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Introduction Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure. Materials and methods The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV. Discussion This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

It is speculated that, in operative environments, real-time visualization of the trainee's viewpoint by the instructor may improve performance and teaching efficacy. We hypothesized that introduction of a wearable surgical visualization system allowing the instructor to visualize otherwise "blind" areas in the operative field could improve trainee performance in a simulated operative setting.A total of 11 surgery residents (4 in general surgery training and 7 in an integrated 6-year cardiothoracic surgery program) participated in the study. Google (Mountain View, CA) Glass hardware running proprietary software from CrowdOptic (San Francisco, CA) was utilized for creation of the wearable surgical visualization system. Both the learner and trainer wore the system, and video was streamed from the learner's system in real time to the trainer, who directed the learner to place needles in a simulated operative field. Subjects placed a total of 5 needles in each of 4 quadrants. A composite error score was calculated based on the accuracy of needle placement in relation to the intended needle trajectories as described by the trainer. Time to task completion (TTC) was also measured and participants completed an exit questionnaire.All residents completed the protocol tasks and the survey. Introduction of the wearable surgical visualization system did not affect mean time to task completion (278 ± 50 vs. 282 ± 69 seconds, p = NS). However, mean composite error score fell significantly once the wearable system was deployed (18 ± 5 vs. 15 ± 4, p0.05), demonstrating improved accuracy of needle placement. Most of the participants deemed the device unobtrusive, easy to operate, and useful for communication and instruction.This study suggests that wearable surgical visualization systems allowing for adoption of the learner's perspective may be a useful educational adjunct in the training of surgeons. Further evaluations of the efficacy of wearable technology in the operating room environment are warranted.

Objectives The purpose of this study was to characterize health status outcomes after transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis among patients at extreme surgical risk and to identify pre-procedural patient characteristics associated with a poor outcome. Background For many patients considering TAVR, improvement in quality of life may be of even greater importance than prolonged survival. Methods Patients with severe, symptomatic aortic stenosis who were considered to be at prohibitive risk for surgical aortic valve replacement were enrolled in the single-arm CoreValve U.S. Extreme Risk Study. Health status was assessed at baseline and at 1, 6, and 12 months after TAVR using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Short Form-12, and the EuroQol-5D. The overall summary scale of the KCCQ (range 0 to 100; higher scores = better health) was the primary health status outcome. A poor outcome after TAVR was defined as death, a KCCQ overall summary score (OS) Results A total of 471 patients underwent TAVR via the transfemoral approach, of whom 436 (93%) completed the baseline health status survey. All health status measures demonstrated considerable impairment at baseline. After TAVR, there was substantial improvement in both disease-specific and generic health status measures, with an increase in the KCCQ-OS of 23.9 points (95% confidence interval [CI]: 20.3 to 27.5 points) at 1 month, 27.4 points (95% CI: 24.2 to 30.6 points) at 6 months, 27.4 points (95% CI: 24.1 to 30.8 points) at 12 months, along with substantial increases in Short Form-12 scores and EuroQol-5D utilities (all p Conclusions Among patients with severe aortic stenosis, TAVR with a self-expanding bioprosthesis resulted in substantial improvements in both disease-specific and generic health-related quality of life, but there remained a large minority of patients who died or had very poor quality of life despite TAVR. Predictive models based on a combination of clinical factors as well as disability and frailty may provide insight into the optimal patient population for whom TAVR is beneficial. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )

Stabilization of β-catenin, through inhibition of glycogen synthase kinase 3 (GSK3) activity, in conjunction with inhibition of mitogen-activated protein kinase kinase 1/2 (MEK) promotes self-renewal of naïve-type mouse embryonic stem cells (ESC). In developmentally more advanced, primed-type, epiblast stem cells, however, β-catenin activity induces differentiation. We investigated the response of rat ESCs to β-catenin signaling and found that when maintained on feeder-support cells in the presence of a MEK inhibitor alone (1i culture), the derivation efficiency, growth, karyotypic stability, transcriptional profile, and differentiation potential of rat ESC cultures was similar to that of cell lines established using both MEK and GSK3 inhibitors (2i culture). Equivalent mouse ESCs, by comparison, differentiated in identical 1i conditions, consistent with insufficient β-catenin activity. This interspecies difference in reliance on GSK3 inhibition corresponded with higher overall levels of β-catenin activity in rat ESCs. Indeed, rat ESCs displayed widespread expression of the mesendoderm-associated β-catenin targets, Brachyury and Cdx2 in 2i medium, and overt differentiation upon further increases in β-catenin activity. In contrast, mouse ESCs were resistant to differentiation at similarly elevated doses of GSK3 inhibitor. Interestingly, without feeder support, moderate levels of GSK3 inhibition were necessary to support effective growth of rat ESC, confirming the conserved role for β-catenin in ESC self-renewal. This work identifies β-catenin signaling as a molecular rheostat in rat ESC, regulating self-renewal in a dose-dependent manner, and highlights the potential importance of controlling flux in this signaling pathway to achieve effective stabilization of naïve pluripotency.

Several modern learning frameworks (eg, cognitive apprenticeship, anchored instruction, and situated cognition) posit the utility of nontraditional methods for effective experiential learning. Thus, development of novel educational tools emphasizing the cognitive framework of operative sequences may be of benefit to surgical trainees. We propose the development and global deployment of an effective, mobile cognitive cardiac surgical simulator. In methods, 16 preclinical medical students were assessed. Overall, 4 separate surgical modules (sternotomy, cannulation, decannulation, and sternal closure) were created utilizing the Touch Surgery (London, UK) platform. Modules were made available to download free of charge for use on mobile devices. Usage data were collected over a 6-month period. Educational efficacy of the modules was evaluated by randomizing a cohort of medical students to either module usage or traditional, reading-based self-study, followed by a multiple-choice learning assessment tool. In results, downloads of the simulator achieved global penetrance, with highest usage in the USA, Brazil, Italy, UK, and India. Overall, 5368 unique users conducted a total of 1971 hours of simulation. Evaluation of the medical student cohort revealed significantly higher assessment scores in those randomized to module use versus traditional reading (75% ± 9% vs 61% ± 7%, respectively; P0.05). In conclusion, this study represents the first effort to create a mobile, interactive cognitive simulator for cardiac surgery. Simulators of this type may be effective for the training and assessment of surgical students. We investigated whether an interactive, mobile-computing-based cognitive task simulator for cardiac surgery could be developed, deployed, and validated. Our findings suggest that such simulators may be a useful learning tool.

