Alan D. Weinberg

Mechanism of Sustained Release of Vascular Endothelial Growth Factor in Accelerating Experimental Diabetic Healing

In this study, we hypothesize that local sustained release of vascular endothelial growth factor (VEGF), using adenovirus vector (ADV)-mediated gene transfer, accelerates experimental wound healing. This hypothesis was tested by determining the specific effects of VEGF(165) application on multiple aspects of the wound healing process, that is, time to complete wound closure and skin biomechanical properties. After showing accelerated wound healing in vivo, we studied the mechanism to explain the findings on multiple aspects of the wound healing cascade, including epithelialization, collagen deposition, and cell migration. Intradermal treatment of wounds in non-obese diabetic and db/db mice with ADV/VEGF(165) improves healing by enhancing tensile stiffness and/or increasing epithelialization and collagen deposition, as well as by decreasing time to wound closure. VEGF(165), in vitro, stimulates the migration of cultured human keratinocytes and fibroblasts, thus revealing a non-angiogenic effect of VEGF on wound closure. In conclusion, ADV/VEGF is effective in accelerating wound closure by stimulating angiogenesis, epithelialization, and collagen deposition. In the future, local administration and sustained, controlled release of VEGF(165) may decrease amputations in patients with diabetic foot ulcers and possibly accelerate closure of venous ulcers and pressure ulcers.

Staphylococcus epidermidis Colonization Is Highly Clonal Across US Cardiac Centers

BACKGROUND Little is known about the clonality of Staphylococcus epidermidis in the United States, although it is the predominant pathogen in infections involving prosthetic materials, including ventricular assist devices (VADs). METHODS Seventy-five VAD recipients at 4 geographically diverse US cardiac centers were prospectively followed up to 1 year of VAD support. The anterior nares, sternum, and (future) driveline exit site were cultured for S. epidermidis before VAD insertion and at 7 times after surgery. Infection isolates were also collected. Isolates were typed by pulsed-field gel electrophoresis. A subset underwent susceptibility testing and staphylococcal chromosomal cassette mec and multilocus sequence typing. RESULTS A total of 1559 cultures yielded 565 S. epidermidis isolates; 254 of 548 typed isolates (46%) belonged to 1 of 7 clonal types as defined by pulsed-field gel electrophoresis. These clones were identified in up to 27 people distributed across all 4 cardiac centers. They caused 3 of 6 VAD-related infections. Disseminated clones were more antibiotic resistant than were less prevalent isolates (eg, 79% vs 54% methicillin resistant; P = .0021). CONCLUSIONS This study revealed that healthcare-associated S. epidermidis infection is remarkably clonal. We describe S. epidermidis clones that are highly resistant to antibiotics distributed across US cardiac centers. These clones may have determinants that enhance transmissibility, persistence, or invasiveness. Clinical Trials Registration. NCT01471795.

Optimized temporary biventricular pacing acutely improves intraoperative cardiac output after weaning from cardiopulmonary bypass: A substudy of a randomized clinical trial

OBJECTIVE Permanent biventricular pacing benefits patients with heart failure and interventricular conduction delay, but the importance of pacing with and without optimization in patients at risk of low cardiac output after cardiac surgery is unknown. We hypothesized that pacing parameters independently affect cardiac output. Accordingly, we analyzed aortic flow measured with an electromagnetic flowmeter in patients at risk of low cardiac output during an ongoing randomized clinical trial of biventricular pacing (n = 11) versus standard of care (n = 9). METHODS A substudy was conducted in all 20 patients in both groups with stable pacing after coronary artery bypass grafting, valve surgery, or both. Ejection fraction averaged 33% ± 15%, and QRS duration was 116 ± 19 ms. Effects were measured within 1 hour of the conclusion of cardiopulmonary bypass. Atrioventricular delay (7 settings) and interventricular delay (9 settings) were optimized in random sequence. RESULTS Optimization of atrioventricular delay (171 ± 8 ms) at an interventricular delay of 0 ms increased flow by 14% versus the worst setting (111 ± 11 ms, P < .001) and 7% versus nominal atrioventricular delay (120 ms, P < .001). Interventricular delay optimization increased flow 10% versus the worst setting (P < .001) and 5% versus nominal interventricular delay (0 ms, P < .001). Optimized pacing increased cardiac output 13% versus atrial pacing at matched heart rate (5.5 ± 0.5 vs 4.9 ± 0.6 L/min, P = .003) and 10% versus sinus rhythm (5.0 ± 0.6 L/min, P = .019). CONCLUSIONS Temporary biventricular pacing increases intraoperative cardiac output in patients with left ventricular dysfunction undergoing cardiac surgery. Atrioventricular and interventricular delay optimization maximizes this benefit.

Inflammatory Kinetics and Efficacy of Anti-inflammatory Treatments on Human Nucleus Pulposus Cells.

