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Aim: The aim of this study was to investigate the short-term effect of levofloxacin on the microbiota of healthy lungs.Material and methods: Male F344 rats received either no levofloxacin (n = 9), ...

Background Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery and is associated with worse outcomes. The cardiac autonomic nervous system is implicated in the pathogenesis of POAF. Objective The purpose of this study was to determine the efficacy and safety of selective cardiac autonomic modulation in preventing POAF. Methods In this randomized, double-blind, placebo-controlled trial, adults undergoing cardiac surgery were randomized 1:1 to intraoperative injection of 250 units onabotulinumtoxinA (botulinum toxin type A [BoNTA]) or placebo into epicardial fat pads. The study was powered to detect a 40% reduction in relative risk of POAF. Time to first episode of in-hospital POAF was the primary outcome, evaluated in patients receiving injection. Additionally, incidence of POAF, length of stay (LOS), and adverse events were examined. Results The trial assigned 145 patients to injection, 15 of whom were dropped before treatment, leaving 130 patients for analysis. Overall, 36.5% (23/63) of BoNTA-treated patients developed POAF compared with 47.8% (32/67) of placebo-treated patients. The time-to-event analysis revealed a hazard ratio of 0.69 (95% confidence interval 0.41–1.19; P = .18) for the BoNTA vs placebo arm. There were no significant differences in postoperative hospital LOS (median [interquartile range] 6.0 [3.4] vs 6.2 [3.7] days; P = .51) or adverse events prolonging LOS (27/63 [42.9%] vs 30/67 [44.8%]; P = .83) in patients receiving BoNTA vs placebo. Conclusion Epicardial injection of onabotulinumtoxinA was without discernible adverse effects, but we failed to detect a significant difference in risk of POAF. Future large-scale studies of epicardial onabotulinumtoxinA injection as a potential POAF prevention strategy should be designed to study smaller, but clinically meaningful, treatment effects.

The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.

Gastroesophageal reflux refers to the reflux of stomach contents into the esophagus. Gastroesophageal reflux disease (GERD) describes the presence of excessive reflux of acid or nonacid stomach contents, with unwanted resultant manifestations. Although traditionally approached as a disease with consequences limited to the gastrointestinal tract, an increasing body of evidence implicates GERD in injury to the respiratory tract. The high prevalence of extraesophageal manifestations of GERD in patients with respiratory illness highlights the importance of the consideration of gastrointestinal causes in the approach to the patient with respiratory illness. In this chapter, respiratory complications associated with GERD will be reviewed.

Purpose: In the clinical setting, there is no reliable tool for diagnosing gastric aspiration. A potential way of diagnosing gastric fluid aspiration entails bronchoalveolar lavage (BAL) with subsequent examination of the BAL fluid for gastric fluid components that are exogenous to the lungs. The objective of this study was to determine the longevity of the gastric fluid components bile and trypsin in the lung, in order to provide an estimate of the time frame in which assessment of these components in the BAL might effectively be used as a measure of aspiration. Materials and Methods: Human gastric fluid (0.5 mg/kg) was infused in the right lung of intubated male Fischer 344 rats (n = 30). Animals were sacrificed at specified times following the experimentally induced aspiration, and bronchoalveolar lavage fluid (BALF) was collected. Bile concentrations were analyzed by an enzyme-linked chromatogenic method, and the concentration of trypsin was quantified using an ELISA. Data were analyzed using non-linear regression and a one-phase decay equation. Results: In this experimental model, the half-life of bile was 9.3 hours (r 2 = 0.81), and the half-life of trypsin was 9.0 hours (r 2 = 0.68). Conclusions: The half-lives of bile and trypsin in the rodent aspiration model suggest that the ability to detect aspiration may be limited to a few days post-aspiration. If studies using rats are any indication, it may be most effective to collect BAL samples within the first 24 hours of suspected aspiration events in order to detect aspiration.

The pulmonary microbiota is important for both normal homeostasis and the progression of disease, and may be affected by aspiration of gastric fluid. The aim of this study was to investigate changes in the lung microbiota induced by aspiration of gastric fluid in a laboratory rat model.Using the intratracheal application method, male rats received aspiration with 0.9% normal saline (n = 11); gastric fluid (n = 24) or sterilized (gamma-irradiated) gastric fluid (n = 12) once-weekly for four weeks. On the fifth week, the animals were sacrificed, and the microbiota of the lung was assessed by 16S ribosomal RNA gene sequencing.Lungs without aspiration and lungs after aspiration with normal saline had similar microbial compositions, dominated by bacteria of the genera Serratia, Ralstonia and Brucella. Evaluation of the microbiota following aspiration of gastric fluid revealed a much different profile that was dominated by bacteria from the genera Romboutsia and Turicibacter and largely independent of sterilization of the gastric fluid.In a laboratory rat model, aspiration with gastric fluid caused a substantial shift of the lung microbiota that could be characterized as a shift from Proteobacteria towards Firmicutes, possibly of enteric origin. Bacteria contained in the gastric fluid are not apparently responsible for this change.