Objective Limited exposure and visualization and technical complexity have affected resident training in mitral valve surgery. We propose simulation-based learning to improve skill acquisition in mitral valve surgery. Methods After reviewing instructional video recordings of mitral annuloplasty in porcine and plastic models, 11 residents (6 integrated and 5 traditional) performed porcine model mitral annuloplasty. Video-recorded performance was reviewed by attending surgeon providing audio formative feedback superimposed on video recordings; recordings were returned to residents for review. After 3-week practice with plastic model, residents repeated porcine model mitral annuloplasty. Performance assessments initially (prefeedback) and at 3 weeks (postfeedback) were based on review of video recordings on 5-point rating scale ( 5, good; 3, average; 1, poor) of 11 components. Ratings were averaged for composite score. Results Time to completion improved from mean 31 ± 9 minutes to 25 ± 6 minutes after 3-week practice ( P = .03). At 3 weeks, improvement in technical components was achieved by all residents, with prefeedback scores varying from 2.4 ± 0.6 for needle angles to 3.0 ± 0.5 for depth of bites and postfeedback scores of 3.1 ± 0.8 for tissue handling to 3.6 ± 0.8 for suture management and tension ( P ≤ .001). Interrater reliability was greater than 0.8. In this sample, composite scores of first-year integrated and traditional residents were lower than those of senior level residents; comparatively, third-year integrated residents demonstrated good technical proficiency. Conclusions Simulation-based learning with formative feedback results in overall improved performance of simulated mitral annuloplasty. In complex surgical procedures, simulation may provide necessary early graduated training and practice. Importantly, a "passing" grade can be established for proficiency-based advancement.

Summary We evaluated an endobronchial valve device in the treatment of surgically created air leak or pneumothorax by eliminating antegrade flow. Methods Six sheep underwent general anesthesia with positive pressure ventilation and left thoracotomy. After division of the mediastinal pleura, the contralateral cranial lobe was identified and a 2.5 cm×1.5 cm laceration created with resultant air leak. Using bronchoscopy, we deployed a valve device in the bronchus of the injured segment. Chest drainage tube was placed and the thoracotomy closed. At 1 week ( n = 3 ) and 4 weeks ( n = 3 ), the animals underwent general anesthesia, bronchoscopy and right thoracotomy. Results All animals survived the procedure. Bronchoscopic valve device placement in the segmental bronchus resolved the air leak immediately. After closure of thoracotomy, the chest tube demonstrated minimal drainage with no air leak. At 1 and 4 weeks, bronchoscopy showed no change in device location, and the treated segments were atelectatic with fibrous scar at the injured site. Conclusions Collapse of a selected lung segment with resolution of air leak can be achieved using bronchoscopically implanted valve device. The valve device may facilitate treatment of patients with post-surgical or post-traumatic persistent air leak.

Intraabdominal anastomotic pseudoaneurysms continue to be a late complication of aortic reconstructive procedures. Early surgical repair is critical but is associated with high operative mortality rates. We present a patient who was diagnosed with a distal anastomotic pseudoaneurysm 13 months after transabdominal repair of a symptomatic abdominal aortic aneurysm. Because of the poor operative risk, the patient was considered for a less invasive approach and underwent coil embolization of the abdominal aortic anastomotic pseudoaneurysm. The patient remains without recurrence of pseudoaneurysm 3.5 years later. (J Vasc Surg 2002;35:811-4.)

Background: Different viewing conditions (two- and three-dimensional National Television Standard Committee [2D-NTSC and 3D-NTSC] and two-dimensional high-definition television [2D-HDTV]) on telemanipulator performance were evaluated. Methods: Six taskes were performed by 15 endoscopic surgeons using the daVinci telemanipulation system. Performance time and errors were measured. Encoder data from the system were used for kinematic analysis of motion. A self-evaluation questionnaire regarding performance under various viewing conditions was obtained. Results: Resolution was better with 2D-HDTV. The estimate of relative distance was not influenced by the different visualization systems. Motor skill tasks were performed faster with binocular vision (3D-NTSC) than with monocular vision (2D-NTSC, 2D-HDTV). For both 2D settings, the deceleration phase of motion was prolonged (p < 0.05 vs 3D). Peak velocity was reduced with 2D-HDTV as compared with 3D-NTSC (p = 0.01). The surgeons tended to favor the 3D system despite their use of 2D systems in their own practice. Conclusions: Three-dimensional vision enhances telemanipulator performance as compared with a 2D system at the same or higher level of resolution. Because it allows faster and more precise movement, future surgical systems should focus on 3D visualization.

Background . Telemanipulation systems have enabled coronary revascularization on the arrested heart. The purpose of this study was to develop a technique for computer-enhanced endoscopic coronary artery bypass grafting on the beating heart. Methods . The operation was performed using the daVinci telemanipulation system. Through three ports, the left internal thoracic artery was harvested in 10 mongrel dogs (30 to 35 kg) using single right-lung ventilation and CO 2 insufflation. Through a fourth port an articulating stabilizer, manipulated from a second surgical console, was inserted to stabilize the heart. The left anterior descending artery was snared using silicone elastomer slings anchored in the stabilizer cleats and the graft to coronary artery anastomosis was performed. Results . In 7of 10 dogs, total endoscopic beating heart bypass grafting, cardiac stabilization, arteriotomy, and arterial anastomosis were performed using computer-enhanced technology. Endoscopic stabilization and temporary left anterior descending artery occlusion were well tolerated. All grafts were patent although minor strictures were found in 2. In 3 dogs, the procedure could not be completed (1 ventricular arrhythmia, 1 left atrial laceration, and 1 right ventricular outflow tract compression). Conclusions . Endoscopic beating heart coronary artery bypass grafting is possible in a canine model using a computer-enhanced instrumentation system and articulating stabilization.

