of atrial fibrillation on AECG monitoring (27.60% [6.57%, 100%] versus 1.65% [0.76%, 4.32%]; P = 0.004). The predischarge arrhythmia subgroup had higher proportions of patients experiencing nonsustained ventricular tachycardia but lower proportions experiencing supraventricular tachycardia. There were no mortalities within 30 d of surgery. Six (14.6%) patients were readmitted within 30 d with equal proportions of readmissions between subgroups (P = 0.662)., Conclusions: Early discharge timelines and noninvasive monitoring techniques can allow patients to return to their normal activities quicker in the comfort of their own home with no increased risk of morbidity or mortality., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of minimally invasive cardiac surgery (MICS) on resource utilization, cost, and postoperative outcomes in patients undergoing left-heart valve operations., Methods: Data were retrospectively reviewed for patients undergoing single-valve surgery (eg, aortic valve replacement, mitral valve replacement, or mitral valve repair) at a single center from 2018 to 2021, stratified by surgical approach: MICS vs full sternotomy (FS). Baseline characteristics and postoperative outcomes were compared. Primary outcome was high resource utilization, defined as direct procedure cost higher than the third quartile or either postoperative LOS ≥7 days or 30-day readmission. Secondary outcomes were direct cost, length of stay, 30-day readmission, in-hospital and 30-day mortality, and major morbidity. Multiple regression analysis was conducted, controlling for baseline characteristics, operative approach, valve operation, and lead surgeon to assess high resource utilization., Results: MICS was correlated with a significantly lower rate of high resource utilization (MICS, 31.25% [n = 115] vs FS 61.29% [n = 76]; P  < .001). Median postoperative length of stay (MICS, 4 days [range, 3-6 days] vs FS, 6 days [range, 4 to 9 days]; P  < .001) and direct cost (MICS, $22,900 [$19,500-$28,600] vs FS, $31,900 [$25,900-$50,000]; P  < .001) were lower in the MICS group. FS patients were more likely to experience postoperative atrial fibrillation ( P  = .040) and renal failure ( P  = .027). Other outcomes did not differ between groups. Controlling for stratified Society of Thoracic Surgeons predicted risk of mortality, cardiac valve operation, and lead surgeon, FS demonstrated increased likelihood of high resource utilization ( P  < .001)., Conclusions: MICS for left-heart valve pathology demonstrated improved postoperative outcomes and resource utilization., (© 2023 The Author(s).)

Background: Establishing cardiopulmonary bypass remains critical to the successful repair of an acute type A aortic dissection. A recent trend away from femoral arterial cannulation has occurred in part due to concerns of stroke risk from retrograde perfusion to the brain. The purpose of this study was to determine if arterial cannulation site for aortic dissection repair impacts surgical outcomes., Methods: A retrospective chart review was performed at Rutgers Robert Wood Johnson Medical School from January 1st, 2011 to March 8th, 2021. Of the 135 patients included, 98 (73%) underwent femoral arterial cannulation, 21 (16%) axillary artery cannulation, and 16 (12%) direct aorta cannulation. The study variables included demographic data, cannulation site, and complications., Results: The mean age was 63.6±14 years, with no difference between the femoral, axillary, and direct cannulation groups. Eighty-four patients (62%) were male, with similar percentages amongst each group. The rates of bleeding, stroke, and mortality specifically due to the arterial cannulation did not significantly differ based on cannulation site. None of the patients had strokes that were attributable to cannulation type. No patients died as a direct complication of arterial access. The overall in-hospital mortality was 22%, similar between groups., Conclusions: This study found no statistically significant different in rates of stroke or other complications based on cannulation site. Femoral arterial cannulation thus remains a safe and efficient choice for arterial cannulation in the repair of acute type A aortic dissection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-576/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Objective: Over the last two decades there has been an increase in the number of cardiac implantable electronic devices and consequently, there has also been an increased need for lead extractions. Fibrotic attachments develop between the lead and the venous and cardiac structures that may require the use of a laser to mobilize the lead. Cardiothoracic surgeons (CTS) have traditionally provided backup for surgical emergencies for these extractions. This study evaluates the surgical outcomes of patients undergoing transvenous laser lead extractions (TLE) and determines if CTS are still needed for backup., Methods: A retrospective review of consecutive patients undergoing laser lead extractions at a single academic center. Lead extractions using only laser sheaths were analyzed. The clinical characteristics, complications, and mortality of the patients were evaluated., Results: One hundred and twenty-one patients underwent TLEs from January 1st, 2014 to December 31st, 2018. The majority were male (N = 80, 66.1%), and the average age was 66.48 ± 14 years. The indication for removal was either laser lead malfunction or infection. A total of 30 patients (24.8%) had complications postoperatively including wound hematomas, superficial infections, and arrhythmias. The average length of stay was 9 ± 12 for all the patients in the study. 2 patients (1.6%) had injuries that required emergency surgical repair with injuries to the posterior superior vena cava and right ventricle. Both patients survived the initial injury with one patient was discharged home on day 4 and the other succumbing to his injuries on postoperative day 20., Conclusion: Although the incidence of surgical emergencies is rare the morbidity and mortality for TLE require that surgical backup be available., (© 2022. The Author(s).)

Background: Empirical studies between anger and anger-provoking cognitive variables in children and adolescents are lacking, despite numerous studies on internalising and externalising problems., Aim: The purpose of this study was to develop new questionnaires for anger-provoking cognitive errors and automatic thoughts, and examine relationships between anger, cognitive errors, and automatic thoughts in children and adolescents., Method: Participants were 485 Japanese children and adolescents aged 9-15 years old (254 females; average age 12.07; SD = 1.81). They completed the Anger Children's Cognitive Error Scale (A-CCES) and the Anger Children's Automatic Thought Scale (A-CATS), which were developed in this study, as well as the Anger Scale for Children and Adolescents and the Japanese version of Short Spence Children's Anxiety Scale., Results: Both the A-CCES and the A-CATS had adequate reliability (internal consistency) and validity (face validity, structural validity and construct validity). A hierarchal regression analysis indicated that automatic thoughts were positively and moderately related to anger ( β = .37) after controlling for age, gender, anxiety symptoms, cognitive errors and interaction term. Moreover, a mediation analysis indicated that automatic thoughts significantly mediated the relationship between cognitive errors and anger (indirect effect, 0.24; 95% CI: .020 to .036)., Conclusions: This study developed the new questionnaires to assess anger-provoking cognitive errors and automatic thoughts. In addition, this study revealed that automatic thoughts rather than cognitive errors are associated with anger in children and adolescents.