Objectives Chronic aspiration of gastric fluid contents can decrease long-term survival of pulmonary transplants due to development of obliterative bronchiolitis. However, little is known about the early immune response and the cascade of events involved in the development of obliterative bronchiolitis. Materials and methods We utilized a rat orthotopic pulmonary transplant model and a single aspiration of either gastric fluid or normal saline to investigate the histologic, cellular, and cytokine changes associated with an acute gastric fluid aspiration event compared with normal saline at 2 and 10 days after aspiration. Results Our observations included a decrease in pulmonary compliance and increased airway inflammation and acute rejection of the transplanted lung, as well as increases in macrophages, granulocytes, and proinflammatory cytokines such as interleukin 1β, transforming growth factor β1 and β2, and tumor necrosis factor α in bronchoalveolar lavage fluid from the transplanted lung of gastric fluid-aspirated rats compared with normal saline-aspirated rats. Conclusions The acute inflammatory response observed in the present study is consistent with changes found in chronic models of aspiration-associated injury and suggests a potentially important role for mast cells in the development of obliterative bronchiolitis.

The aim of this study was to investigate a new method for visualization and quantification of intrapulmonary liquid distribution after oropharyngeal gastric fluid aspiration in mice.Eleven mice received oropharyngeal aspiration with a gastric fluid, India ink, and saline solution. Digital imaging and pixel calculation were used to analyze intrapulmonary fluid distribution selectively.Digital pixel analysis and orophanryngeal aspiration are both safe techniques in mice and deliver reproducible/valid results. Analysis revealed an average aspirate distribution of 86.8% of the total lung area. The proportional amount of the left lung was significantly greater than that of the right lung (P = 0.023). The lobe with the lowest mean distribution was the right lower lobe (79.2% ± 4.4%).Digital pixel calculation is a reliable method for quantitative, macroscopic evaluation of fluid distribution in the lung. This method is a useful tool for training purposes and it can be used to ensure interinvestigator reproducibility.

Despite improving outcomes following lung transplantation, chronic rejection continues to limit survival. The predominant form of chronic rejection, bronchiolitis obliterans syndrome, has been associated with multiple etiologies including aspiration from gastroduodenal reflux. This article reviews the current literature with regards to the incidence of reflux following lung transplantation, the association of reflux with allograft dysfunction and survival, and the success of prevention and treatment of reflux in this patient population. Although antireflux surgery has been demonstrated to be safe in this population and leads to a stabilization of lung function in patients with reflux, there have not been definitive data that it improves survival.

Rates of repeat lung transplantation have increased since implementation of the lung allocation score (LAS). The purpose of this study is to compare survival between repeat (ReTx) and primary (LTx) lung transplant recipients in the LAS era.We extracted data from 9,270 LTx and 456 ReTx recipients since LAS implementation, from the United Network for Organ Sharing registry. Propensity scoring was used to match ReTx and LTx recipients. Kaplan-Meier analysis compared survival between LTx and ReTx groups, with and without stratification based on time between first and second transplant. Multivariable Cox models estimated predictors of survival in lung recipients.Comparing all ReTx to LTx demonstrates a survival advantage for LTx that is diminished with propensity score matching (p = 0.174). Considering LTx against ReTx greater than 90 days after the initial procedure, there are similar survival results (p0.067). In contrast, ReTx within 90 days was associated with a survival disadvantage that persisted despite matching (p = 0.011). In ReTx populations, factors conferring worse outcomes include intensive care unit admission, unilateral transplantation, poor functional status, and primary graft dysfunction as the indication for retransplantation (p0.05).Late lung retransplantation appears to be as beneficial as primary transplantation in propensity-matched patients. However, survival is severely diminished in those retransplanted less than 90 days after primary transplantation. The utility of early retransplantation needs to be carefully weighed in light of risks.

Helminthic therapy has shown considerable promise as a means of alleviating some inflammatory diseases that have proven resistant to pharmaceutical intervention. However, research in the field has been limited by a lack of availability to clinician scientists of a helminth that is relatively benign, non-communicable, affordable, and effectively treats disease. Previous socio-medical studies have found that some individuals self-treating with helminths to alleviate various diseases are using the rat tapeworm (cysticercoid developmental stage of Hymenolepis diminuta; HDC). In this study, we describe the production and use of HDCs in a manner that is based on reports from individuals self-treating with helminths, individuals producing helminths for self-treatment, and physicians monitoring patients that are self-treating. The helminth may fit the criteria needed by clinical scientists for clinical trials, and the methodology is apparently feasible for any medical center to reproduce. It is hoped that future clinical trials using this organism may shed light on the potential for helminthic therapy to alleviate inflammatory diseases. Further, it is hoped that studies with HDCs may provide a stepping stone toward population-wide restoration of the biota of the human body, potentially reversing the inflammatory consequences of biota depletion that currently affect Western society.