Background: Minimally invasive cardiac surgery has been developed in part as a result of progress in video-assisted and endovascular surgical techniques. Port-access cardiac surgery, which provides cardiopulmonary bypass, cardioplegic arrest, myocardial protection, and ventricular decompression, permits various procedures to be performed through smaller, less invasive incisions. Methods: Proper patient selection is emphasised in order to minimise potential complications with the port-access system. For port-access coronary revascularisation procedures, a limited left anterior thoracotomy allows harvesting of the internal mammary artery and access to the target coronary arteries. The ascending aorta can be exposed for placement of vein grafts. For port-access mitral valve surgery, a limited right thoracotomy provides direct visualisation of the left atrium and the mitral valve. Results: The feasibility and efficacy of port-access coronary revascularisation and mitral valve surgery have been demonstrated in experimental and clinical settings. Peripheral cardiopulmonary bypass with cardioplegic arrest has been reproducibly achieved based on indices of cardiac function. Port-access multivessel coronary revascularisation and port-access mitral valve procedures have been performed with acceptable results. Conclusions: The port-access catheter system effectively achieves peripheral cardiopulmonary bypass, aortic occlusion, cardioplegia delivery, and left ventricular decompression. Alternative, less invasive methods of coronary revascularisation and various intracardiac procedures can be performed without a conventional median sternotomy.

Atrial septal defects are among the most common congenital anomalies requiring surgical repair. Thrombus formation after patch-based repair is a recognized complication, usually manifested by an embolic event. However, thromboembolic complications after primary repair of atrial septal defects are exceedingly rare. We present a 38-year-old woman found to have a right atrial mass diagnosed as a myxoma by echocardiography and magnetic resonance imaging 3 years after primary atrial septal defect repair. However, final pathology revealed an organized thrombus. A review of the literature and clinical management of postoperative atrial thrombi are discussed.

Minimally invasive cardiac surgery has generated a tremendous amount of enthusiasm in the cardiology and cardiac surgical communities. Coronary revascularization without cardiopulmonary bypass through a small anterior thoracotomy or mediastinotomy has been introduced as an alternative to the conventional approach. An endovascular or port-access technique for cardiopulmonary bypass and cardioplegic arrest has been developed for use in cardiac surgery. This peripherally based system achieves aortic occlusion, cardioplegia delivery, and left ventricular decompression; thus, coronary revascularization and various cardiac procedures can be effectively performed in a less invasive fashion than conventional median sternotomy. Continued technical advances in minimally invasive cardiac surgery will facilitate these procedures, increase patient safety, and contribute to acceptable long-term results.

BACKGROUND To extend the applications of minimal access cardiac surgery, an endovascular cardiopulmonary bypass (CPB) system that allows cardioplegia delivery and cardiac venting was used to perform bilateral internal mammary artery (IMA) bypass grafting in six dogs. METHODS The left IMA (LIMA) was taken down thoracoscopically from three left lateral chest ports, followed by the right IMA (RIMA) from the right side. One left-sided port was extended medially 5 cm with or without rib resection, to expose the pericardium. Both IMAs were divided and exteriorized through the left anterior mediastinotomy. Flow and pedicle length were satisfactory in all cases. Femoral-femoral bypass was used and the heart arrested with antegrade delivery of cardioplegic solution via the central lumen of a balloon catheter inflated to occlude the ascending aorta. All anastomoses were made through the mediastinotomy under direct vision. In five studies the RIMA was attached to the left anterior descending artery (LAD) and the LIMA to the circumflex, and in one study the RIMA was tunneled through the transverse sinus to the circumflex and the LIMA was anastomosed to the LAD. All animals were weaned from CPB in sinus rhythm without inotropes. CPB duration was 108 +/- 27 minutes (mean +/- SD) and the clamp duration was 54 +/- 10 minutes. RESULTS Preoperative and postoperative cardiac outputs were 2.9 +/- 0.71/min and 2.4 +/- 0.31/min, respectively (p = NS), and corresponding pulmonary artery occlusion pressures were 6 +/- 3 mmHg and 7 +/- 2 mmHg, respectively (p = NS). All 12 grafts were demonstrated to be fully patent. Postmortem examination revealed well aligned pedicles and correctly grafted target vessels. CONCLUSION This canine model demonstrates the potential for a less invasive approach to the surgical management of left main coronary artery disease in humans.

A 43-year-old woman underwent mitral valve replacement for severe mitral regurgitation nine years after orthotopic heart transplant. Histopathology showed chronic rejection of the mitral valve with lymphocytic infiltrates. The patient is well at one year follow-up. This report describes an identified case of chronic mitral valve rejection requiring valve replacement.