Foreign bodies in the heart are a rare condition and an exact mechanism for this occurrence has not been well described. These objects can reach the heart by direct penetration due to local trauma or through intravenous migration or may remain in the heart after medical procedures. The most common foreign bodies that reach the heart are bullets and shrapnel. The purpose of this study is to review a case where a patient injected himself with recreational drugs. The needle subsequently dislodged from the syringe and migrated into the heart., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Lemaire et al.)

Delayed presentation of penetrating cardiac injuries is exceedingly rare due to the observed near 100% pre-hospital mortality. We describe a case of a patient who presented for evaluation nearly 24 h after sustaining a self-inflicted pneumatic nail gun injury to the right ventricular outflow tract. Remarkably, the patient had no evidence of hemodynamic compromise. This case highlights the importance of maintaining a high index of suspicion for cardiac injury with penetrating trauma to the cardiac box regardless of presenting signs and symptoms, and the value of adhering to advanced trauma life support principles., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. No funding was received to assist with this publication., (© 2021 The Authors.)

A 73-year-old male with a history of severe coronary artery disease and prior coronary artery bypass grafting (CABG) presented with chest pain and elevated troponins. His workup revealed an ejection fraction of 15%, severe native coronary disease, as well as stenosis of his bypass grafts. He underwent a high-risk redo CABG with an Impella 5.5® (Abiomed, Danvers, MA) placement. The device was removed on postoperative day eight, at which time he went into cardiogenic shock from aortic valve leaflet injury. Given that he had no calcium deposits around the aortic valve annulus and severe aortic insufficiency, a multidisciplinary heart team decided he would be best served by a surgical aortic valve replacement. He was taken back to the operating room for a surgical aortic valve and intra-aortic balloon pump. His postoperative course was complicated by pneumonia, sepsis, and renal failure requiring continuous renal replacement therapy. He was discharged to a rehabilitation facility after 42 days. The following case encompasses the high morbidity risk of acute aortic valve insufficiency after Impella placement, never before documented in an Impella 5.5., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ghannam et al.)

Photoactivated adenylyl cyclase (PAC) is a unique protein that, upon blue light exposure, catalyzes cAMP production. The crystal structures of two PACs, from Oscillatoria acuminata (OaPAC) and Beggiatoa sp. (bPAC), have been solved, and they show a high degree of similarity. However, the photoactivity of OaPAC is much lower than that of bPAC, and the regulatory mechanism of PAC photoactivity, which induces the difference in activity between OaPAC and bPAC, has not yet been clarified. Here, we investigated the role of the C-terminal region in OaPAC, the length of which is the only notable difference from bPAC. We found that the photoactivity of OaPAC was inversely proportional to the C-terminal length. However, the deletion of more than nine amino acids did not further increase the activity, indicating that the nine amino acids at the C-terminal critically affect the photoactivity. Besides, absorption spectral features of light-sensing domains (BLUF domains) of the C-terminal deletion mutants showed similar light-dependent spectral shifts as in WT, indicating that the C-terminal region influences the activity without interacting with the BLUF domain. The study characterizes new PAC mutants with modified photoactivities, which could be useful as optogenetics tools.

Objective: Our study investigates the incidence, cumulative incidence, natural history, and factors associated with intraoperative paravalvular leak (PVL) and the development of a postoperative PVL in a contemporary consecutive cohort of patients following surgical aortic valve replacement. Methods: A total of 636 patients underwent surgical aortic valve replacement from 2006 to 2016; 410 (64.5%) underwent minimally invasive aortic valve replacement and 226 (35.5%) underwent conventional aortic valve replacement. Primary outcomes were the incidence of intraoperative PVL and cumulative incidence of postoperative PVL. Secondary outcomes were the incidence of in-hospital and long-term death and need for reoperation. Results: The overall incidence of intraoperative PVL was 1.4% (95% confidence interval [CI]: 1% to 3%). All intraoperative PVLs developed in the hand-tied group. The overall incidence of postoperative PVL was 5.3% (95% CI: 4% to 7%). In the univariable and multivariable analyses, postoperative renal failure was the only factor significantly associated with the development of a postoperative PVL. Conclusions: The incidence of intraoperative PVL is low. Cumulative incidence of postoperative PVL was 3.1% (95% CI: 1.0% to 13.6%), 4.3% (95% CI: 1.3% to 16.5%), and 5.0% (95% CI: 1.4% to 17.9%) at 1, 3, and 5 years, respectively. All intraoperative PVLs occurred with hand-tied knots. A larger cohort may identify additional risk factors.

Objectives: Patients with patent internal thoracic artery (ITA) grafts after prior coronary artery bypass grafting surgery who require aortic valve replacement (AVR) pose unique technical challenges for safe and optimal myocardial protection. The purpose of this study is to review our short- and long-term outcomes with redo minimally invasive AVR in patients with patent in situ ITA grafts., Methods: From 2008 to 2016, 48 patients with at least 1 patent in situ mammary artery graft underwent minimally invasive AVR. Preoperative computed tomography was performed in all patients to evaluate the relationship of patent grafts to the sternum. Retrograde coronary sinus and pulmonary vent catheters were placed via the right internal jugular vein. The in situ ITA grafts were not clamped during AVR. Transverse aortotomy, taking care to avoid the grafts arising from the aorta, was performed to expose the aortic valve., Results: The median age of the patients was 78 years [Quartile 1 (Q1)-Quartile 3 (Q3): 71-81]. Thirty-nine (81%) patients were men, and 46 (96%) patients had aortic stenosis. The median cardiopulmonary bypass and cross-clamp times were 124 (Q1-Q3: 108-164) and 92 (Q1-Q3: 83-116) min, respectively. Moderate hypothermia at 28-30°C was used in all patients. Most patients received cold blood cardioplegia with antegrade induction and continuous retrograde delivery. Four patients received only retrograde delivery due to some degree of aortic insufficiency. Thirty-day mortality was 4% (2 of 48 patients). There was no conversion to full sternotomy, and no reoperations were performed for postoperative bleeding or sternal wound infection. Excluding the 2 patients who died in the hospital, the median postoperative length of stay was 7 days (Q1-Q3: 5-8). Overall survival at 1, 5 and 10 years was 94%, 87% and 44%, respectively., Conclusions: Percutaneous retrograde cardioplegia combined with antegrade cardioplegia and moderate hypothermia, without interruption of ITA flow, is a safe and reliable strategy in patients with patent ITA grafts undergoing aortic valve replacement. This strategy combined with a minimally invasive approach may reduce surgical trauma, and is a safe and effective technique in these challenging patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with a high level (20%) of isoflavone inhibits muscle atrophy after short-term denervation (at 4 days) in mice. The present study was designed to elucidate whether the dietary isoflavone aglycone (AglyMax) at a 0.6% prevents denervation-mediated muscle atrophy, based on the modulation of atrogin-1- or apoptosis-dependent signaling., Methods: Mice were fed either a normal diet or 0.6% AglyMax diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, amount of atrogin-1 and cleaved caspase-3 proteins, and the percentages of apoptotic nuclei were examined in the gastrocnemius muscle at 14 days after denervation., Results: The 0.6% AglyMax diet significantly attenuated denervation-induced decreases in fiber atrophy but not the muscle wet weight. In addition, dietary isoflavone suppressed the denervation-induced apoptosis in spite of there being no significant changes in the amount of cleaved caspase-3 protein. In contrast, the 0.6% AglyMax diet did not significantly modulate the protein expression of atrogin-1 in the denervated muscle of mice., Conclusions: The isoflavone aglycone (AglyMax) at a 0.6% significantly would modulate muscle atrophy after denervation in mice, probably due to the decrease in apoptosis-dependent signaling.

Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE., (© 2018 International Society for Neurochemistry.)

Atrial fibrillation is associated with increased morbidity and mortality in patients undergoing mitral valve surgery. There is a growing consensus that patients with preexisting atrial fibrillation should undergo surgical ablation at the time of mitral valve surgery. Novel surgical ablation techniques, including cryoablation, have been developed to facilitate concurrent minimally invasive procedures. This video tutorial describes a combined cryo-maze procedure and mitral valve repair through an upper ministernotomy in a patient with long-standing persistent atrial fibrillation and severe mitral regurgitation., (© The Author 2016. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Degenerative mitral valve disease is associated with variable and complex defects in valve morphology. Three-dimensional echocardiography (3DE) has shown promise in aiding preoperative planning for patients with this disease but to date has not been as transformative as initially predicted. The clinical usefulness of 3DE has been limited by the laborious methods currently required to extract quantitative data from the images., Methods: To maximize the utility of 3DE for preoperative valve evaluation, this work describes an automated 3DE image analysis method for generating models of the mitral valve that are well suited for both qualitative and quantitative assessment. The method is unique in that it captures detailed alterations in mitral leaflet and annular morphology and produces image-derived models with locally varying leaflet thickness. The method is evaluated on midsystolic transesophageal 3DE images acquired from 22 subjects with myxomatous degeneration and from 22 subjects with normal mitral valve morphology., Results: Relative to manual image analysis, the automated method accurately represents both normal and complex leaflet geometries with a mean boundary displacement error on the order of one image voxel. A detailed quantitative analysis of the valves is presented and reveals statistically significant differences between normal and myxomatous valves with respect to numerous aspects of annular and leaflet geometry., Conclusions: This work demonstrates a successful methodology for the relatively rapid quantitative description of the complex mitral valve distortions associated with myxomatous degeneration. The methodology has the potential to significantly improve surgical planning for patients with complex mitral valve disease., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cyclic-AMP is one of the most important second messengers, regulating many crucial cellular events in both prokaryotes and eukaryotes, and precise spatial and temporal control of cAMP levels by light shows great promise as a simple means of manipulating and studying numerous cell pathways and processes. The photoactivated adenylate cyclase (PAC) from the photosynthetic cyanobacterium Oscillatoria acuminata (OaPAC) is a small homodimer eminently suitable for this task, requiring only a simple flavin chromophore within a blue light using flavin (BLUF) domain. These domains, one of the most studied types of biological photoreceptor, respond to blue light and either regulate the activity of an attached enzyme domain or change its affinity for a repressor protein. BLUF domains were discovered through studies of photo-induced movements of Euglena gracilis, a unicellular flagellate, and gene expression in the purple bacterium Rhodobacter sphaeroides, but the precise details of light activation remain unknown. Here, we describe crystal structures and the light regulation mechanism of the previously undescribed OaPAC, showing a central coiled coil transmits changes from the light-sensing domains to the active sites with minimal structural rearrangement. Site-directed mutants show residues essential for signal transduction over 45 Å across the protein. The use of the protein in living human cells is demonstrated with cAMP-dependent luciferase, showing a rapid and stable response to light over many hours and activation cycles. The structures determined in this study will assist future efforts to create artificial light-regulated control modules as part of a general optogenetic toolkit.