Background Preprocedural multidetector computed tomography (MDCT) may identify patients at risk for mechanical complications during lead extraction. Methods To describe the use and feasibility of computed tomography scanning for preprocedural planning of lead extraction, we conducted a retrospective study of high-risk patients, who underwent electrocardiogram (ECG)-gated MDCT before planned lead extraction between January 1, 2012, and March 30, 2013. Results Among 30 patients the mean age was 63 ± 15 years, 60% were male, and 20% had prior sternotomy. Most devices were left sided (93%) and 24 had implantable defibrillators (80%). Indications for extraction included lead malfunction (n = 15; 50%), class I lead advisories (n = 11; 37%), and infection (n = 10; 33%). Overall, there were 65 leads extracted (mean 2.1 leads per patient). One extraction procedure was deferred due to MDCT evidence of significant myocardial perforation with the lead tip > 1 cm beyond the epicardium (n = 1, 3%). MDCT suggestion of lead adherence to central venous structures (n = 13, 43%) was associated with significantly longer laser times (88 ± 71 seconds vs 30 ± 37 seconds, P = 0.02) and larger sheath size (14.9 ± 1.3 vs 13.5 ± 1.2 French, P = 0.02). MDCT evidence of central venous occlusion or stenosis was not associated with increased laser times. Excluding the patient with MDCT evidence of significant perforation, clinical success was achieved in all patients (n = 29/29). Conclusions ECG-gated MDCT scanning before lead extraction may facilitate the identification of significant perforation and patients at high risk for mechanical complication.

Worldwide experience and expertise in lung transplant are increasing. For patients with end-stage respiratory disease this therapy greatly improves symptoms, eliminates the need for home oxygen therapy, and restores overall capacity. A major obstacle to increasing its availability as a treatment option is the limited number of donor organs. Patients who develop severe and progressive respiratory failure and are believed to be candidates for this treatment may be eligible for urgent lung transplantation. While waiting for donor organs to become available, methods to support respiratory function are essential to facilitate survival to transplant. Use of extracorporeal support to maintain gas exchange was first described two decades ago and has since developed substantially. We review current techniques available for bridging patients to lung transplant, and the indications and procedures for such support. Recent and historical clinical experience in this field is also discussed.

Chronic aspiration of gastric fluid potentially plays a central role in the pathogenesis of obliterative bronchiolitis, which is often associated with chronic pulmonary allograft failure. It remains unknown whether pharmaceutical-induced increases in gastric pH might effectively prevent any putative pulmonary injury associated with chronic aspiration.To test the hypothesis that neutralization of gastric fluid would affect the development of aspiration-associated obliterative bronchiolitis, an established rat lung transplant model (WKY-to-F344) was utilized. Pulmonary allograft recipients were subjected to eight weekly aspirations of gastric fluid at pH 2.5 (low-pH), gastric fluid at pH 7.4 (neutralized-pH), or saline as a control.Histologic analysis revealed that the fraction of airways affected with lesions consistent with obliterative bronchiolitis was 0.55 ± 0.08 (mean ± SEM) in rats receiving aspiration with low-pH gastric fluid, 0.49 ± 0.07 in animals receiving neutralized-pH gastric fluid, and 0.07 ± 0.05 in rats receiving normal saline only. The difference between groups receiving gastric fluid, regardless of pH, was significantly different from the saline control (P 0.0001), whereas the difference between the groups receiving low-pH gastric fluid and neutralized-pH gastric fluid was not significant (P = 0.75).Effective management of gastroesophageal reflux disease in lung transplant recipients should probably include more than neutralization of gastric fluid.

To extend previous models of hexavalent chromium [Cr(VI)] reduction by gastric fluid (GF), ex vivo experiments were conducted to address data gaps and limitations identified with respect to (1) GF dilution in the model; (2) reduction of Cr(VI) in fed human GF samples; (3) the number of Cr(VI) reduction pools present in human GF under fed, fasted, and proton pump inhibitor (PPI)-use conditions; and (4) an appropriate form for the pH-dependence of Cr(VI) reduction rate constants. Rates and capacities of Cr(VI) reduction were characterized in gastric contents from fed and fasted volunteers, and from fasted pre-operative patients treated with PPIs. Reduction capacities were first estimated over a 4-h reduction period. Once reduction capacity was established, a dual-spike approach was used in speciated isotope dilution mass spectrometry analyses to characterize the concentration-dependence of the 2nd order reduction rate constants. These data, when combined with previously collected data, were well described by a three-pool model (pool 1 = fast reaction with low capacity; pool 2 = slow reaction with higher capacity; pool 3 = very slow reaction with higher capacity) using pH-dependent rate constants characterized by a piecewise, log-linear relationship. These data indicate that human gastric samples, like those collected from rats and mice, contain multiple pools of reducing agents, and low concentrations of Cr(VI) (