Objective“Field dependence” is used in cognitive psychology to describe an individual's tendency to be visually distracted by the surrounding environment. Notwithstanding the role of field dependence in contexts in which spatial judgment is important, such as piloting an aircraft, to date, studies linking field dependence to surgical skills have been limited. We evaluated whether field dependence correlates with an ability to anticipate appropriate needle angles in a simulated setting.MethodsTrainees underwent field dependence testing and then participated in a surgical skills exercise. Correlations between field dependence and surgical skill were computed. Specifically, cardiothoracic surgery residents (n = 11) took a battery of cognitive examinations to assess general reasoning and visuospatial judgment. Two written tests, the Rod and Frame test and the Judgment of Line Orientation test, measured the degree of field dependence. The subjects then underwent surgical skills testing. Using a standard needle driver, the participants placed curved needles into a cylindrical silicone mitral valve model with 10 premarked needle entry and exit sites. The components assessed included the ability to load a needle on driver at the appropriate angle.ResultsThe test results showed a parametric distribution, with internal cognitive testing controls demonstrating valid testing techniques and methods. Performance on the cognitive tests measuring spatial judgment and field dependence correlated significantly with skill at determining the appropriate needle angle load in an inverse fashion (Judgment of Line Orientation test, r = 0.61, P

Background. Our goal is to perform minimally invasive coronary artery bypass grafting without sacrificing the benefits of myocardial protection with cardioplegia. Methods. Twenty-three dogs underwent acute studies and 4 dogs underwent survival studies. The left internal mammary artery was taken down using a thoracoscope. Cardiopulmonary bypass was conducted via femoral cannulas and using an endovascular balloon catheter for ascending aortic occlusion, root venting, and delivery of antegrade blood cardioplegia. Pulmonary artery venting was achieved with a jugular vein catheter. An internal mammary artery-to-coronary artery anastomosis was performed using a microscope through a 10 mm port. Results. All animals were weaned from cardiopulmonary bypass in sinus rhythm without inotropes. Cardiopulmonary bypass duration was 104 ± 28 minutes and aortic clamp duration was 61 ± 22 minutes. Cardiac output and pulmonary artery occlusion pressure were unchanged. The internal mammary artery was anastomosed to the left anterior descending artery (25) or the first diagonal (2) with patency shown in 25 of 27. One dog in the survival study had a very short internal mammary artery pedicle under tension and was euthanized for excessive postoperative hemorrhage. Three weeks postoperatively the remaining dogs had angiographically patent anastomoses, normal transthoracic echocardiograms, and histologically normal healing and patent grafts. Conclusions. Endovascular cardiopulmonary bypass using a balloon catheter is effective in arresting and protecting the heart to allow thoracoscopic internal mammary artery-to-coronary artery anastomosis.

Minimally invasive surgical methods have been developed to provide patients the benefits of open operations with decreased pain and suffering. We have developed a system that allows the performance of cardiopulmonary bypass and myocardial protection with cardioplegic arrest without sternotomy or thoracotomy. In a canine model, we successfully used this system to anastomose the internal thoracic artery to the left anterior descending coronary artery in nine of 10 animals. The left internal thoracic artery was dissected from the chest wall, and the pericardium was opened with the use of thoracoscopic techniques and single lung ventilation. The heart was arrested with a cold blood cardioplegic solution delivered through the central lumen of a balloon occlusion catheter (Endoaortic Clamp; Heartport, Inc., Redwood City, Calif.) in the ascending aorta, and cardiopulmonary bypass was maintained with femorofemoral bypass. An operating microscope modified to allow introduction of the 3.5× magnification objective into the chest was positioned through a 10 mm port over the site of the anastomosis. The anastomosis was performed with modified surgical instruments introduced through additional 5 mm ports. In the cadaver model (n = 7) the internal thoracic artery was harvested and the pericardium opened by means of similar techniques. A precise arteriotomy was made with microvascular thoracoscopic instruments under the modified microscope on four cadavers. In three other cadavers we assessed the exposure provided by a small anterior incision (4 to 6 cm) over the fourth intercostal space. This anterior port can assist in dissection of the distal internal thoracic artery and provides direct access to the left anterior descending, circumflex, and posterior descending arteries. We have demonstrated the potential feasibility of grafting the internal thoracic artery to coronary arteries with the heart arrested and protected, without a major thoracotomy or sternotomy. (J THORAC CARDIOVASC SURG 1996;111:567-73)

To identify cis-acting prolactin (PRL) response elements within the sheep β-lactoglobulin (BLG) promoter, CHO cells were cotransfected with a rabbit PRL-receptor (PRL-R) expression plasmid and a number of BLG-CAT constructs. Resection through the 4200 bp BLG promoter diminished the PRL response. Mutation of the proximal binding site for milk protein binding factor (MPBF), a previously described mammary gland transcription factor, abolished the PRL inducibility of full length and shorter forms of the promoter. MPBF was shown to be similar to the Stat protein mammary gland factor (MGF) which has been shown to mediate PRL responsiveness of the rat β-casein gene in mammary cells. MPBF binding activity was detected in the nucleus of CHO cells and was increased 2–6-fold in cells stably transfected with the PRL-R. The lactating mammary gland has high levels of MPBF binding activity and it is likely that this has an important role in the PRL induction of a variety of milk protein genes.

Background The US Food and Drug Administration recently approved a transcatheter aortic valve for patients for whom open heart surgery is prohibitively risky. Methods A multidisciplinary heart valve team partnered with administration to launch a transcatheter aortic valve replacement (TAVR) program. Clinical registries were used to show robust valve caseloads and outcomes at our Veterans Affairs (VA) facility and to project future volumes. A TAVR business plan was approved by the VA leadership as part of a multiphase project to upgrade and expand our surgical facilities. Results The heart valve team completed a training program that included simulations and visits to established TAVR centers. Patients were evaluated and screened through a streamlined process, and the program was initiated successfully. Conclusions Establishing a TAVR program at a VA facility requires a multidisciplinary team with experience in heart valve and endovascular therapies and a supportive administration willing to invest in a sophisticated infrastructure.

Polypeptide and steroid hormones regulate the transcription of milk protein genes in the mammary gland. The promoter sequence motifs and factors through which these hormones mediate their effects in vivo are not clearly defined. Milk protein binding factor (MPBF) is a factor that has recognition sites in the promoters of many milk protein genes including three sites in the promoter of the sheep beta-lactoglobulin (BLG) gene. Mutagenesis of these sites reduced expression of the BLG gene in lactating mammary glands of transgenic mice but did not affect the tissue specificity of the transgene. Furthermore, mutation of all three sites abolished the response of the BLG gene to lactogenic hormones in HC11 mammary cells. Together these results indicate that MPBF mediates the effects of lactogenic hormones in the mammary gland but does not play a role in determining mammary specificity. The similarity between the MPBF binding site and the gamma-interferon activating site suggests that MPBF is related to the STAT family of cytokine-induced transcription factors.

