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During the 7-year period from August 1986 to December 1993, 242 patients with malignant ventricular arrhythmias underwent 242 ICD implantations and 50 subcutaneous generator changes. Wound infections developed in 5 patients (1.7%): in 3 cases, after primary implantation (3/242 [1.2%]); and in 2 following a generator change (2/50 [4.0%]). This difference was not statistically significant. Infection developed at the generator pocket and became clinically manifest between 6 weeks and 40 months, postoperatively. Our treatment approach with the first patient consisted of simple debridement of the pocket and reimplantation of the existing generator. This led to recurrence, and the generator was safely explanted. In the remaining four patients, our approach has been that of local treatment, with wide debridement of the pocket, and placement of a closed irrigation system with continuous irrigation with a bacitracin, polymyxin, neomycin solution, and culture-specific antibiotic therapy. We have successfully controlled the infection and salvaged the generator with this approach in all four patients, who are all alive and well at a mean follow-up of 25.0 +/- 17.3 months with no recurrence. The good results obtained in these patients suggest that the concept of total explanation of the infected ICD should be reassessed.

I read with the interest the article by Noguera et al. [1] in which they describe a randomized trial of conventional laparoscopy and two hybrid NOTES approaches for cholecystectomy. The authors found no significant differences in outcomes among the three treatment groups. The authors are to be commended for the performance of a randomized controlled trial (RCT) on this controversial topic. While one could quibble over the article’s minor nonadherence to the CONSORT Statement [2, 3], my primary criticism is that the authors made conclusions that have no basis. Here is a quote from the final paragraph of the Discussion section: ‘‘...it is safe to conclude that the transvaginal approach with the flexible endoscope is not inferior to conventional laparoscopy in either effectiveness or safety, and that the transumbilical approach with the flexible endoscope is as effective and safe as the transvaginal approach.’’ With 20 patients per group, this study was underpowered to make such a conclusion. Based on the authors’ own power analysis, the estimated sample size to see a difference of 1 versus 3 % in complication rates would have been 285 patients per group. Incidentally, these numbers would have been even higher if the authors wanted to rule out differences in bile duct injury. The authors stated that their study was done as a ‘‘pilot study,’’ since the calculated sample size was too high. While I would not accept such a statement as justification for an underpowered trial, my main objection is that the authors’ data do not support their conclusions. The only conclusion that can be drawn from this paper is simply this: in a trial of 60 women, no differences in outcome among three cholecystectomy techniques were observed. After this statement, the authors would have to make the concession that their study, by their own admission, was underpowered to make any conclusion that could be generalized beyond their 60-patient experience. To reiterate, it is not valid to extrapolate the data of this study and instruct the general readership that gallbladder technique A is not inferior to technique B, or that various techniques are safe and effective, and so forth. The other major concern that I have is why the data– conclusion incongruity was not corrected during the Surgical Endoscopy peer review process. This suggests an issue with the manuscript’s peer review. Unfortunately, we now have an article that has been vetted, published, and is searchable on the internet, a paper that contains the laudable ‘‘prospective randomized clinical trial’’ in its title, yet makes unfounded conclusions that could mislead surgeons and patients. The adequacy of planning, performing, and reporting surgical clinical trials has been under increasing scrutiny [4–6]. Unfortunately, it appears that this article is not helping this situation or surgical science in general.

Fibroblasts in the attached collagen matrix are in a pro-survival, pro-proliferative state relative to fibroblasts in the released collagen matrix, such that matrix cell number increases in the former over time. Gene array data from attached vs. released matrices were analyzed for putative networks that regulated matrix cell number. Select networks then underwent augmentation and/or inhibition in order to determine their biologic relevance. Matrix stress-release was associated with modulation of signaling networks that involved IL6, IL8, NF-κB, TGF-β1, p53, interferon-γ, and other entities as central participants. Perturbation of select networks in multiple fibroblast strains suggested that IL6 and IL8 secretion may have been involved in preservation of matrix cell population in the released matrix, though there was variability in testing results among the strains. NF-κB activation may have contributed to the induction of population regression after matrix release.