Aspiration of gastric fluid into the lung mediates the development of obliterative bronchiolitis (OB) in orthotopic WKY-to-F344 rat pulmonary transplants that have been subjected to immunosuppression with cyclosporine. However, the contribution of ischemic time to this process remains unknown. In this study, the effect of long (n = 16) and short (n = 12) ischemic times (average of 6 h and of 73 min, respectively) on rat lung transplants receiving aspiration of gastric fluid was assessed. Long ischemic times (LIT) led to significantly (p < 0.05) greater development of OB (ratio of OB lesions/total airways = 0.45 ± 0.07, mean ± standard error) compared to short ischemic times (ratio = 0.19 ± 0.05). However, the development of OB was dependent on aspiration, as controls receiving aspiration with normal saline showed little development of OB, regardless of ischemic time (p < 0.05). These data suggest that LIT, while insufficient by itself to lead to OB, works synergistically with aspiration of gastric fluid to exacerbate the development of OB.

Ten years ago, Christian Longo had been deeply enmeshed in a career of minor crimes and crushing financial burdens that had led to bankruptcy. He saw only one way out: relieving his family, his wife Mary Jane and their three children, of their dependency on him. He strangled Mary Jane and 2-year old daughter Madison, put them into suitcases and threw them into Yaquina Bay in Newport, Oregon. He stuffed his 3-year old daughter Sadie and 4-year old son Zachery into pillow cases, weighted them down with rocks, and threw them, still alive, into a nearby pond where they drowned. His crime was discovered when Zachery's body floated to the surface of the pond. He was placed on the FBI's 10 most wanted list, was found two years later living with his girlfriend in Cancun, Mexico, and was arrested, brought back to Oregon, put on trial, found guilty on four counts of murder, and sentenced to death. Several months ago, he wrote an editorial that was published in the New York Times: “Giving life after death row.”1 The editorial began with these words: “Eight years ago I was sentenced to death for the murders of my wife and three children. I am guilty. I once thought that I could fool others into believing this was not true. Failing that, I tried to convince myself that it didn't matter. But gradually, the enormity of what I did seeped in; that was followed by remorse and then a wish to make amends.” He continued: “There is no way to atone for my crimes, but I believe that a profound benefit to society can come from my circumstances. I have asked to end my remaining appeals, and then donate my organs after my execution to those who need them.” He went on to say, “And yet, the prison authority's response to my latest appeal to donate was this: `The interests of the public and condemned inmates are best served by denying the petition.'” Longo claimed that half of the other inmates on death row wanted to do the same and that there was no valid reason to prohibit them from donating. The question of who was right, the condemned prisoner or the prison parole board., was debated at the Southern Thoracic Surgical Association Annual Meeting in November 2011. by Dr. Shu Lin, who sided with the prisoner, and Dr. Jay Pal on the side of the parole Board.

The hypothesis that aspiration of gastric fluid drives the anti-ovalbumin response toward a Th2 reaction even in animals not prone to Th2 responses was evaluated.Forty-eight male C57BL/6 mice were used.Mice were sensitized and challenged with ovalbumin starting 5 weeks prior to the initiation of weekly aspirations of either gastric fluid or normal saline as a control. Weekly aspiration continued during the course of exposure to ovalbumin.Aspiration consisted of 50 μl of gastric fluid with 50 μl of 0.9 % normal saline used as a control. Antigen exposure consisted of sensitization to ovalbumin via intraperitoneal injection on days 0 and 14 and challenge on day 21 with aerosolized antigen for 30 min.No evidence of a shift toward a Th2 response as a result of gastric fluid aspiration was seen in the Th1-prone strain utilized, although a profound down-regulation of a broad array of T cell-associated cytokines and chemokines and up-regulation of macrophage-associated markers was observed as a result of aspiration.These data provide support for the hypothesis that the clinical association between asthma and gastroesophageal reflux disease (GERD) does not involve an exacerbation of asthma by GERD-associated aspiration of gastric fluid, but may cause immune reactions unrelated to the asthma pathology.

Biome depletion, or loss of co-evolved constituents within the ecosystem of the human body, has become the leading suspect in epidemics of allergic, inflammatory and autoimmune diseases associated with post-industrial culture. Immunity in wild and laboratory rats has been used as a model for immunity in biomenormal and biome depleted environments, respectively. In this study, the ranges of numerous immune parameters (such as cytokine production and cell surface marker expression) in 8 wild rats overlapped with the ranges found in 7 laboratory rats. However, considering a number of parameters simultaneously as an “expression index” revealed a substantially greater range of immune activity in the wild compared with laboratory rats. These findings are consistent with the intuitive idea that the immune system is inherently malleable or flexible within environments of evolutionary adaptedness, and might suggest that biome reconstitution as an effective therapy could be achieved in a variety of ways.