Site-directed mutagenesis of the three binding sites for the mammary factor MPBF in the β-lactoglobulin (BLG) promoter demonstrates that MPBF is a transcriptional activator of the BLG gene in mammary cells. MPBF requires phosphorylation on tyrosine for maximum binding activity and binds to GAS (interferon γ-activation site) elements which are similar to the MPBF binding sites. Prolactin induces MPBF binding activity in CHO cells and is not antigenically related to Stat1 (p91) and Stat2 (p113), suggesting that this transcription factor is likely to be another member of the STAT family of cytokine/growth factor-induced transcription factors.

Isolated aortic (n = 857) or mitral (n = 793) valve replacement with a porcine bioprosthesis was performed in 1650 patients between 1971 and 1980. Follow-up (total = 12,012 patient-years) extended to more than 15 years and was 96 % complete. Patient age ranged from 16 to 87 years; mean age was 59 ± 11 years (±1 standard deviation) for the aortic valve replacement cohort and 56 ± 12 years for the mitral valve replacement cohort. The operative mortality rates were 5% ± 1 % (±70% confidence limits) and 8% ±1%, respectively, for the aortic and mitral subgroups. Estimated freedom from structural valve deterioration (± 1 standard error of the mean) after 10 and 15 years was significantly higher for the aortic than for the mitral valve replacement subgroup (85% ± 0.4% and 63% ±3% versus 78% ±2% and 45% ±3%, respectively, p = 0.001). Reoperation-free actuarial estimates were also significantly greater for the aortic valve replacement cohort: 83% ±2% and 57% ±3% versus 78% ±2% and 43% ± 3% for mitral valve replacement at 10 and 15 years, respectively. The mortality rate for reoperative aortic valve replacement was 11% ± 1%; it was 8% ± 1% for reoperative mitral valve replacement. Importantly, the estimates of freedom from valve-related death (including sudden, unexplained deaths) were relatively high at 10 and 15 years: 78% ±2% and 69% ± 3% in the aortic cohort and 74% ±2% and 63 ± 3% in the mitral cohort (p = not significant). Excluding sudden, unexplained deaths, these estimates were 81% ±3% (aortic) and 73% ±4% (mitral) at 15 years. Thromboembolism-free rates were 84% ±3% (aortic) and 78% ±6% (mitral) at 15 years, and freedom from anticoagulant-related hemorrhage was 96% ± 1% and 89% ± 2%, respectively. At the time of current follow-up, 13% of patients having aortic valve replacement and 50% of patients having mitral valve replacement were receiving warfarin sodium. The hazard functions for thromboembolism and prosthetic valve endocarditis were constant and remained less than 1%/pt-yr over the entire follow-up period. Considering all 1650 patients, multivariate (Cox model) regression analysis revealed that mitral valve replacement (versus aortic) and younger operative age were the only significant, independent predictors of structural valve deterioration or reoperation (p horac C ardiovasc S urg 1992;103:238—52)

Objective Cardiac surgery trainees might benefit from simulation training in coronary anastomosis and more advanced procedures. We evaluated distributed practice using a portable task station and experience on a beating-heart model in training coronary anastomosis. Methods Eight cardiothoracic surgery residents performed 2 end-to-side anastomoses with the task station, followed by 2 end-to-side anastomoses to the left anterior descending artery by using the beating-heart model at 70 beats/min. Residents took home the task station, recording practice times. At 1 week, residents performed 2 anastomoses on the task station and 2 anastomoses on the beating-heart model. Performances of the anastomosis were timed and reviewed. Results Times to completion for anastomosis on the task station decreased 20% after 1 week of practice (351 ± 111 to 281 ± 53 seconds, P = .07), with 2 residents showing no improvement. Times to completion for beating-heart anastomosis decreased 15% at 1 week (426 ± 115 to 362 ± 94 seconds, P = .03), with 2 residents demonstrating no improvement. Home practice time (90–540 minutes) did not correlate with the degree of improvement. Performance rating scores showed an improvement in all components. Eighty-eight percent of residents agreed that the task station is a good method of training, and 100% agreed that the beating-heart model is a good method of training. Conclusions In general, distributed practice with the task station resulted in improvement in the ability to perform an anastomosis, as assessed by times to completion and performance ratings, not only with the task station but also with the beating-heart model. Not all residents improved, which is consistent with a "ceiling effect" with the simulator and a "plateau effect" with the trainee. Simulation can be useful in preparing residents for coronary anastomosis and can provide an opportunity to identify the need and methods for remediation.

This report describes a 61-year-old patient on chronic hemodialysis with multiple, left-sided, intracardiac masses causing intermittent coronary obstruction. Mitral valve replacement was performed. Massive deposition of calcium pyrophosphate crystals in and around the valve cusps led to the diagnosis of tophaceous pseudogout (tumoral calcinosis) of the mitral valve.