Human fibrinogen is a biomaterial used in surgical tissue sealants, scaffolding for tissue engineering, and wound healing. Here we report on the post-translational structure and functionality of recombinant human FI (rFI) made at commodity levels in the milk of transgenic dairy cows. Relative to plasma-derived fibrinogen (pdFI), rFI predominantly contained a simplified, neutral carbohydrate structure and >4-fold higher levels of the γ'-chain transcriptional variant that has been reported to bind thrombin and Factor XIII. In spite of these differences, rFI and pdFI were kinetically similar with respect to the thrombin-catalyzed formation of protofibrils and Factor XIIIa-mediated formation of cross-linked fibrin polymer. However, electron microscopy showed rFI produced fibrin with much thicker fibers with less branching than pdFI. In vivo studies in a swine liver transection model showed that, relative to pdFI, rFI made a denser, more strongly wound-adherent fibrin clot that more rapidly established hemostasis.

Doubts have been expressed about the clinical usefulness of time domain analysis of the signal averaged electrocardiogram in patients with prolonged QRS complex duration. We studied 147 patients using a signal averaged ECG (40-250 Hz) whose QRS complex was longer than 100 ms. A baseline electrophysiology study was also performed in 128 of these patients. Seventy-seven patients had a minor (QRS120 and100 ms) conduction defect. Thirty-seven of these 77 had either induced or spontaneous sustained ventricular tachycardia (group I) and 40 had no sustained ventricular tachycardia (group II). Seventy patients had a major (QRSor = 120 ms) conduction defect, 44 of whom had sustained ventricular tachycardia (group A). The remaining 26 without this condition formed Group B. Group I compared to group II patients had a longer filtered QRS duration (120.8 +/- 14 vs 104.5 +/- 9.5 ms, P0.001), a longer low amplitude signal duration (41 +/- 12.1 vs 31 +/- 12.6 ms, P0.0001) and a lower root mean square of the last 40 ms of the filtered QRS complex (27 +/- 29.8 vs 35 +/- 25.3 microV, P = ns). Group A compared to group B had a longer filtered QRS duration (157.7 +/- 20.2 vs 140.7 +/- 15.7 ms, P0.001), a longer low amplitude signal duration (57.3 +/- 24.9 vs 37.8 +/- 20.3 ms P0.001) and a lower root mean square of the last 40 ms of the filtered QRS complex (14.3 +/- 11.2 vs 22.0 +/- 10.5 microV, P0.01). Using conventional late potential criteria, the sensitivity and specificity of the signal averaged ECG for the detection of sustained ventricular tachycardia patients with a minor conduction defect were 89% and 75%, respectively. The same criteria applied to patients with a major conduction defect were sensitive (sensitivity: 87%) but non-specific (specificity: 50%). However, by using modified late potential criteria, such as the presence of two of any of the following three signal averaged parameters: filtered QRS durationor = 145 ms, low amplitude signal durationor = 50 ms, root mean square of the last 40 ms of the filtered QRS complexor = 17.5 microV, we derived a non-optimal but still acceptable combination of sensitivity (68%) and specificity (73%). We conclude that traditional late potential criteria can be applied in patients with a minor conduction defect, but modification of these criteria is necessary to derive useful clinical information for risk stratification of patients with a QRS complex durationor = 120 ms.

During the 7-year period from August 1986 to July 1993, 203 patients with malignant ventricular arrhythmias underwent 203 implantable cardioverter-defibrillator (ICD system) implantations at the University Hospitals of Cleveland. Sixty-four patients had significant coronary artery stenoses amenable to myocardial revascularization and thus, at the time of the operation for ICD placement, also underwent coronary artery bypass graft. A retrospective analysis of the course of these 64 patients was carried out to determine the effect of two different treatment strategies on the outcome and cost of therapy. Thirty-six patients (group 1) underwent concomitant implantation of the ICD leads, patches and generator at the time of myocardial revascularization; 28 patients (group 2) underwent a two-stage strategy of initial placement of the ICD leads and patches at the time of myocardial revascularization followed by postoperative electrophysiologic testing to determine the persistent need for generator implantation. Of this latter group, 16 patients still had inducible sustained ventricular tachycardia during postoperative electrophysiologic testing and underwent generator implantation; 12 patients did not receive an ICD generator. The overall 30-day mortality rate was 4.7%. Two patients died in group 1 for a mortality rate of 5.5% and one died in group 2 for a mortality rate of 3.6%. The mean(s.d.) length of stay was 22.8(9.6) days at a mean(s.d.) cost of $93 000(33 000) for group 1 and 24.5(9.6) days at a mean cost of $82 900(30 000) for group 2 (P = n.s.). The mean(s.d.) postoperative length of stay was 13.7(7.8) days for group 1 and 15.4(6.5) days for group 2 (P = n.s.). Other complications occurred in 23% of surviving patients in group 1 and 29% of surviving patients in group 2 (P = n.s.). Mean follow-up was 33 months for group 1 and 23 months for group 2. At the end of 2 years, 78% of patients in group 1 and 86% in group 2 were alive (P = n.s.). It is concluded that concomitant coronary artery bypass grafting and ICD implantation does not result in significantly shorter hospitalization or lower costs. A staged approach appears equally economical, particularly as some patients are spared the cost of the initial ICD generator, the subsequent periodic generator replacements and the mandatory ICD follow-up. This has important implications when the use of non-thoracotomy devices becomes widespread.