Deformable modeling with medial axis representation is a useful means of segmenting and parametrically describing the shape of anatomical structures in medical images. Continuous medial representation (cm-rep) is a "skeleton-first" approach to deformable medial modeling that explicitly parameterizes an object's medial axis and derives the object's boundary algorithmically. Although cm-rep has effectively been used to segment and model a number of anatomical structures with non-branching medial topologies, the framework is challenging to apply to objects with branching medial geometries since branch curves in the medial axis are difficult to parameterize. In this work, we demonstrate the first clinical application of a new "boundary-first" deformable medial modeling paradigm, wherein an object's boundary is explicitly described and constraints are imposed on boundary geometry to preserve the branching configuration of the medial axis during model deformation. This "boundary-first" framework is leveraged to segment and morphologically analyze the aortic valve apparatus in 3D echocardiographic images. Relative to manual tracing, segmentation with deformable medial modeling achieves a mean boundary error of 0.41 ± 0.10 mm (approximately one voxel) in 22 3DE images of normal aortic valves at systole. Deformable medial modeling is additionally demonstrated on pathological cases, including aortic stenosis, Marfan syndrome, and bicuspid aortic valve disease. This study demonstrates a promising approach for quantitative 3DE analysis of aortic valve morphology., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: There is continued need for therapies which reverse or abate the remodeling process after myocardial infarction (MI). In this study, we evaluate the longitudinal effects of calcium hydroxyapatite microsphere gel on regional strain, global ventricular function, and mitral regurgitation (MR) in a porcine MI model., Methods: Twenty-five Yorkshire swine were enrolled. Five were dedicated weight-matched controls. Twenty underwent posterolateral infarction by direct ligation of the circumflex artery and its branches. Infarcted animals were randomly divided into the following 4 groups: 1-week treatment; 1-week control; 4-week treatment; and 4-week control. After infarction, animals received either twenty 150 μL calcium hydroxyapatite gel or saline injections within the infarct. At their respective time points, echocardiograms, cardiac magnetic resonance imaging, and tissue were collected for evaluation of MR, regional and global left ventricular function, wall thickness, and collagen content., Results: Global and regional left ventricular functions were depressed in all infarcted subjects at 1 week compared with healthy controls. By 4-weeks post-infarction, global function had significantly improved in the calcium hydroxyapatite group compared with infarcted controls (ejection fraction 0.485 ± 0.019 vs 0.38 ± 0.017, p < 0.01). Similarly, regional borderzone radial contractile strain (16.3% ± 1.5% vs 11.2% ± 1.5%, p = 0.04), MR grade (0.4 ± 0.2 vs 1.2 ± 0.2, p = 0.04), and infarct thickness (7.8 ± 0.5 mm vs 4.5 ± 0.2 mm, p < 0.01) were improved at this time point in the treatment group compared with infarct controls., Conclusions: Calcium hydroxyapatite injection after MI progressively improves global left ventricular function, borderzone function, and mitral regurgitation. Using novel biomaterials to augment infarct material properties is a viable alternative in the current management of heart failure., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Epigenetic programming, dynamically regulated by histone acetylation, may play a key role in the pathophysiology of sepsis. We examined whether histone deacetylase (HDAC) can contribute to sepsis-associated inflammation and apoptosis., Materials and Methods: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. An intraperitoneal injection of CG200745 (10 mg/kg), a novel broad-spectrum HDAC inhibitor, or valproic acid (500 mg/kg), a predominant inhibitor of class I HDACs, was given 3 h before surgery., Results: HDAC1, HDAC2, and HDAC3 protein levels were decreased in lungs after CLP. Furthermore, CLP-induced sepsis increased both histone H3 and H4 acetylation levels in lungs. When CG200745 was given, apoptosis induction was strongly suppressed in lungs and spleens of septic mice. This antiapoptotic effect of CG200745 was not accompanied by upregulation of antiapoptotic and downregulation of proapoptotic Bcl-2 family member proteins. Treatment with CG200745 failed to inhibit elevated levels of serum cytokines and prevent lung inflammation in septic mice. Valproic acid also showed antiapoptotic but not anti-inflammatory effects in septic mice., Conclusions: These findings imply that HDAC inhibitors are a unique agent to prevent cell apoptosis in sepsis at their doses that do not improve inflammatory features, indicating that septic inflammation and apoptosis may not necessarily be essential for one another's existence. This study also represents the first report that CLP-induced sepsis downregulates HDACs. Nevertheless, the data with HDAC inhibitors suggest that imbalance in histone acetylation may play a contributory role in expression or repression of genes involved in septic cell apoptosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A 74-year-old woman underwent replacement of the ascending aorta for acute type A aortic dissection. The patient suffered from bacteremia postoperatively and repeated computed tomography showed an increasing diameter of pseudoaneurysms at the site of the proximal anastomosis due to graft infection. Re-mechanical Bentall operation and arch replacement were therefore performed using a composite graft of a rifampicin-bonded gelatin-sealed 24-mm woven Dacron graft and a mechanical valve. The postoperative course was uneventful. We report the successful in situ reconstruction using the above-mentioned Dacron graft and describe the preparation of the rifampicin solution using a surfactant.

Objective: Despite advances in design, modern ventricular assist device placement involves median sternotomy and cardiopulmonary bypass and is associated with infectious/embolic complications. In this study, we examine the feasibility and function of a novel minimally invasive, non-blood-contacting epicardial assist device in a porcine ischemic cardiomyopathy model., Methods: Feasibility was first tested in an ex vivo thoracoscopic trainer box with slaughterhouse hearts. Five male Yorkshire swine underwent selective ligation of the circumflex artery to create a posterolateral infarct Twelve weeks after infarct, all animals underwent left minithoracotomy. A custom inflatable bladder was positioned over the epicardial surface of the infarct and firmly secured to the surrounding border zone myocardium with polypropylene mesh and minimally invasive mesh tacks. An external gas pulsation system actively inflated and deflated the bladder in synchrony with the cardiac cycle. All animals then underwent cardiac magnetic resonance imaging to assess ventricular function., Results: All subjects successfully underwent off-pump placement of the epicardial assist device via minithoracotomy. Ejection fraction significantly improved from 29.1% ± 4.8% to 39.6% ± 4.23% (P < 0.001) when compared with pretreatment. End-systolic volume decreased (76.6 ± 13.3 mL vs 62.4 ± 12.0 mL, P < 0.001) and stroke volume increased (28.6 ± 3.4 mL vs 37.9 ± 3.1 mL, P < 0.05) when assisted. No change was noted in end-diastolic volume (105.1 ± 11.4 vs 100.3 ± 12.7). On postmortem examination, mesh fixation and device position were excellent in all cases. No adverse events were encountered., Conclusions: Directed epicardial assistance improves ventricular function in a porcine ischemic cardiomyopathy model and may provide a safe alternative to currently available ventricular assist device therapies. Further, the technique used for device positioning and fixation suggests that an entirely thoracoscopic approach is possible.