Proinflammatory cytokines inhibit growth plate development. However, their underlying mechanisms of action are unclear. These effects may be mediated by ceramide, a sphingosine-based lipid second messenger, which is elevated in a number of chronic inflammatory diseases. To test this hypothesis, we determined the effects of C2-ceramide, a cell permeable ceramide analogue, on the growth of the ATDC5 chondrogenic cell line and on cultured fetal mice metatarsals. In ATDC5 cells, C2-ceramide significantly induced apoptosis at both 40 (82%; P < 0.05) and 25 μM (53%; P < 0.05). At 40 μM, C2-ceramide significantly reduced proliferation ([3H]-thymidine uptake/mg protein) (62%; P < 0.05). C2-ceramide did not markedly alter the differentiation state of the cells as judged by the expression of markers of chondrogenesis and differentiation (sox 9, collagen II and collagen X). The IGF-I signalling pathway is the major autocrine/paracrine regulator of bone growth. Both in the presence and absence of IGF-I, C2-ceramide (25 μM) induced an equivalent reduction in proliferation (60%; P < 0.001). Similarly, C2-ceramide (40 μM) induced a 31% reduction in fetal metatarsal growth both in the presence and absence of IGF-I (both P < 0.001). Furthermore, C2-ceramide reduced ADCT5 proliferation in the presence of AG1024, an IGF-I and insulin receptor blocker. Therefore, C2-ceramide-dependent inhibition appears to be independent of IGF-mediated stimulation of bone growth. Indeed, biochemical studies demonstrated that C2-ceramide (25 μM) pretreatment did not alter IGF-I-stimulated phosphorylation of insulin receptor substrate-1, Akt or P44/42 MAP kinase. In conclusion, C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes through an IGF-I independent mechanism.

The POU domain transcription factor OCT4 is a key regulator of pluripotency in the early mammalian embryo and is highly expressed in the inner cell mass of the blastocyst. Consistent with its essential role in maintaining pluripotency, Oct4 expression is rapidly downregulated during formation of the trophoblast lineage. To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. Our data set includes regulators of ACTIVIN, BMP, fibroblast growth factor, and WNT signaling. These pathways are implicated in regulating human ESC differentiation and therefore further validate the results of our analysis. In addition, we identified a number of differentially expressed genes that are involved in epigenetics, chromatin remodeling, apoptosis, and metabolism that may point to underlying molecular mechanisms that regulate pluripotency and trophoblast differentiation in humans. Significant concordance between this data set and previous comparisons between inner cell mass and trophectoderm in human embryos indicates that the study of human ESC differentiation in vitro represents a useful model of early embryonic differentiation in humans.

Peripheral cardiopulmonary bypass with cardioplegia has facilitated minimally invasive coronary artery bypass grafting and mitral valve replacement. The cardiopulmonary bypass system was modified to allow bicaval occlusion for right heart operations. In 4 canine studies, three variants of bicaval cannulation techniques were successfully used for atrial septal defect repair via a right minithoracotomy.

We report a 55-year-old man, the recipient of a cardiac allograft for ischemic cardiomyopathy 9 years earlier, who presented with progressive aortic root dilation, worsening aortic insufficiency, and an incidentally discovered chronic type A aortic dissection limited to the donor aorta. The patient was taken to the operating room, and the aortic dissection successfully repaired using standard reoperative techniques. This is the sixth case reported in the literature, and only the fourth survivor. To our knowledge, this case represents the first successful repair, of a limited aortic dissection of the donor aorta postcardiac transplantation, using a composite valve graft and modified-Cabrol coronary reconstruction.

Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer. A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis. Signal transducer and activator of transcription 3 (Stat3) is an essential mediator of this switch but the mechanism has not yet been defined. Stat3-dependent cell death during involution can be blocked by activation of Akt/protein kinase B (PKB), a downstream effector of the phosphoinositide-3-OH kinase (PI(3)K) pathway. Here we show that expression of the PI(3)K regulatory subunits p55alpha and p50alpha is induced by Stat3 during involution. In the absence of Stat3 in vivo, upregulation of p55alpha and p50alpha is abrogated, levels of activated Akt are sustained and apoptosis is prevented. Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55alpha and p50alpha promoters in vivo. Overexpression of either p55alpha or p50alpha reduces levels of activated Akt. We propose a novel mechanism in which Stat3 regulates apoptosis by inducing expression of distinct PI(3)K regulatory subunits to downregulate PI(3)K-Akt-mediated survival signalling.

Background— Surgical edge-to-edge repair has been used in the treatment of mitral regurgitation. We evaluated the ability of a catheter-delivered clip (Evalve, Inc) to achieve edge-to-edge mitral valve approximation without cardiopulmonary bypass and the healing response of this technique. Methods and Results— Twenty-one pigs underwent general anesthesia and left thoracotomy. A 10F flexible delivery catheter with a clip was placed into the left atrium. With echocardiographic and fluoroscopic guidance, the clip grasped and approximated the mid portion of the anterior and posterior leaflets. After a double orifice had been confirmed, the clip was detached and the catheter withdrawn. All animals survived and had successful clip placement. Three animals were euthanized at 4 weeks, 9 at 12 weeks, 1 at 17 weeks, 7 at 24 weeks, and 1 at 52 weeks. The clip was well positioned, with leaflet approximation in all animals except 1, in which the clip separated from the posterior leaflet at 4 weeks without affecting valve function. The clip was modified and implanted in 4 pigs; all were intact at 12 to 24 weeks. Scanning electron microscopy showed clip encapsulation with complete endothelialization. Mitral stenosis and thromboembolism did not develop. Two animals developed endocarditis (1 at 12 weeks and 1 at 17 weeks). Progressive healing occurred in all other animals. Conclusions— Edge-to-edge mitral valve approximation can be successfully and reliably achieved with a catheter-delivered clip without cardiopulmonary bypass, resulting in durable healing. The success of this device supports the development of a percutaneous catheter-based system for mitral valve repair.