Platelet-derived growth factor and insulin-like growth factor-I have been shown to interact synergistically to enhance repair of skin wounds in normal healing swine. Platelet-derived growth factor alone has shown promise in treating human chronic ulcers. The objective of this study was to compare the wound healing effects of platelet-derived growth factor-BB alone with those of a combination of platelet-derived growth factor-BB and insulin-like growth factor-I in an improved model with the use of "older" animals with diabetes. Older diabetic (db/db) mice (>15 weeks of age) have less elevated insulin levels compared with young db/db mice. The serum insulin levels in the older animals is 1.0 to 2.5 times that of the nondiabetic animals, a similar increase to that which occurs in human patients with type II diabetes. Healing was evaluated in two studies involving a total of 104 animals. Treatment groups included the following: 4.0 microg/cm(2) of platelet-derived growth factor-BB, 40.0 microg/cm(2) of platelet-derived growth factor-BB, 4.0 microg/cm(2) of both platelet-derived growth factor-BB and insulin-like growth factor-I or vehicle. All growth factors were applied topically in a methylcellulose vehicle to full-thickness wounds every other day for 24 days. Efficacy end points were median and mean time to complete healing and rate of wound closure. The median time to complete healing for animals receiving the platelet-derived growth factor-BB/insulin-like growth factor-I combination was 38% and 33% faster (p < 0.001) than animals receiving 4.0 microg/cm(2) and 40.0 microg/cm(2) of platelet-derived growth factor-BB, respectively. The mean time to complete healing for platelet-derived growth factor/insulin-like growth factor-I treated animals was 31% and 29% faster (p < 0.001) than 4.0 microg/cm(2) and 40.0 microg/cm(2) platelet-derived growth factor-BB treated animals, respectively. Wounds treated with 4.0 microg/cm(2) platelet-derived growth factor-BB/insulin-like growth factor-I healed, on average, in 22 days compared with 31 days for 40.0 microg/cm(2) platelet-derived growth factor-BB alone and 38 days for vehicle. Also, platelet-derived growth factor-BB/insulin-like growth factor-I significantly improved the rate of wound closure throughout the duration of the studies compared with either dose of platelet-derived growth factor-BB alone (p < 0.005) or vehicle (p < 0.001). In conclusion, the data show that the combination of platelet-derived growth factor-BB and insulin-like growth factor-I is more effective than platelet-derived growth factor-BB alone at the doses tested or vehicle treatment in stimulating cutaneous wound healing in older, diabetic mice.

In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.

We report an unusual case of a relatively regular wide QRS complex tachycardia alternating with periods of an irregular narrow QRS complex tachycardia during atrial fibrillation in a patient with Wolff-Parkinson-White syndrome. Both tachycardias resulted from atrial fibrillation, the wide QRS complex tachycardia being due to 2:1 AV conduction of a type I atrial fibrillation across a posteroseptal accessory AV connection.

We report the outcome in 1,079 consecutive clean or clean-contaminated midline abdominal incisions closed with running 0-loop nylon suture after both elective and emergency operations done between 1984 and 1991. Postoperatively, 79 patients were lost to follow-up, resulting in 1,000 having long-term follow-up. Mean follow-up among these patients was 22 months. Early wound complications included subcutaneous wound infection (18), deep wound infection (17), dehiscence (13), fistula (2), and suture sinus (2). A ventral hernia developed in 42 (4.2%) cases during follow-up. By chi-square analysis, wound infection, dehiscence, class of clean-contaminated wound, patient age > 65, or previous midline abdominal incision were not identified as risk factors for development of a ventral hernia. Reuse of a previous midline incision in combination with any wound infection was associated with an increased risk of subsequent ventral hernia (stepwise regression). In our experience, running closure of a vertical midline abdominal wound has not been associated with an excessive incidence of wound complications or of ventral hernia.