Cardiac hemangiomas are extremely rare benign tumors. These tumors are usually asymptomatic but they can present symptoms such as palpitations, shortness of breath, and arrythmia. We report the case of a 73-year-old man who presented with an abnormal shadow on chest computed tomography during follow-up for lung metastatic tumor after resection of his rectal cancer. A cardiac tumor was detected, and surgical resection and right ventricular plasty were successfully performed with the patient under cardiopulmonary bypass. Histopathologic examination revealed a benign cardiac hemangioma, which was categorized as a hemangioma of the mixed cavernous and capillary type., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Transcatheter mitral valve replacement would represent a major advance in heart valve therapy. Such a device requires a specialized anchoring and sealing technology. This study was designed to test the feasibility of a novel mitral valve replacement device (the sutureless mitral valve [SMV]) designed to anchor and seal in the mitral position without need for sutures., Description: The SMV is a self-expanding device consisting of a custom-designed nitinol framework and a pericardial leaflet valve mechanism., Evaluation: Ten sheep underwent successful surgical SMV device implantation. All animals underwent cardiac catheterization 6 hours postoperatively. Hemodynamic, angiographic, echocardiographic and necroscopic data were recorded. The mean aortic cross-clamp time was 9.5 ± 3.1 minutes. Echocardiography and angiography revealed excellent left ventricular systolic function, no significant perivalvular leak, no mitral valve stenosis, no left ventricular outflow tract obstruction, and no aortic valve insufficiency. Necropsy demonstrated that the SMV devices were anchored securely., Conclusions: This study demonstrates the feasibility and short-term success of sutureless mitral valve replacement using a novel SMV device., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure after myocardial infarction (MI) is a result of increased myocardial workload, adverse left ventricular (LV) geometric remodeling, and less efficient LV fluid movement. In this study we utilize cardiac magnetic resonance imaging to evaluate ventricular function and flow after placement of a novel directed epicardial assist device., Methods: Five swine underwent posterolateral MI and were allowed to remodel for 12 weeks. An inflatable bladder was positioned centrally within the infarct and secured with mesh. The device was connected to an external gas exchange pump, which inflated and deflated in synchrony with the cardiac cycle. Animals then underwent cardiac magnetic resonance imaging during active epicardial assistance and with no assistance., Results: Active epicardial assistance of the infarct showed immediate improvement in LV function and intraventricular flow. Ejection fraction significantly improved from 26.0% ± 4.9% to 37.3% ± 4.5% (p < 0.01). End-systolic volume (85.5 ± 12.7 mL versus 70.1 ± 11.9 mL, p < 0.01) and stroke volume (28.5 ± 4.4 mL versus 39.9 ± 3.1 mL, p = 0.03) were also improved with assistance. End-diastolic volume and regurgitant fraction did not change with treatment. Regional LV flow improved both qualitatively and quantitatively during assistance. Unassisted infarct regional flow showed highly discoordinate blood movement with very slow egress from the posterolateral wall. Large areas of stagnant flow were also identified. With assistance, posterolateral wall blood velocities improved significantly during both systole (26.4% ± 3.2% versus 12.6% ± 1.2% maximum velocity; p < 0.001) and diastole (54.3% ± 9.3% versus 24.2% ± 2.5% maximum velocity; p < 0.01)., Conclusions: Directed epicardial assistance can improve LV function and flow in ischemic cardiomyopathy. This novel device may provide a valuable alternative to currently available heart failure therapies., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The functions of MAELSTROM protein (MAEL) in spermatogenesis are gradually being identified but the precise distribution of MAEL in spermatogenic cells during spermatogenesis has not yet been mapped. We studied the expression of MAEL in rat testis by immunofluorescence and immunoelectron microscopy (IEM). Immunofluorescence staining showed that MAEL was localized in intermitochondrial cement, irregularly-shaped perinuclear granules and satellite bodies of pachytene spermatocytes, and in chromatoid bodies of spermatids. The SBs appeared exclusively in pachytene spermatocytes at stages IX-X and were stained strongly for MAEL. In step 12-19 spermatids, many granules stained for MAEL but not DDX4. These granules were confirmed to be non-nuage structures, including mitochondria-associated granules, reticulated body, granulated body by IEM. In the neck region of late spermatids and sperm, MAEL-positive small granules were found. MAEL is colocalized with MIWI in nuage and non-nuage. The results suggest that MAEL seems to function in nuage and non-nuage structures and interacts with MIWI.

Olprinone, a specific phosphodiesterase III inhibitor, and corforsin daropate, a direct adenylate cyclase activator, are now being used in critical conditions. We investigated whether their therapeutic use provides protection against septic acute lung injury (ALI) and mortality. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. Olprinone or colforsin daropate was continuously given through an osmotic pump that was implanted into the peritoneal cavity immediately following CLP. These treatments prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage were strikingly remedied. Furthermore, continued administration of olprinone or colforsin daropate suppressed apoptosis induction in septic lungs and improved the survival of CLP mice. Olprinone and corforsin daropate enhanced Akt phosphorylation in septic lungs. Wortmannin, which inhibits the Akt upstream regulator phosphatidylinositol 3-kinase, abrogated the protective effects of olprinone and corforsin daropate on sepsis-associated lung inflammation and apoptosis. In vivo transfection of cyclic AMP response element binding protein (CREB) decoy oligodeoxynucleotide failed to negate the abilities of these agents to increase Akt phosphorylation and to inhibit IκBα degradation in septic lungs. These results demonstrate for the first time that CREB-independent Akt-mediated signaling is a critical mechanism contributing to the therapeutic effects of olprinone and corforsin daropate on septic ALI. Moreover, our data also suggest that these cyclic AMP-related agents, by blocking both nuclear factor-κB activation and apoptosis induction, may represent an effective therapeutic approach to the treatment of the septic syndrome.

Background: The recurrence of regurgitation after surgical mitral valve (MV) repair remains a significant clinical problem. Mitral annuloplasty rings are commonly used in MV repair procedures. The purpose of this study was to demonstrate the feasibility of transvenous valve-in-ring (VIR) implantation using the Melody valve (Medtronic, Minneapolis, MN), which is a valved-stent designed for percutaneous pulmonary valve replacement, and 4 distinct types of annuloplasty ring (AR) in an ovine model., Methods: Ten sheep underwent surgical MV annuloplasty ring placement (n=10): CE-Physio, Edwards Lifesciences, Irvine, CA [n=5]; partial ring [n=3]; flexible ring [n=1]; and saddle ring [n=1]). All animals underwent cardiac catheterization, hemodynamic assessment, and Melody VIR implantation through a transfemoral venous, transatrial septal approach 1 week after surgery. Follow-up hemodynamic, angiographic, and echocardiographic data were recorded., Results: Melody VIR implantation was technically successful in all but 1 animal. In this animal a 26-mm partial AR proved too large for secure anchoring of the Melody valve. In the remaining 9 animals, fluoroscopy showed the Melody devices securely positioned within the annuloplasty rings. Echocardiography revealed no perivalvular leak, and angiography revealed no left ventricular outflow tract obstruction, vigorous left ventricular function, and no aortic valve insufficiency. The median procedure time was 55.5 (range, 45 to 78) minutes., Conclusions: This study demonstrates the feasibility of a purely percutaneous approach to MV replacement in patients with preexisting annuloplasty rings, regardless of ring type. This approach may be of particular benefit to patients with failed repair of ischemic mitral regurgitation., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Either suprarenal or infrarenal aortic clamping markedly reduces renal blood flow. This aortic clamping may cause postoperative acute kidney injury(AKI)., Methods: Fifty-four patients undergoing open abdominal aortic aneurysm (AAA) surgery were included in a retrospective study. Postoperative AKI defined as an absolute increase in serum creatinine (Cre) of more than or equal to 0.3 mg x dl(-1) or an increase in Cre of more than or equal to 50% within 48 hours after the end of the procedure., Results: Thirteen patients developed AKI, but none of them required dialysis. The patients with AKI had higher preoperative Cre, longer operation, longer clamp time and more use of diuretics intra- and postoperatively., Conclusions: AKI occurred in 24.1% of patients undergoing AAA surgery. Risk factors for AKI were preoperative Cre, operation time, clamp time and use of diuretics.