Study Design. Human nucleus pulposus (NP) cell culture study investigating response to tumor necrosis factor-&agr; (TNF&agr;), effectiveness of clinically available anti-inflammatory drugs, and interactions between proinflammatory cytokines. Objective. To characterize the kinetic response of proinflammatory cytokines released by human NP cells to TNF&agr; stimulation and the effectiveness of multiple anti-inflammatories with 3 substudies: Timecourse, Same-time blocking, Delayed blocking. Summary of Background Data. Chronic inflammation is a key component of painful intervertebral disc degeneration. Improved efficacy of anti-inflammatories requires better understanding of how quickly NP cells produce proinflammatory cytokines and which proinflammatory mediators are most therapeutically advantageous to target. Methods. Degenerated human NP cells (n = 10) were cultured in alginate with or without TNF&agr; (10 ng/mL). Cells were incubated with 1 of 4 anti-inflammatories (anti-IL-6 receptor/atlizumab, IL-1 receptor anatagonist, anti-TNF&agr;/infliximab and sodium pentosan polysulfate/PPS) in 2 blocking-studies designed to determine how intervention timing influences drug efficacy. Cell viability, protein, and gene expression for IL-1&bgr;, IL-6, and IL-8 were assessed. Results. Timecourse: TNF&agr; substantially increased the amount of IL-6, IL-8, and IL-1&bgr;, with IL-1&bgr; and IL-8 reaching equilibrium within ∼72 hours (IL-1&bgr;: 111 ± 40 pg/mL, IL-8: 8478 ± 957 pg/mL), and IL-6 not reaching steady state after 144 hours (1570 ± 435 pg/mL). Anti-TNF&agr; treatment was most effective at reducing the expression of all cytokines measured when added at the same time as TNF&agr; stimulation. Similar trends were observed when drugs were added 72 hours after TNF&agr; stimulation, however, no anti-inflammatories significantly reduced cytokine levels compared with TNF control. Conclusion. IL-1&bgr;, IL-6, and IL-8 were expressed at different rates and magnitudes suggesting different roles for these cytokines in disease. Autocrine signaling of IL-6 or IL-1&bgr; did not contribute to the expression of any proinflammatory cytokines measured in this study. Anti-inflammatory treatments were most effective when applied early in the inflammatory process, when targeting the source of the inflammation. Level of Evidence: N/A

Prostate-specific antigen screening and prostate cancer treatment in renal transplantation candidates: A survey of U.S. transplantation centers.

INTRODUCTION Renal transplantation candidates are a highly screened population. There are currently no guidelines or consensus on prostate cancer (CaP) screening in these patients. In light of the recent United States Preventive Services Task Force recommendations against prostate-specific antigen (PSA) screening, we conducted a survey of transplantation surgeons to gain a better understanding of practice patterns among U.S. centers. MATERIALS AND METHODS A 14-question multiple-choice online survey was e-mailed to 195 U.S. renal transplantation centers. The questionnaire assessed CaP screening and treatment practices. The survey also evaluated characteristics of the respondents institution. Descriptive statistics were used for each of the responses, and associations were made with program characterization using logistic or linear regression models. RESULTS A total of 90 surgeons responded, representing 65 of 195 programs (33% response rate). Overall, 89% of respondents reported routinely screening for CaP in renal transplantation candidates and 71% had set guidelines for PSA screening. The most common age to start PSA screening was 50 years (51%) and 79% of respondents reported no age limit to stop PSA screening. Definitive treatment of CaP was required before proceeding to transplantation in 45% of respondents. Active surveillance was a viable option in 67% of responders. Most respondents (73%) replied that the waiting time for eligibility after treatment depended on the CaP stage and risk. CONCLUSIONS Although most programs have guidelines on PSA screening in renal transplantation candidates, there is still variation nationwide in screening and treatment practices. AS is a viable treatment option in most of the programs. Our results suggest a benefit of a consensus panel to recommend guidelines in this population.

Ambulatory Spine Surgery: A Survey Study

Study Design Cross-sectional study. Objective To assess the current practices of spine surgeons performing ambulatory surgery in the United States. Methods An electronic survey was distributed to members of the International Society for the Advancement of Spine Surgery. Data were initially examined in a univariate manner; variables with a p value < 0.25 were entered into a multiple logistic regression model. All statistical analyses were performed using the SAS System software Version 9.2 (SAS Institute, Inc., Cary, North Carolina, United States). Results Overall, 84.2% of respondents performed some manner of ambulatory spine surgery, and 49.1% were investors in an ambulatory surgery center. Surgeon investors in ambulatory surgery centers were more likely to perform procedures of increased complexity than noninvestors, though limited data precluded a statistical correlation. Surgeons in private practice were more likely to perform ambulatory surgery (94.3%; p = 0.0176), and nonacademic surgeons were both more likely to invest in ambulatory surgery centers (p = 0.0024) and perform surgery at least part of the time in a surgery center (p = 0.0039). Conclusions Though the numbers were too few to calculate statistical significance, there was a trend toward the performance of high-risk procedures on an ambulatory basis being undertaken by those with investment status in an ambulatory center. It is possible that this plays a role in the decision to perform these procedures in this setting versus that of a hospital, where a patient may have better access to care should a complication arise requiring emergent assessment and treatment by a physician. This decision should divest itself of financial incentives and focus entirely on patient safety.

High-resolution microendoscope imaging of inverted papilloma and normal sinonasal mucosa: evaluation of interobserver concordance

High‐resolution microendoscopy (HRME) enables real‐time imaging of epithelial tissue. The utility of this novel imaging modality for inverted papilloma has not been previously described. This study examines the ability of otolaryngologists to differentiate between images of inverted papilloma and normal sinonasal mucosa obtained with a HRME.

Response to Letter Regarding Article, “Direction of Preoperative Shunting Affects Ventricular Mechanics After Tetralogy of Fallot Repair”

We thank Dr DeGroff for his comments on our study of ventricular mechanics during repair of tetralogy of Fallot.1 We acknowledge that the use of 2-dimensional echo sections to represent the 3-dimensional left ventricle (LV) is limiting. The degree of error introduced by this compromise is unknown in the absence of more comprehensive imaging. However, we believe that our conclusions are essentially correct. As noted, Matsumori et al2 defined limitations of a biplane Simpson rule for LV volume determination in the presence of right ventricular (RV) pressure and volume overload. A modified Simpson rule, including area planimetry of …