Objective.The goal of this study was to establish guidelines for the prognostic use of the time domain signal-averaged electrocardiogram (ECG) after myocardial infarction.Background.Previous studies of the prognostic use of the signal-averaged ECG in postinfarction patients had one or more of the following limitations: a small study group, empiric definition of an abnormal recording and possible bias in the selection of high risk groups or classification of arrhythmic events, or both. To correct for these limitations, a substudy was conducted in conjunction with the Cardiac Arrhythmia Suppression Trial (CAST).Methods.Ten centers recruited 1,211 patients with acute myocardial infarction without application of the ejection fraction or Holter criteria restrictions of the main CAST protocol. Several clinical variables, ventricular arrhythmias on the Holter recording, ejection fraction and six signal-averaged ECG variables were analyzed. Patients with bundle branch block were exluded from the analysis, and the remaining 1,158 were followed for up to 1 year after infarction. The classification of arrhythmic events was reviewed independently by the CAST Events Committee.Results.During an average (±SD) follow-up of 10.3 ± 3.2 months, 45 patients had a serious arrhythmic event (nonfatal ventricular tachycardia or sudden cardiac arrhythmic death). A Cox regression analysis with only the six signal-averaged ECG variables indicated that the filtered QRS duration at 40 Hz ≥120 ms (QRSD-40 Hz) at a cutpoint ≥120 ms was the most predictive criterion of arrhythmic events. In a regression analysis that included all clinical, Holter and ejection fraction variables, a QRSD-40 Hz ≥120 ms was the most significant predictor (p < 0.0001). The positive, negative and total predictive accuracy and odds ratio for QRSD-40 Hz ≥120 ms were 17%, 98%, 88% and 8.4, respectively, and improved to 32%, 97% 94% and 16.7, respectively, after combination with ejection fraction ≤40% and complex ventricular arrhythmias on the Holter recording.Conclusions.The signal-averaged ECG predicts serious arrhythmic events in the first year after infarction better than do clinical, ejection fraction and ventricular arrhythmia variables, and QRSD-40 Hz ≥120 ms provides the best predictive criterion in this clinical setting.

The purpose of this research is to develop effective hemostatic devices for two difficult types of hemorrhage: (1) traumatic non-compressible (also known as truncal) hemorrhage; and (2) traumatic hemorrhage in the cold coagulopathic subject. The scope of this research will include both military and civilian trauma victims, particularly those suffering from hemorrhagic truncal injury and/or coagulopathic hemorrhage. During the fourth year (Y4) of this project, we continued to generate stocks of two clotting factors (fibrinogen and Factor XIII) needed for the development and manufacture of our hemostatic devices. In addition, we improved our prototypes to deliver foaming technology for the treatment of non-compressible hemorrhage. We performed efficacy testing of the dual (fibrin sealant-alginate) foam technology in our non-compressible model, and we currently are making modifications to both our model system and our foam technology to increase the resultant device utility. We devised an ex vivo adhesion assay to help progress in developing treatments for cold coagulopathic hemorrhage. In addition, we obtained a one year no-cost extension on this award, through 25 Sep 2016. In Y5 we will continue to develop our foam technology for non-compressible hemorrhage, and continue our work on treatments for cold coagulopathic hemorrhage, using both ex vivo tensiometer studies and in vivo procedures with our cold coagulopathic porcine hemorrhage model.