Background: Intraoperative use of remifentanil requires much more analgesics postoperatively. Moreover, remifentanil causes intraoperative hypotension and bradycardia., Methods: The objectives are to compare intra- and post-operative drug cost between patients who received remifentanil (Group R, n = 72) and those who received fentanyl (Group F, n = 66) during laparoscopic cholecystectomy retrospectively., Results: The baseline demographics were similar between the two groups. Intraoperative drug costs were 7,782 +/- 1,579 yen in Group R and 6,235 +/- 1,037 yen in Group E Postoperative drug costs were 364 +/- 521 yen in Group R and 146 +/- 153 yen in Group E Total drug costs were 8,167 +/- 1,607 yen in Group R and 6,381 +/- 1,042 yen in Group E These reached statistical significance (P < 0.01). Length of hospital stay (days) between the two groups were comparable., Conclusions: Remifentanil anesthesia requires much more intra- and post-operative drug cost than fentanyl anesthesia for laparoscopic cholecystectomy.

A mathematical scheme has been proposed to extend the applicability of the generalized trajectory method to deal with curved cathodes such as cold field emitters and thermionic point cathodes. A connecting space is introduced between the cathode surface and the first reference plane, and the actual ray condition on the cathode is transformed into the trajectory condition at the reference plane: the generalized trajectory calculation is commenced from the reference plane. The electron acceleration due to the cathode surface field, which results in the increase of the transverse momentum p(x) at the reference plane, has been found to significantly influence the estimate of the spherical aberration coefficient. The new mathematical formulation has been incorporated into the upgraded G-optk programme and enabled it to carry out precise characterization of curved cathode guns.

The paraxial trajectory method has been generalized for the application to the cathode rays inside electron guns. The generalized method can handle rays that initially make a large angle with the optical axis with a satisfactory accuracy. The key to success of the generalization is the adoption of the trigonometric function sine for the trajectory slope specification, instead of the conventional use of the tangent. Formulas have been derived to relate the ray conditions (position and slope of the ray at reference planes) on the cathode to those at the crossover plane using third-order polynomial functions. Some of the polynomial coefficients can be used as the optical parameters in the characterization of electron sources; the electron gun focal length gives a quantitative estimate of both the crossover size and the angular current intensity. An electron gun simulation program G-optk has been developed based on the mathematical formulations presented in the article. The program calculates the principal paraxial trajectories and the relevant optical parameters from axial potentials and fields. It gives the electron-optical-column designers a clear physical picture of the electron gun in a much more faster way than the conventional ray-tracing methods.

Background and Aim: Dysregulated immune responses in the gut to luminal antigens can cause inflammatory bowel diseases (IBD). The roles played by dietary antigens in the pathogenesis or prevention of IBD are poorly understood. Soybean isoflavones are digested in large amounts and have many biological activities. The aim of this study was to determine whether isoflavones in aglycon and bioavailable forms have any effect on gut immunity and protect the host from tissue damage in a mouse model of colitis., Methods: We administered daidzein-rich isoflavone aglycones (DRIA) to mice for 1 week and then treated them with 2% dextran sodium sulfate (DSS) in drinking water for 4 days to induce colitis. The effect of DRIA was evaluated by examining the histopathology of the colon, body weight changes, and functional analysis of mesenteric lymph node cells (MLN)., Results: DRIA inhibited interleukin (IL)-6 and IL-8 production by Toll-like receptor (TLR)2, and TLR4-stimulated monocytes in a dose-dependent manner. The mice administered DRIA had less inflammation and tissue damage in the colon than the control mice. This protective effect of DRIA was associated with a decrease in interferon-gamma, IL-6, and IL-12p40 secretion, and an increase in IL-10 secretion and low cell-activation status of antigen-presenting cells (APC) in MLN., Conclusion: Ingested DRIA can downregulate the functions of APC and inhibit DSS colitis.

Background: ImmuBalance is a koji fungus (Aspergillus oryzae) and lactic acid fermented soybean product. This unique production process is believed to create a food supplement that helps to induce or maintain normal immune response., Objective: To assess possible therapeutic effects of ImmuBalance on peanut (PN) hypersensitivity using a murine model of peanut allergy (PNA)., Methods: PN allergic C3H/HeJ mice were fed standard mouse chow containing 0.5% or 1.0% ImmuBalance (ImmuBalance 2X), radiation-inactivated 1.0% ImmuBalance (I-ImmuBalance 2X), or regular diet chow (sham) for 4 weeks, beginning 10 weeks after the initial PN sensitization, and then challenged with PN. Anaphylactic symptom scores, plasma histamine, serum PN specific-IgE levels and splenocyte cytokine profiles were determined., Results: While 100% of sham-treated PNA mice developed anaphylactic reactions with a median score of 3.3 following PN challenge, only 50% of ImmuBalance, 30% of ImmuBalance 2X and 40% of I-ImmuBalance 2X-treated mice developed allergic reactions with median scores of 1.0, 0.4 and 0.5 respectively, which were significantly less than that in the sham-treated mice (P<0.05). Plasma histamine and PN specific-IgE levels were also significantly less in all treated mice than in sham-treated mice (P<0.05). Furthermore, IL-4, IL-5 and IL-13 production by PN-stimulated splenocytes in vitro from ImmuBalance fed mice were markedly reduced compared with sham-treated mice, whereas IFN-gamma production was moderately increased. TGF-beta and TNF-alpha production were similar., Conclusions: ImmuBalance protects against PN-induced anaphylaxis when administered as a food supplement in this model. Protection was associated with down-regulation of Th2 responses. This supplement may provide a potential novel therapy for PNA.

To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized C(max) and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.

The nitrogen (N) status of a plant determines the composition of its major components (amino acids, proteins, carbohydrates and organic acids) and, directly or indirectly, affects the quality of agricultural products in terms of their calorific value and taste. Although these effects are guided by changes in metabolic pathways, no overall metabolic analysis has previously been conducted to demonstrate such effects. Here, metabolite profiling using gas chromatography-mass spectrometry (GC-MS) was used to evaluate the effect of N levels on spinach tissue, comparing two cultivars that differed in their ability to use N. Wide variation in N content was observed without any distinct inhibition of growth in either cultivar. Principal component analysis (PCA) and self-organizing mapping (SOM) were undertaken to describe changes in the metabolites of mature spinach leaves. In PCA, the first component accounted for 44.5% of the total variance, the scores of which was positively correlated with the plant's N content, and a close relationship between metabolite profiles and N status was observed. Both PCA and SOM revealed that metabolites could be broadly divided into two types, correlating either positively or negatively with plant N content. The simple and co-coordinated metabolic stream, containing both general and spinach-specific aspects of plant N content, will be useful in future research on such topics as the detection of environmental effects on spinach through comprehensive metabolic profiling.