Background Gastroesophageal reflux disease (GERD) in lung recipients is associated with decreased survival and attenuated allograft function. This study evaluates fundoplication in preventing GERD-related allograft dysfunction. Methods Prospectively collected data on patients who underwent transplantation between January 2001 and August 2009 were included. Lung transplant candidates underwent esophageal pH probe testing before transplantation and surveillance spirometry evaluation after transplantation. Bilateral lung transplant recipients who had pretransplant pH probe testing and posttransplant 1-year forced expiratory volume in the first second of expiration (FEV 1) data were included for analysis. Results Of 297 patients who met study criteria, 222 (75%) had an abnormal pH probe study before or early after transplantation and 157 (53%) had a fundoplication performed within the first year after transplantation. Patients with total proximal acid contact times greater than 1.2% or total distal acid contact times greater than 7.0% demonstrated an absolute decrease of 9.4% (± 4.6) or 12.0% (± 5.4) in their respective mean 1-year FEV 1 values. Patients with abnormal acid contact times who did not undergo fundoplication had considerably worse predicted peak and 1-year FEV 1 results compared with recipients receiving fundoplication (peak percent predicted=75% vs. 84%; p = 0.004 and 1-year percent predicted=68% vs. 77%; p = 0.003, respectively). Conclusions Lung transplant recipients with abnormal esophageal pH studies attain a lower peak allograft function as well as a diminished 1-year FEV 1 after transplantation. However a strategy of early fundoplication in these recipients appears to preserve lung allograft function.

Bush EL, Barbas AS, Holzknecht ZE, Byrne GW, McGregor CG, Parker W, Duane Davis R, Lin SS. Coagulopathy in α-galactosyl transferase knockout pulmonary xenotransplants. Xenotransplantation 2011; 18: 6–13. © 2011 John Wiley & Sons A/S. Abstract: Background: After substantial progress on many fronts, one of the remaining barriers still opposing the clinical application of xenotransplantation is a disseminated intravascular coagulopathy (DIC) that is observed in the pre-clinical model of porcine-to-primate transplantation. The onset of DIC is particularly rapid in recipients of pulmonary xenografts, usually occurring within the first days or even hours of reperfusion. Methods: In this study, we describe the results of two porcine-to-baboon transplants utilizing porcine lungs depleted of macrophages, deficient in the α-1,3-galactosyltransferase gene, and with the expression of human decay-accelerating factor, a complement regulatory protein. Results: In both cases, evidence of DIC was observed within 48 h of reperfusion, with thrombocytopenia and increases in levels of thrombin–antithrombin complex evident in both cases. Depletion of fibrinogen was observed in one graft, whereas elevation of D-dimer levels was observed in the other. One graft, which showed focal lymphocytic infiltrates pre-operatively, failed within 3 h. Conclusions: The results indicate that further efforts to address the coagulopathy associated with pulmonary xenotransplantation are needed. Further, evidence suggests that resident porcine immune cells can play an important role in the coagulopathy associated with xenotransplantation.

Extracorporeal membrane oxygenation (ECMO) is increasingly implemented in patients with end-stage pulmonary disease as a bridge to lung transplant. Several centers have instituted an approach that involves physical rehabilitation and ambulation for patients supported with ECMO. Recent reports describe the successful use of ambulatory ECMO in patients with chronic respiratory illnesses being bridged to lung transplant. We describe the first case of a previously healthy pediatric patient with acute respiratory failure successfully supported with ambulatory ECMO as a bridge to lung transplant after an unsuccessful bridge to recovery. Although there are challenges associated with awake and ambulatory ECMO in children, this strategy represents an exciting breakthrough and a potential paradigm shift in ECMO management for pediatric acute respiratory failure.

Publicly available program-specific data from the scientific registry of transplant recipients were used to determine the association between adult lung transplant center volume and 1-year recipient mortality from 2000 to 2007. We found a significant inverse association between the center volume of adult lung transplants and 1-year recipient mortality that is growing more pronounced over time. We conclude that procedure volume is an increasingly important determinant of lung transplant center volume and that policies that improve the performance of low-volume centers or reduce the number of patients who use such centers may be warranted.