Special Operations Forces (SOF) soldiers must undergo a rigorous selection process that requires high levels of physical fitness and stamina to complete. Physical preparedness is crucial for an applicant's performance during a selection process; preselection physical training programs for SOF applicants must be specific to the demands of the selection process. The purpose of this study was to analyze the physical demands of the Canadian Special Operations Regiment (CSOR) Assessment Center (AC) to develop an evidence-based physical fitness program to assist future applicants to CSOR with their physical preparation. Seventy-one men volunteered to undergo a battery of fitness tests before attending the CSOR AC. Forty-six (mean [SD]: age 26.2 [4.4] years, height 176.5 [7.4] cm, body mass 82.4 [10.1] kg) of the 71 participants further volunteered to participate in the characterization of the physical demands of the AC. Heart rate (HR) data were collected during the physically demanding sessions, and a subsequent task and physiological analysis was conducted to determine key performance variables for exercise prescription. The physically demanding sessions ranged in length from 26.38 (4.24) minutes to 668.52 (30.09) minutes, with the mean HR data ranging from 169.81 (6.64) to 97.51 (6.65) b·min⁻¹, respectively. Key predictors of completion of the AC were V[Combining Dot Above]O2peak (βexp: 5.92; confidence interval [CI]: 1.1-31.0), and 1-repetition maximum (1RM) squats (βexp: 5.16; CI: 1.2-22.2). The information derived from this study provided the foundation for the design of an evidence-based preparatory training program for future applicants that is reflective of the physical demands of the selection process.

Thrombolytic therapy and angioplasty during the early phase of an acute myocardial infarction (AMI) have been shown to improve prognosis. Time-domain analysis of the signal-averaged electrocardiogram (SAECG) provides strong, independent prediction of arrhythmic events (arrhythmic death/resuscitated cardiac arrest) after AMI. To determine whether the prognostic significance of an abnormal SAECG (QRS duration ≥120 ms) measured after AMI is influenced by thrombolytic therapy/angioplasty given in the AMI period, the predictive value of SAECG was compared in patients with and without prior thrombolysis/angioplasty in a substudy of the Cardiac Arrhythmia Suppression Trial. Information was available in 787 patients. The average follow-up was 10 ± 3 months and arrhythmic events occurred in 33 patients (4.2%). The prevalence of abnormal SAECG in patients with and without thrombolytic therapy/angioplasty was 9.4% (34 of 363 patients) and 14.9% (63 of 424 patients), respectively (p

A traumatic diaphragmatic hernia that appears late may have a fatal outcome. Traditionally, the most sensitive diagnostic modality for diaphragmatic injuries has been laparotomy. This results in unnecessary laparotomies. Laparoscopy is now an alternative method for the diagnosis and treatment of numerous intraabdominal disorders. We present a case of a penetrating diaphragmatic injury that was diagnosed and repaired via the laparoscope.

Objectives. The purpose of this study was to determine whether the induction at electrophysiologic study of sustained monomorphic ventricular tachycardias with multiple QRS complex configurations predicted failure of subsequent serial electrophysiologic study guided antiarrhythmic drug testing. Background. Ventricular tachycardias with multiple QRS complex configurations are associated with failure of surgical therapy for ventricular tachycardia. As such, the presence of multiple monomorphic QRS complex ventricular tachycardias during electrophysiologic testing may predict failure of subsequent medical therapy. Methods. Fifty-one consecutive patients with coronary artery disease had reproducible induction of monomorphic ventricular tachycardia during a baseline electrophysiologic study. Each patient then underwent a mean of 1.5 antiarrhythmic drug trials. An antiarrhythmic drug regimen that suppressed induction of ventricular tachycardia was identified in 13 (26%) of the 51 patients. Results. Patients with only one inducible monomorphic QRS complex ventricular tachycardia at baseline study were more likely to have an antiarrhythmic drug regimen identified that suppressed inducible ventricular tachycardia than were patients with multiple monomorphic QRS complex ventricular tachycardias (12 [36%] of 33 patients vs. 1 [6%] of 18, p = 0.04). In seven patients with only one induced configuration of ventricular tachycardia, a second monomorphic ventricular tachycardia with a different QRS complex configuration occurred during attempts at pacing termination of the induced ventricular tachycardia. None of these seven patients then had successful drug suppression of inducible ventricular tachycardia. Thus, 12 (46%) of 26 patients with a single monomorphic QRS complex ventricular tachycardia observed at baseline study had successful serial drug testing compared with 1 (4%) of 25 patients with multiple QRS complex ventricular tachycardia configurations (p = 0.002). Conclusions. The induction or observation of multiple monomorphic QRS complex ventricular tachycardias at baseline electrophysiologic study predicted failure of subsequent serial electrophysiologic study-guided antiarrhythmic drug therapy.