We previously reported that continuous intravenous (IV) administration of nicorandil (NIC) inhibits QT dispersion (QTd). However, no prior study has evaluated the efficacy of NIC when administered orally to acute myocardial infarction (AMI) patients following continuous IV administration. Thirty patients with anteroseptal infarction in whom revascularization was performed successfully within 6 hours of AMI onset were included in the study and assigned to one of 3 groups: group A (continuous IV administration of NIC), group B (continuous IV and oral administration of NIC), and group C (no treatment with NIC). After 24 hours, QTd in groups A and B was significantly decreased compared to QTd in group C (P < 0.01) (group A, 58.1; group B, 58.2; and group C, 81.3). The QTd obtained 3 months later was significantly shorter in group B subjects who were orally administered NIC, and QTd before percutaneous coronary intervention (PCI) was restored in group A, in which no NIC had been administered orally [group A, 66.7; group B, 54.1; and group C, 73.9; P < 0.05 (group A versus group B) and P < 0.01 (group B versus group C)]. The effects were evaluated by comparing different routes of administration. Continuous IV and subsequent oral administration of NIC inhibited prolongation of QTd, suggesting that these effects may prevent the occurrence of cardiac events during both the acute and chronic phases of AMI.

Levels of cytokinins and abscisic acid (ABA) and the expression of senescence-related genes were investigated in two maize (Zea mays L.) cultivars of different senescence type, cv. P3845 (stay-green) and cv. Hokkou 55 (earlier senescent), in a field study. The delay in leaf senescence in P3845 was correlated with increased levels of chlorophyll and nitrogen and a higher photon-saturated photosynthetic rate (P(sat)). Compared with the earlier senescent Hokkou 55, P3845 showed enhanced contents of cytokinins (trans-zeatin riboside, t-ZR; dihydrozeatin riboside, DHZR; isopentenyladenosine, iPA) and reduced levels of ABA in its leaves. In roots, P3845 had increased levels of t-ZR, DHZR, and ABA, but decreased concentrations of iPA. It was concluded that a higher rate of cytokinin transport from roots to leaves contributes to the delay of senescence in P3845. By contrast, the translocation of ABA from roots to shoots may be blocked in the stay-green cultivar, which also results in retarded leaf senescence. P3845 ear leaves contained more malondialdehyde (MDA) and higher catalase (CAT) and superoxide dismutase (SOD) activities than Hokkou 55. Since the accumulation of the mRNAs for Rubisco small subunit (rbcS), phosphoenolpyruvate carboxylase (PEPC), and SOD peaked after Chl content and P(sat) had reached their maxima, it is speculated that when leaf senescence is initiated, Chl contents decrease first, followed by the degradation of the photosynthetic apparatus and of photosynthesis-related enzymes. See1 and See2 encode senescence-related cysteine proteases; their mRNAs were most abundant in yellowing leaves, suggesting that these proteins are involved in the process of senescence rather than its initiation. mRNAs of both genes were more abundant in Hokkou 55 than in P3845, which suggests a regulation of leaf senescence at the transcriptional level.

The isoflavones genistein and daidzein and the daidzein metabolite equol have been reported to interact with estrogen receptors (ERs). Some studies indicate that they behave clinically like estrogen in some estrogen-deficiency diseases. However, the detailed molecular mechanism used by these compounds to create beneficial effects in patients with estrogen-related diseases has not been clarified. Using histone acetyltransferase (HAT) assay, we found that equol, genistein, and AglyMax had significant effects on ERalpha-mediated histone acetylation. Although 17beta-estradiol (E2)-dependent HAT activity of steroid receptor coactivators 2 (SRC2) and p300 mediated by ERbeta could be detected, it was weaker than that mediated by ERalpha. Equol, genistein, AglyMax, and daidzein all markedly stimulated ERbeta-mediated histone acetylation. On the other hand, anti-estrogenic compounds ICI 182,780 (ICI) and tamoxifen (TA) did not have an effect on HAT activity mediated by either ERalpha or ERbeta. Our data indicate that estrogenic ligands exert their effects by elevating histone acetylation and coactivator activity of ER, and suggest that the risk of estrogen-related diseases might be reduced by a sufficient amount of genistein or AglyMax supplements.

It is well known that neonatal exposure to estrogen induces masculinization or defeminization of the brain. In this study, the effects of neonatal treatment with two kinds of soybean isoflavone aglycone, genistein (GS) and daidzein (DZ), on the estrous cycle and lordosis behavior were investigated. Female rats were injected subcutaneously with 1 mg GS, 1 mg DZ, 100 microg estradiol (E2), or oil daily for 5 days from birth. As a result, vaginal opening was advanced in GS- or E2-treated females. A vaginal smear check indicated that oil- or DZ-treated females showed a constant 4- or 5-day estrous cycle, whereas GS- or E2-treated rats showed a persistent or prolonged estrus. Ovariectomy was performed in all females at 60 days of age. The ovaries in the GS- or E2-treated groups were smaller than those in the oil- and DZ-treated groups and contained no corpora lutea. In the DZ group, although corpora lutea were seen, ovaries were smaller than that of control females. Behavioral tests were carried out after implantation of E2-tubes. All of the oil- or DZ-treated females showed lordosis with a high lordosis quotient (LQ). On the other hand, as male rats, LQs were extremely low in the E2-treated group, when compared to the oil-treated group. In the GS-treated group, the mean LQ was lower than that in the oil-treated group, but higher than those in the E2-treated female or male groups. These results suggest that genistein acts as an estrogen in the sexual differentiation of the brain and causes defeminization of the brain in regulating lordosis and the estrous cycle in rats. In addition, neonatal daidzein also has some influence on ovarian function.