A large number of studies point toward chronic aspiration associated with gastroesophageal reflux disease (GERD) as an important factor involved in the development of asthma, the incidence of which has increased dramatically in industrially developed countries. Recent work suggests that medical intervention aimed at acid blockade is not sufficient to relieve the effects of chronic aspiration on asthma pathology, leaving surgical treatment of the disease as one of the few remaining options. This study examined the effect of chronic aspiration on the airway-associated immune response to allergens using a model of experimentally induced airway hypersensitivity in Balb/c mice.The mice received aspiration of gastric fluid on days 1, 8, 15, 22, 29, 36, 43, and 50 and were sensitized to ovalbumin by intraperitoneal (IP) injection on days 33 and 47, challenged with aerosolized ovalbumin on day 54, and killed on day 56. Control mice received sham gastric fluid aspirations, sham induction of airway hypersensitivity, or both.Chronic aspiration of 50 microl murine gastric fluid once per week for 8 weeks had a profound effect on the immune system in the lung, with upregulation of the macrophage/monocyte-associated cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) and profound downregulation of a broad array of T-cell-associated cytokines including interleukins 2, 4, 5, 6, 10, 13, and 23, as well as interferon-gamma. The aspiration-induced depression of IL-5 production in particular was found only in mice with airway hypersensitivity and not in control mice without airway hypersensitivity.The results indicate that chronic aspiration of gastric fluid has a profound effect on the nature of the allergic response to aerosolized allergens, suggesting that the aspiration may be an important factor affecting the pathogenesis of asthma.

Background The development of laser-assisted extraction techniques for chronically implanted pacemaker and defibrillator leads has reduced the need for open surgical removal. Reports of the mortality from laser-assisted extraction range from 1.9% to 3.4%. The purpose of this study was to determine the rate of major cardiovascular injury and emphasize the need for cardiothoracic surgical participation in this procedure. Methods A retrospective cohort study was performed of 112 consecutive laser-assisted lead extractions at a single university medical center during a 6-year period. Patient and lead characteristics were analyzed as well as indications, outcomes, and major complications. Results Successful lead extraction was accomplished in 103 (92%) of the 112 patients. Elective sternotomy after failure of laser-assisted lead removal was successfully performed in 4 patients. Emergent surgical intervention was required in 4 patients for caval perforation (n = 2), subclavian vein injury (n = 1), or right atrial injury (n = 1). Three of the 4 patients requiring emergent intervention died, for an overall series mortality of 2.6%. In July of 2006, a policy of cardiothoracic surgeon presence during the laser-assisted extraction was instituted. Since that time, there has been one emergent sternotomy and one elective sternotomy for lead removal with no procedure-related deaths. Conclusions Despite recent advances in laser technology for the removal of pacemaker and defibrillator leads, the potential for major cardiovascular injury and death remains. Involvement of the cardiothoracic surgeon in both the preoperative decision-making process as well as the laser-assisted lead extraction is critical to prevent or emergently treat any major complications.

Gastroesophageal reflux has become a major health concern in industrialized countries, with drugs aimed at blocking acid production being more frequently prescribed than any other drug. Damage to lung tissue as a result of chronic aspiration of gastric fluid is a primary health risk associated with gastro-esophageal reflux, with such aspiration being suspected in the induction or exacerbation of asthma and other lung diseases. In this study, a rodent model of chronic aspiration was used to characterize the pulmonary histopathology produced by repetitive aspiration events and to investigate the pathologic roles of individual gastric fluid components such as acid and particulate food matter. Rats exposed to chronic aspiration of whole gastric fluid developed a pathology distinct from that of acute lung injury, characterized by granulomatous interstitial pneumonitis with prominent formation of multinucleated giant cells. This pattern of injury could be reproduced with chronic aspiration of particulate food matter and with chronic aspiration of pH-neutralized gastric fluid, but not with chronic aspiration of hydrochloric acid. Thus, since acid-neutralizing therapy is currently the mainstay of treatment for patients with reflux-associated respiratory symptoms, these results strongly suggest that alternative therapeutic approaches aimed at preventing chronic-aspiration induced lung injury may be warranted.

In lung transplants necessitating cardiopulmonary bypass (CPB), aprotinin has been shown to decrease transfusion requirements. More recently, off-pump transplantation has become the standard of care. The efficacy of aprotinin use in this population has yet to be definitively examined. We completed a retrospective review of all adult OP-BOLTs performed between January 2000 and January 2006 at a single university center (n=215). Aprotinin use was determined by the attending anesthesiologist or surgeon. It was administered at the time of induction. The primary outcome was total blood products utilized in terms of units transfused during postoperative days 0, 1 and 2. One-hundred and one patients received aprotinin and 114 did not. An overall analysis of all of the patients in this study demonstrated a trend towards statistical significance for reduced total blood product transfusion for the aprotinin group compared to the non-aprotinin group (P=0.13). A subgroup analysis was performed in relation to each diagnosis. The use of aprotinin was associated with a significant reduction in peri-operative total blood products transfused in COPD patients (P=0.03) undergoing OP-BOLT. Subgroup analysis demonstrated that the use of aprotinin in the COPD population did result in a statistically significant decrease in total blood products transfused, specifically the total number of units of packed red blood cells given. These findings suggest that aprotinin administration should be considered for all patients undergoing OP-BOLT to reduce exposure to blood products and potential immune sensitization and infectious complications.

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TGF-beta in BAL and of IL-1 alpha, IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.