Laparoscopic surgery is associated with a lack of postoperative ileus. To determine if differences exist in postoperative motility patterns, 8 dogs were instrumented with bipolar electrodes 10-14 days prior to open (n = 4) or laparoscopic (n = 4) cholecystectomy. In both groups, Phase II activity disappeared in the first 24 h after operation. The appearance of the migrating myoelectric complex in the small intestine and the migrating colonic complex were used as criteria for recovery from postoperative ileus. Postoperative migrating myoelectric complex cycle length, migrating myoelectric complex, migration velocity, and colonic spike bursts/hour were also measured. No statistically significant differences were observed between groups in study parameters examined. Postoperative myoelectric motility patterns in dogs undergoing open versus laparoscopic cholecystectomy are not different. Other factors may be responsible for the rapid return to oral intake following laparoscopic cholecystectomy.

The routine versus selective use of intraoperative cholangiography has been the subject of debate for some time. Most authors currently advocate routine intraoperative cholangiography with laparoscopic cholecystectomy. The authors report their experience with the selective and routine utilization of intraoperative cholangiography at two institutions. At institution A, 155 laparoscopic cholecystectomies were attempted, and 21 cholangiograms were performed (based on preoperative criteria of ultrasound, liver function tests, and history of jaundice, or intraoperative anatomical uncertainty). At institution B, 164 laparoscopic cholecystectomies were attempted and 127 cholangiograms were performed (a routine intraoperative cholangiography policy). At institution A, there were no common bile duct injuries but there was one retained stone. At institution B, there was one common bile duct injury and no retained stones. The patient with the retained stone from institution A had a preoperative indication (total bilirubin = 4.4 mg/dl) for a cholangiogram, but it was not performed due to technical difficulties. This patient later required endoscopic sphincterotomy with stone extraction. One patient at institution B had a choledochotomy which was detected by intraoperative cholangiography (IOC). This was managed with a T-tube. The selective use of cholangiograms in laparoscopic cholecystectomy will not yield a higher incidence of common bile duct injuries or retained stones compared to routine use. Further, a cholangiogram may not necessarily prevent choledochotomy but can prevent extension of common bile duct injury. Thus, it should always be performed when there is anatomic uncertainty.

We appreciate the useful insights contributed by the authors of the Letter to the Editor. Although the published article from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) investigators1 did not view the data from the perspective of evaluating the different modes of death given that a death occurred (as did the authors of the letter), we appreciate that this approach provides a different perspective of the data. We simply note that if one considers the percent of deaths attributable to heart failure among the patients who died in each arm, this percentage would be higher in the implantable cardioverter-defibrillator (ICD) arm (even if the numbers of heart failure deaths in each arm were identical) simply because the total number of deaths in the ICD arm is reduced compared with the other arms. That is, the …

Scholars differ on whether Federal Reserve intervention mitigated banking panics during the Great Depression and in recent years. The last panic prior to the Depression sheds light on this debate. In April 1929, a fruit fly infestation in Florida forced the U.S. government to quarantine fruit shipments from the state and destroy infested groves. When Congress recessed in June without approving compensation for farmers, depositors in citrus growing regions began withdrawing deposits from banks, culminating in runs on institutions in the financial center of Tampa and surrounding cities. Using archival evidence, we describe how the Federal Reserve Bank of Atlanta halted the spread of the panic by rushing currency to member banks. Analysis based on a new micro-level database of commercial banks in Florida shows that bank failures would have been twice as high without the Fed's intervention. The policy response of the Fed ended the panic and suggests that similar interventions by the Fed may have been useful during the Great Depression, even in cases where banks faced questions about their solvency.

Objectives Chronic ulcerative stomatitis is a condition characterized by chronic, painful oral ulcers, whose pathogenesis is unknown. Patients demonstrate specific IgG autoantibodies against ΔNp63α, an epithelial nuclear transcription factor. The aim of this study was to investigate the role of patient autoantibodies in the disease pathogenesis. Methods Three-dimensional in vitro tissues consisting of a fully differentiated, multilayer epithelium that mimics its in vivo counterpart were incubated with serum from patients with chronic ulcerative stomatitis. Results Our results show a subepithelial detachment of the epithelium at the basement membrane interface, mimicking the oral ulcerations that are seen clinically. Expression of basement membrane proteins Type IV collagen and laminin-5 was unaltered, whereas the expression of α6β4 integrins, hemidesmosome components that attach basal keratinocytes to the basement membrane, was reduced, as determined by immunohistochemistry. Conclusion These results give evidence that patient autoantibodies are pathogenic; and support an autoimmune pathogenesis in chronic ulcerative stomatitis.