In the trigone (three portions) and proximal urethra isolated from castrated male pigs, transmural electrical stimulation (0.5-10 Hz) induced no or slight contractions followed by frequency-related relaxations. Atropine suppressed the contraction and potentiated the relaxation. N(G)-nitro-L-arginine methylester (L-NAME), a nitric oxide (NO) synthase inhibitor, depressed or abolished the relaxation induced by low frequency stimulation, but only slightly attenuated the response to high frequency stimulation. L-Arginine reversed the inhibitory effect. L-NAME-sensitive relaxation by 1 Hz stimulation was abolished by 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. Release of NO by nerve stimulation to trigonal strips was determined by increased formation of cyclic GMP in the incubation media containing guanylate cyclase and GTP. L-NAME-resistant relaxation by 10 Hz stimulation was not impaired by ODQ, capsaicin, chymotrypsin, K(+) channel inhibitors and beta-adrenoceptor antagonists. Similar results were obtained in the trigone and urethra from normal male and female pigs. Detrusor muscle responded to nerve stimulation with contraction followed by slight relaxation. Relaxations at 1 and 10 Hz stimulation under treatment with atropine and alpha,beta-methylene ATP were partially attenuated by L-NAME. It is concluded that there is no significant difference in the inhibitory responses, sensitive and resistant to L-NAME, to nerve stimulation in the trigone and proximal urethra from castrated and non-castrated male and female pigs. Relaxations to stimulation at 1 Hz seem to be mediated exclusively by neurogenic NO and cyclic GMP generation, whereas those to 10 Hz stimulation is mainly associated with non-NO relaxing factor(s), peptides, K(+) channel openers and beta-adrenoceptor agonist being unlikely involved.

Recent studies have reported that estrogen replacement therapy (ERT) reduces the risk of cardiovascular diseases in postmenopausal women. However, mechanisms responsible for this effect are not yet completely understood, and ERT is associated with carcinogenic side effects in women and feminizing effects in men. Because soybean isoflavones, a group of natural phytoestrogens, have only weak estrogenic activity and are not known to have side effects such as carcinogenesis and feminization, we evaluated the effects of genistein, daidzein and glycitein on the growth and DNA synthesis of aortic smooth muscle cells (SMC) from stroke-prone spontaneously hypertensive rats (SHRSP). SMC were cultured in dishes and proliferated on 10% dextran-coated charcoal/fetal bovine serum, and then treated with 0.1-30 micromol/L of genistein, daidzein or glycitein to investigate cell proliferation (cell number) and DNA synthesis (cell proliferation ELISA system), respectively. We also studied their effects on platelet-derived growth factor (PDGF)-BB (20 microg/L)-induced SMC proliferation. Soybean isoflavones inhibited proliferation and DNA synthesis of SMC from SHRSP in a concentration-dependent manner. Inhibition was significant at 3 micromol/L of genistein and 10 micromol/L of both daidzein and glycitein. For significant inhibition of PDGF-BB-induced SMC proliferation, concentrations as low as 0.1 micromol/L of each isoflavone were effective. These isoflavones, with their inhibitory effects on natural and PDGF-BB-induced SMC proliferation, may be useful in attenuatating such proliferation, a basic mechanism involved in atherosclerotic vascular change, thereby preventing atherosclerotic cardiovascular diseases.

The effect of soybean meal fermented by Aspergillus awamori on the acute lethality of acetaldehyde, pentobarbital sleeping time, and cytochrome P-450 content of the hepatic microsomes was studied in mice. Most of the daidzin and genistin in soybean meal (SBM) were converted into the respective aglycones, daidzein and genistein, by fermentation. In experiment 1, mice were fed isonitrogenic test diets with one of the following five protein sources for 28 d: casein, SBM, fermented and hot-air-dried SBM (FSBM-HD), fermented and freeze-dried SBM (FSBM-FD), or methanol-extracted FSBM-FD (FSMB-FD-R). The acute lethality of acetaldehyde in mice fed the FSBM-FD diet was significantly lower than that in mice fed the SBM, FSBM-HD, or FSBM-FD-R diet. In experiments 2 and 3, mice were fed isonitrogenic test diets with one of the following four protein sources for 28 d: casein, SBM, FSBM-FD, and FSBM-FD-R. The pentobarbital sleeping time was significantly shorter and the cytochrome P-450 content was significantly higher in the mice fed the FSBM-FD diet than the respective value in mice fed the other test diets. In experiment 4, mice were fed one of eight diets which contained different levels of aglycone obtained by varying the proportion of FSBM-FD and FSBM-FD-R, for 28 d. The cytochrome P-450 content in hepatic microsomes increased as the dietary level of isoflavonoid aglycones increased, but there was a saturation phenomenon. These results suggest that soy isoflavonoid aglycones are more potent inducers of cytochrome P-450 than isoflavonoid glycosides.

The truncated Aalpha-chain of fibrinogen Marburg is partly linked with albumin by a disulfide bond. Based on the recovery of the first six amino acid residues assigned to the subunit polypeptides of fibrinogen (the Aalpha-and gamma-chains) and albumin, 0.33 mol of albumin was estimated to be linked to 1 mol of the Marburg fibrinogen. When the Marburg fibrinogen was clotted with thrombin-factor XIIIa-Ca2+, various alpham gamman heteromultimers were produced, and part of the albumin was cross-linked to the gamma-chain. Acid-solubilized Marburg fibrin monomer failed to form large aggregates that could be detected by monitoring turbidity at A350, but it was able to enhance tissue-type plasminogen-activator-catalyzed plasmin generation, though not as avidly as the normal control, indicating that the double-stranded protofibrils had, to some extent, been constructed. This idea seems to be supported by normal factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains. However, the cross-linked Marburg fibrin, being apparently fragile and translucent, was highly resistant against plasmin, and its subunit components were considerably retained for 48 hours as noted by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Although the exact mechanisms are still unclear, the albumin-incorporated factor XIIIa-cross-linked Marburg fibrin seems to have undergone a critical structural alteration(s) to acquire resistance against plasmin. This aquisition of plasmin resistance may be contributed to the postoperative pelvic vein thrombosis and recurrent pulmonary embolisms in the patient after caesarian section for her first delivery at the age of 20 years.

This paper describes a use of Monte Carlo integration for population pharmacokinetics with multivariate population distribution. In the proposed approach, a multivariate lognormal distribution is assumed for a population distribution of pharmacokinetic (PK) parameters. The maximum likelihood method is employed to estimate the population means, variances, and correlation coefficients of the multivariate lognormal distribution. Instead of a first-order Taylor series approximation to a nonlinear PK model, the proposed approach employs a Monte Carlo integration for the multiple integral in maximizing the log likelihood function. Observations below the lower limit of detection, which are usually included in Phase 1 PK data, are also incorporated into the analysis. Applications are given to a simulated data set and an actual Phase 1 trial to show how the proposed approach works in practice.