The transcription factor Oct-4 is a marker of pluripotency in mouse and human embryonic stem (ES) cells. Previous studies using a tetracycline-regulated Oct-4 transgene in the ZHBTc4 cell line demonstrated that downregulation of Oct-4 expression induced dedifferentiation into trophoblast, a lineage mouse ES cells do not normally generate. We found that transfection of Oct-4-specific short interfering RNA significantly reduced expression and functional activity of Oct-4 in mouse and human ES cells, enabling its role to be compared in both cell types. In mouse ES cells, Oct-4 knockdown produced a pattern of morphological differentiation and increase in expression of the trophoblast-associated transcription factor Cdx2, similar to that triggered by suppressing the Oct-4 transgene in the ZHBTc4 cell line. In addition, downregulation of Oct-4 was accompanied by increased expression of the endoderm-associated genes Gata6 and α-fetoprotein, and a gene trap associated with primitive liver/yolk sac differentiation. In human ES cells, Oct-4 knockdown also induced morphological differentiation coincident with the upregulation of Gata6. The induction of Cdx2 and other trophoblast-associated genes, however, was dependent on the culture conditions. These results establish the general requirement for Oct-4 in maintaining pluripotency in ES cells. Moreover, the upregulation of endoderm-associated markers in both mouse and human ES cells points to overlap between development of trophoblast and endoderm differentiation.

Left ventricular-right atrial (LV-RA) communications are rare intracardiac defects, often congenital in nature and clinically apparent during childhood. Acquired LV-RA shunts are encountered occasionally in the adult population as a result of a defect in the upper portion of the membranous ventricular septum. We describe the clinical and echocardiographic features of an elderly patient with an acquired LV-RA communication in the setting of an aortic composite valve graft and endocarditis. We also review the anatomical features and hemodynamic consequences of such defects.

Pluripotent mouse embryonic stem (ES) cells can be expanded in large numbers in vitro owing to a process of symmetrical self-renewal. Self-renewal entails proliferation with a concomitant suppression of differentiation. Here we describe how the cytokine leukaemia inhibitory factor (LIF) sustains self-renewal through activation of the transcription factor STAT3, and how two other signals – extracellular-signal-related kinase (ERK) and phosphatidylinositol-3-OH kinase (PI3K) – can influence differentiation and propagation, respectively. We relate these observations to the unusual cell-cycle properties of ES cells and speculate on the role of the cell cycle in maintaining pluripotency.

The indications for tissue valves in the aortic and mitral positions are becoming better defined with advances in valve design, valve preservation, and management of reoperations. Although some patients who require cardiac valve replacement clearly benefit more from one type of valve than from another, not infrequently one encounters a patient who is in the “gray zone,” where the optimal choice is difficult. At present, bioprostheses for the diseased aortic valve include stented porcine and pericardial valves, stentless porcine valves, aortic homograft, and pulmonary autograft. For patients with mitral valve disease, options for tissue valve replacement are a stented porcine or pericardial prosthesis. Generally, factors to consider in choosing the appropriate valve substitute include the patient’s age, expected life expectancy, coexisting medical problems, lifestyle, and socioeconomics; the etiology of the valve disease, annular size, and physician and patient preference are also relevant. Despite the known finite durability of tissue valves, which is the main limitation in their use, the long-term results have been satisfactory, particularly in older patients, patients with a limited life expectancy, and those undergoing valve replacement in the aortic position. Distillation of available information and ongoing communication between the surgeon and the cardiologist will enable us to assist the patient in choosing the best valve substitute. Curr Opin

diagnosis has been confirmed. In this case not treating the traumatic diaphragmatic rupture for a long period caused a very rare complication. Arriving at the diagnosis of diaphragmatic rupture was difficult because we did not consider the possibility of diaphragmatic rupture causing lung lobar torsion. However, torsion was suggested by the opacity observed in the left lung on the chest radiogram and the nearcomplete occlusion of the bronchus revealed by means of bronchoscopy. It is important to consider that lung lobar torsion can occur as a a result of diaphragmatic rupture, and repair should be performed before lung lobar torsion occurs.

Background . For minimally invasive cardiac operations to be widely applicable, the risks must be equivalent to those of standard open-chest operations. This study analyzed the outcomes of patients recorded in the multicenter Port Access (PA) International Registry to establish operative risks. Methods . Data were analyzed for intent to treat in 583 patients who underwent PA coronary artery bypass grafting (CABG), 184 who underwent PA mitral valve replacement, and 137 who underwent PA mitral valve repair at 121 centers. Results . Port Access was attempted in 1,063 patients and completed in 1,004 (94%). The operative mortality rate was 1% for PA CABG, 3.3% for PA mitral valve replacement, and 1.5% for PA mitral valve repair. Perioperative morbidity was low in all categories: stroke=1.1% to 3.6%, myocardial infarction=0 to 1%, primary procedure reoperation=0 to 0.7%, renal failure=0.2% to 0.7%, multiorgan failure=0 to 0.5%, and atrial fibrillation=5% to 7.3%. Conclusions . Data on 1,063 patients from 121 centers demonstrate that PA CABG and PA mitral valve operations can be performed safely, with morbidity and mortality rates similar to those associated with open-chest operations. Further studies are indicated to establish the long-term efficacy of this method and to analyze its effect on recovery time.

Background A method for monitoring patients was evaluated in a clinical trial of minimally invasive port-access cardiac surgery with closed chest endovascular cardiopulmonary bypass. Methods and Results Cardiopulmonary bypass was conducted in 25 patients through femoral cannulas. An endovascular pulmonary artery vent was placed in the main pulmonary artery through a jugular vein. For mitral valve surgery, a catheter was placed in the coronary sinus for delivery of cardioplegia. A balloon catheter (“endoaortic clamp,” EAC) used for occlusion of the ascending aorta, delivery of cardioplegia, aortic root venting, and pressure measurement was inserted through a femoral artery and initially positioned by use of fluoroscopy and transesophageal echocardiography (TEE). Potential migration of the EAC was monitored by (1) TEE of the ascending aorta, (2) pulsed-wave Doppler of the right carotid artery, (3) balloon pressure, (4) comparison of aortic root pressure and right radial artery pressure, and (5) fluoroscopy. TEE, fluoroscopy, and pressure measurement were effective in monitoring catheter insertion and position. With inadequate balloon inflation, migration of the EAC toward the aortic valve could be detected with TEE. During administration of cardioplegia, TEE showed movement of the balloon away from the aortic valve, and migration into the aortic arch was detectable with loss of carotid Doppler flow. Stability of EAC position was demonstrated with appropriate balloon volume. Cardioplegic solution was visualized in the aortic root, and aortic root pressure changed appropriately during administration of cardioplegia. Venous cannula position was optimized with TEE and endopulmonary vent flow measurement. Conclusions An effective method has been developed for monitoring patients and the catheter system during port-access cardiac surgery.