It is unknown if epidermal stem cells are maintained during the commercial-scale manufacture of Apligraf, a bilayered living cellular construct (BLCC). To answer this question, we genetically marked replicating keratinocytes, derived from production-scale expansion of working cell banks, in two-dimensional culture with a beta-galactosidase-expressing retrovirus and monitored their fate after incorporation into BLCC and subsequent in vivo transplantation to a nude mouse. Histological analysis of BLCCs showed distinct beta-galactosidase-positive clusters similar to clonal proliferation units visible 8-32 weeks after grafting. Keratinocytes recovered from grafts at week 32 were expanded in vitro in two-dimensional culture, and clonal growth of recovered cells was then compared to the original pregraft population of keratinocytes by colony-forming efficiency (CFE) assays. The CFE of the cells regrown from the grafts was similar to pregraft CFEs (45% and 40%, respectively). Cells regrown from the grafts were then used to produce a second BLCC and generated a well-differentiated epithelium that was histologically similar to pregraft BLCC. These findings provide clear evidence that epidermal stem cells were sustained during the process of large-scale tissue fabrication and that the process of isolation and expansion of cells in BLCC construction retains viable stem cells.

Introduction Pluripotent, human stem cells hold tremendous promise as a source of progenitor and terminally differentiated cells for application in future regenerative therapies. However, such therapies will be dependent upon the development of novel approaches that can best assess tissue outcomes of pluripotent stem cell-derived cells and will be essential to better predict their safety and stability following in vivo transplantation. Methods In this study we used engineered, human skin equivalents (HSEs) as a platform to characterize fibroblasts that have been derived from human embryonic stem (hES) cell. We characterized the phenotype and the secretion profile of two distinct hES-derived cell lines with properties of mesenchymal cells (EDK and H9-MSC) and compared their biological potential upon induction of differentiation to bone and fat and following their incorporation into the stromal compartment of engineered, HSEs. Results While both EDK and H9-MSC cell lines exhibited similar morphology and mesenchymal cell marker expression, they demonstrated distinct functional properties when incorporated into the stromal compartment of HSEs. EDK cells displayed characteristics of dermal fibroblasts that could support epithelial tissue development and enable re-epithelialization of wounds generated using a 3D tissue model of cutaneous wound healing, which was linked to elevated production of hepatocyte growth factor (HGF). Lentiviral shRNA-mediated knockdown of HGF resulted in a dramatic decrease of HGF secretion from EDK cells that led to a marked reduction in their ability to promote keratinocyte proliferation and re-epithelialization of cutaneous wounds. In contrast, H9-MSCs demonstrated features of mesenchymal stem cells (MSC) but not those of dermal fibroblasts, as they underwent multilineage differentiation in monolayer culture, but were unable to support epithelial tissue development and repair and produced significantly lower levels of HGF. Conclusions Our findings demonstrate that hES-derived cells could be directed to specified and alternative mesenchymal cell fates whose function could be distinguished in engineered HSEs. Characterization of hES-derived mesenchymal cells in 3D, engineered HSEs demonstrates the utility of this tissue platform to predict the functional properties of hES-derived fibroblasts before their therapeutic transplantation.

Lesser omental transection during gastric bypass for morbid obesity may be associated with postoperative dumping. A survey of postoperative symptoms was performed in patients undergoing laparoscopic Roux-en-Y gastric bypass with transection vs. preservation of the lesser omentum. A written questionnaire on dumping symptoms was administered to patients 2 years after laparoscopic Roux-en-Y gastric bypass with or without transection of the lesser omentum. Statistical testing was performed to determine whether the rate of various symptoms was related to the transection of the lesser omentum. The patients without lesser omental transection had significantly less symptoms than the patients with transection for 11 out of the 17 symptoms that were queried (p