Background Chronic aspiration associated with gastro oesophageal reflux disease (GERD) is thought to play a substantial role in the development of asthma, the incidence of which is dramatically increasing in industrially developed countries. The majority of data examining the association between aspiration and asthma has been obtained from epidemiological studies, which show that between 50 and 90% of individuals with asthma experience some element of GERD. This study describes the effect of chronic aspiration on a model of experimentally induced airway hypersensitivity in Balb/c mice. Materials and methods Four experimental groups were utilized: Aspiration/Asthma, Sham/Asthma, Aspiration/Sham and Sham/Sham. Mice were sensitized with aerosolized 1% ovalbumin on days 1 to 10 (sensitization phase), followed by repeated exposure on days 31 to 40 (challenge phase). Aspiration events occurred on days 1, 8,15, 22, 29, 36, 43 and 50. Animals were sacrificed on days 56 and 57. Results Chronic aspiration of 10 µL of murine gastric fluid per week for eight weeks produced an injury pattern distinct from that of acute aspiration, with lung injury characterized by hyperplasia, neutrophil infiltration of the bronchioles and relative parenchymal sparing. Aspiration during induction of ovalbumin-induced airway hypersensitivity was associated with a trend toward decreased production of antiovalbumin IgG, antiovalbumin IgE, and total IgE. Further, aspiration induced a substantial and significant increase in antiovalbumin IgG1/IgG2a ratios, consistent with a shift toward a predominantly Th2 response. Conclusion These findings indicate that chronic aspiration has a profound effect on the nature of the immune response to aerosolized allergens in a model of experimentally induced airway hypersensitivity.

Background Lung transplant survival is limited by the development of bronchiolitis obliterans syndrome (BOS). The strongest risk factor for BOS is acute rejection (AR). We have previously shown that rabbit anti-thymocyte globulin (RATG) induction therapy is associated with a decrease in early AR. Thus, we hypothesized that RATG induction would translate to reduced BOS and improved long-term graft survival. Methods Forty-four lung recipients were prospectively randomized to receive conventional immunosuppression with RATG induction (RATG group) or conventional immunosuppression alone (control group). End-points included graft survival, early and total acute rejection, BOS and treatment complications. Results There was no difference in graft survival between the groups at 8 years (RATG: 36%; control: 23%; p = 0.48). The RATG group had fewer early rejections compared with the control group (5% vs 41%; p = 0.01). However, the overall rejection incidence did not differ (RATG: 62%; control: 68%; p = 0.52). There was a trend toward a delay in BOS onset among RATG subjects compared with control subjects (2,376 days vs 1,108 days; log rank, p = 0.15). There was no difference in the incidence of infections, but the RATG group had a higher rate of malignancies. Conclusions Our results suggest that alternative approaches to anti-thymocyte induction should be pursued to reduce BOS and prolong allograft survival.

Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant-related morbidity and mortality. We have utilized alemtuzumab, a humanized anti-CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 +/- 0.25 preceding alemtuzumab versus 0.33 +/- 0.14 posttreatment, p-value

Galphaq-coupled receptors such as alpha1-adrenergic, angiotensin, and endothelin receptors, play key roles in cardiac physiology. These receptors have also been shown to couple to G proteins of the G12 family, including Galpha12 and Galpha13. In this report, we determined whether these G proteins interact with endothelin, angiotensin, and alpha1-adrenergic receptors in the human heart. We find that these receptors activate cardiac Galpha12 and Galpha13 differentially; endothelin receptors activate only Galpha12 (to 218 +/- 22% of unstimulated levels), angiotensin receptors activate only Galpha13 (to 236 +/- 49% of unstimulated levels), and alpha1-adrenergic receptors activate neither Galpha12 (123 +/- 18% of unstimulated levels) nor Galpha13 (113 +/- 12% of unstimulated levels). Consistent with these data, translocation of guanine nucleotide exchange factor p115RhoGEF, which responds to Galpha13, occurs only after stimulation of angiotensin receptors (shifting from 73 +/- 12% to 41 +/- 10% cytosolic). These differences in the activation of Galpha12 and Galpha13 by Galphaq-coupled receptors may underlie reported differences in the functions of these receptors.

Repetitive gastric fluid aspirations have been shown to lead to obliterans bronchiolitis (OB), but the component or components of gastric fluid that are responsible are unknown. This study investigates the role of particulates and, separately, soluble material in gastric fluid during the development of OB. Whole gastric fluid (WGF) was collected from male Fischer 344 (F344) rats and separated by centrifugation into particle reduced gastric fluid (PRGF) and particulate components resuspended in normal saline (PNS). Orthotopic left lung transplants from male Wistar-Kyoto rats into F344 rats were performed using a modification of the nonsuture external cuff technique with prolonged cold ischemia. Rats were subjected to weekly aspiration of 0.5 ml/kg of WGF (n = 9), PRGF (n = 10), PNS (n = 9), or normal saline (control, NS; n = 9) for 8 weeks following transplantation. Lung allografts treated with WGF, PRGF, or PNS developed a significantly greater percentage of OB-like lesions compared with the control. No statistical difference was observed when comparing the fibrosis grades or the percentage of OB lesions of WGF, PRGF, and PNS groups, suggesting that both soluble and insoluble components of gastric fluid can promote the development of aspiration-induced OB and fibrosis in lung allografts.