Background . We developed a method of closed-chest cardiopulmonary bypass to arrest and protect the heart with cardioplegic solution. This method was used in 54 dogs and the results were retrospectively analyzed. Methods . Bypass cannulas were placed in the right femoral vessels. A balloon occlusion catheter was passed via the left femoral artery and positioned in the ascending aorta. A pulmonary artery vent was placed via the jugular vein. In 17 of the dogs retrograde cardioplegia was provided with a percutaneous coronary sinus catheter. Results . Cardiopulmonary bypass time was 111 ± 27 minutes (mean ± standard deviation) and cardiac arrest time was 66 ± 21 minutes. Preoperative cardiac outputs were 2.9 ± 0.70 L/min and postoperative outputs were 2.9 ± 0.65 L/min ( p = not significant). Twenty-one–French and 23F femoral arterial cannulas that allowed coaxial placement of the ascending aortic balloon catheter were tested in 3 male calves. Line pressures were higher, but not clinically limiting, with the balloon catheter placed coaxially. Conclusions . Adequate cardiopulmonary bypass and cardioplegia can be achieved in the dog without opening the chest, facilitating less invasive cardiac operations. A human clinical trial is in progress. (Ann Thorac Surg 1997;63:1748–54)

We have investigated the activity of STAT family members throughout a mammary developmental cycle. Transcripts for Stat 5 were upregulated during pregnancy whilst STAT1 and STAT3 mRNAs were expressed at constant levels. DNA binding complexes containing both STAT5a and 5b showed differing affinities for two naturally occurring STAT5 binding sites. In the involuting mammary gland STAT5 activity decreased whereas STAT3 was specifically activated. These observations reveal a complex pattern of activation of STAT factors during mammary growth, differentiation and remodelling and provide the first evidence for the involvement of STAT3 in development of the mammary gland.

Pluripotent stem cells are essential for embryonic development and regeneration of adult tissues. But when the molecular pathways that control stem cells go awry, the result can often be the development of tumors. Wnt signaling mediated by the intracellular transducer β-catenin and the tumor suppressor APC (adenomatosis polyposis coli) is pivotal in embryogenesis and frequently associated with cancer. The investigation of different mutations in Apc that lead to increased levels of β-catenin in pluripotent cells supports the notion that many cancers may result from the dysregulation of stem-cell programs.

The state of genes microinjected into mouse embryos was followed from the one-cell to the blastocyst stage using the polymerase chain reaction (PCR). Microinjected DNA was detected in all one-, two-, and four-cell injected embryos and in 44% of morula and 26% of blastocysts. Head-to-tail ligation of microinjected genes, a common feature of stably integrated transgene arrays, was detected in all embryos after injection of microinjected genes and occurred irrespective of the structure at the ends of the injected genes. Sensitivity of microinjected DNA to a methylation-dependent restriction endonuclease Dpn I was lost in all embryos by the two-cell stage (24 hr), indicating a change in DNA methylation, independent of transgene integration. Dissociation of blastomeres prior to compaction revealed a mosaic distribution of the microinjected DNA within the embryo and supports the notion that injected genes form a limited number of arrays, which segregate independently until they integrate into the genome or are degraded. Published 1992 Wiley-Liss, Inc.

We report a case of a patient who sustained superior vena cava perforation just proximal to the innominate-caval confluence during pacemaker implantation. Because this complication was recognized early and the dilator was left in place, the patient remained hemodynamically stable and successfully underwent a videoscopically assisted repair of the superior vena caval perforation through a limited thoracotomy incision.

The JAK-STAT pathway is a direct signalling pathway from the cell surface to the nucleus which is utilised by the cytokine receptor superfamily [ 11. Upon ligand engagement, receptor chain(s) aggregate and this results in the activation of the catalytic activity of the associated Janus kinases (JAKs) by transphosphorylation. Subsequent phosphorylation of the receptor allows docking of specific members of the family of signal transducers and activators of transcription (STAT) factors which, upon phosphorylation on a single tyrosine residue, dimerise and translocate to the nucleus where the activated dimer binds to its recognition sequence. Seven members of the STAT family have been identified and of these, STAT5 is encoded by two closely related genes. We have previously shown that the promoter of the milk protein gene p-lactoglobulin (BLG) has three STAT factor binding sites within the proximal 400bp region and that these sites have different affinities for STAT5 [2]. We demonstrated, by site-directed mutagenesis of combinations of these motifs, that at least two functional sites are required for the transcriptional activation of BLG by STAT5 in transgenic mice and that mutation of a single site does not abolish the response to prolactin [3]. This suggests some synergism between the sites which may involve the formation of larger complexes or the interaction with additional factors such as nuclear factor 1 which has multiple binding sites in the BLG promoter [2]. We have also shown that STAT5 is a target for regulation by extracellular mamx [4] and that STAT factors are aberrantly activated in invasive breast cancers [5]. These results suggest that STATs may play a role in normal mammary gland development. STAT5 is expressed in most tissues and cell types. STATsl and 3, which are activated in response to a different subset of cytokines, are also widely expressed. In order to determine the specific requirement for individual STAT factors during mammary gland development, we investigated the expression and binding activity of STATs 1, 3, 5a and 5b throughout a complete cycle of mammary gland development. The developmental regulation of STAT5 binding activity during pregnancy, lactation and involution in the mouse mammary gland was investigated by electrophoretic mobility shift assay (EMSA). The three STAT binding sites in the BLG promoter were used as probes. The sequence of these motifs is shown in Figure 1 and compared with the STAT5 consensus.