Introduction of the automatic implantable cardioverter defibrillator (AICD) has dramatically affected the surgical treatment of malignant ventricular tachyarrhythmias. The authors continue to perform electrophysiologically directed subendocardial resection (SER) of left ventricular (LV) scars in selected patients, and we revascularize (CABG) those patients undergoing AICD implantation who have significant myocardial ischemia. In an attempt to define the optimal role of each procedure, this report analyzes our 8-year experience with 348 consecutive patients treated surgically for these arrhythmias (SER since 1983 and AICD since 1986). All patients undergoing SER had organized ventricular tachycardia (VT) as a result of myocardial infarction, and most had LV aneurysms; of those undergoing AICD or AICD/CABG, 60% had VT, 15% had ventricular fibrillation, and 25% had both or were noninducible. The thirty-day mortality rate was 1.5% (3/197) for AICD, 5.4% (5/93) for AICD/CABG, and 8.6% (5/58) for SER; these mortality figures are not significant different. Late deaths in all groups were predominantly due to congestive heart failure, and actuarial survival as well as freedom from sudden death was similar between the groups at 4 years. Recurrent VT occurred in 167 of 282 (59%) of long-term survivors of AICD or AICD/CABG during follow-up and in nine of 53 (17%) of those with SER. Forty-eight per cent of survivors of AICD or AICD/CABG required antiarrhythmic medications, whereas only 11% of those with SER required antiarrhythmics. Long-term survival in each group is much higher than that reported for comparable patients with severe LV dysfunction treated medically. In those patients with organized VT and LV aneurysm who are judged able to survive the procedure, SER offers a high likelihood of cure rather than simple prevention of sudden death.

BACKGROUND In animals, parasympathetic nerve fibers that innervate the sinoatrial node can be selectively stimulated to increase atrial cycle length. These nerve fibers course through an epicardial fat pad at the margin of the right superior pulmonary vein, the superior vena cava, and the right atrium. We hypothesized that similar nerves exist and can be selectively stimulated in humans. METHODS AND RESULTS Microscopic examination of fat pads excised from the margin of the right superior pulmonary vein, the superior vena cava, and the right atrium during two human autopsies revealed the presence of nerve fibers and ganglia. We electrically stimulated this epicardial fat pad in 16 patients during cardiac surgery. The fat pads were stimulated with continuous-pulse trains for 15 seconds via a hand-held bipolar electrode using constant current (10-15 mA), constant pulse width (0.02-0.05 msec), and at 6.6, 10, 20, 25, and 30 Hz. The mean atrial cycle length +/- 1 SEM increased from 734 +/- 34 msec at baseline to a maximum of 823 +/- 61 msec at 6.6 Hz, 1,167 +/- 125 msec at 10 Hz, 1,734 +/- 281 msec at 20 Hz, 2,993 +/- 661 msec at 25 Hz, and 2,461 +/- 668 msec at 30 Hz during nerve stimulation. Linear regression analysis showed that the response of atrial cycle length to sinoatrial parasympathetic nerve stimulation was frequency dependent. The maximum response and complete decay of the response occurred within 4-8 seconds of initiation or termination of sinoatrial parasympathetic nerve stimulation. Atrioventricular conduction time and the PR interval did not change during sinoatrial parasympathetic nerve stimulation, even when the atria were paced at the baseline heart rate. CONCLUSIONS Electrical stimulation of parasympathetic nerve fibers in a fat pad near the sinoatrial node increased atrial cycle length without affecting atrioventricular nodal conduction. This is the first study in which such nerve fibers that innervate the sinoatrial node have been selectively stimulated in humans.

Background— The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown. Methods and Results— SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death. Conclusions— ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000609.

Background The fibroblast-populated 3D collagen matrix is a model of tissue and healing which has been used since the 1980's. It was hypothesized that anchorage disruption of the collagen matrix would produce p53-dependent apoptosis in the embedded fibroblasts, but results of hypothesis testing were variant. Findings The response of p53 to anchorage disruption in 3D culture or to UV irradiation in 2D culture was influenced both by fibroblast strain and culture conditions. It also was determined that data scatter in a collagen matrix contraction assay was related to fibroblast strain and possibly to technical factors, such as cell culture technician and/or number of matrices utilized. Subsequent analysis suggested that phenotypic drift and/or inter-strain genetic variability may have been responsible for the data scatter. In addition, several technical factors were identified that may have contributed to the scatter. Conclusion Experimentation with human foreskin fibroblasts in both 2D and 3D culture can produce variant data. The underlying cause of the data scatter appears to be partially due to the biologic variability of the fibroblast.