Background: Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized. We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.Methods: Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves. Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test. Results: Twenty-seven probes in 9 genes showed significant differential methylation and expression (P-4). The top gene was protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10-5) in bicuspid patients, as compared to tricuspid patients. Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range: -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissectionsConclusions: Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms. The top gene was PTPN22, which is involved in T-cell receptor signaling and associated with various immune disorders. These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

Since the advent of various novel immunosuppressants, including tacrolimus, rapamycin, and daclixumab. expanding variations of protocols have been developed. Little evidence exists to substantially support a single agent over another. or a combination regimen protocol over another. Therefore, the principles and the goals of immunosuppression in lung transplantation recipients will remain moving targets and continue to evolve, and the use of large-scale, multi-institutional clinical trials is imperative to develop optimal immunosuppressive strategies.

Background Controversy exists regarding the optimal use of bilateral lung transplant (BLT) in older recipients in diseases where either single or bilateral transplant is appropriate. International Society for Heart and Lung Transplant (ISHLT) guidelines suggest an upper age limit of 60 for BLT, despite limited data regarding outcomes with BLT in patients over 60. We hypothesize that BLT offers comparable, if not superior, clinical outcomes to SLT in all patients independent of recipient age. Methods In order to test our hypothesis, we conducted a case-control study to compare the effect of transplant operation on survival and the onset of bronchiolitis obliterans syndrome (BOS) in consecutive lung transplant recipients 61 years of age or older using Kaplan- Meier analysis and Cox proportional hazard models. Results We identified 107 consecutive lung transplant recipients 61 or older at the time of transplant. Patients received SLT (n=46) or BLT (n=61) based on donor organ availability. Comparable survival was achieved with BLT in older patients vs. SLT P=0.19). One-, two-, and five-year survival estimates in BLT were 82%, 75% and 68%, respectively, vs. in SLT 78%, 70% and 44%, respectively. A comparable onset of BOS was also observed in the patients who received BLT vs. SLT (P=0.23). Conclusion Successful short- and medium-term outcomes are achieved with BLT in older recipients and are comparable to those achieved with SLT. Our results suggest that age over 60 should not exclude patients from consideration of BLT.

Background Primary graft failure remains a significant source of mortality after lung transplantation. Extracorporeal membrane oxygenation (ECMO) provides treatment for affected recipients. We hypothesized that venovenous membrane oxygenation provides a safer alternative than venoarterial support for lung recipients suffering from primary graft failure. Methods We conducted an analysis of 522 patients who underwent lung transplantation from April 1992 to July 2004. Twenty-three (4.5%) patients required membrane oxygenation secondary to primary graft failure unresponsive to conventional treatment. Of these recipients, 15 (65%) were treated with venoarterial, while 8 (35%) underwent venovenous membrane oxygenation. Results Median days to initiation and duration of membrane oxygenation did not differ between groups. Eight of 15 patients (53%) from the venoarterial group were successfully weaned from life support, with one surviving greater than 45 days. This lone long-term survivor required retransplantation 4 days after initial transplant. In contrast, all venovenous patients were weaned from support, with 7 of 8 surviving greater than 30 days. The 30-day survival for venovenous recipients (88%) approximates that of all lung recipients at our center (94%, p = 0.42). Noted complications for ECMO patients included renal failure (n = 16), neurologic catastrophes (n = 8), sepsis (n = 5), and hemorrhage (n = 10). The venoarterial recipients suffered 30 of 39 total complications. Most of the complications for venovenous recipients involved renal failure, but by hospital discharge these patients demonstrated a mean creatinine of 0.9 mg/dL. Conclusions For lung recipients with primary graft failure, venovenous membrane oxygenation provides better outcomes, with fewer complications, than venoarterial membrane oxygenation.

Background. The most difficult barrier to organ transplantation is humoral rejection, a condition initiated by binding of antibodies to blood vessels in the graft. Fortunately, humoral rejection is not the only outcome of antibody binding to the graft. In some cases, accommodation, a condition in which the graft does not undergo humoral injury despite the existence of humoral immunity directed against it, occurs and the graft remains seemingly inured. The mechanism underlying accommodation is uncertain, but changes in the function of antibodies, changes in the target antigen, and changes in the graft imparting resistance to injury have been implicated. Methods. Using the swine-to-baboon cardiac xenograft model, we asked which mechanism(s) may distinguish acute vascular rejection from accommodation. Results. In both acute vascular rejection and accommodation, antibodies were bound and complement activated in blood vessels of the graft. However, in acute vascular rejection, the full complement cascade was activated; while in accommodation, the complement cascade was interrupted, suggesting complement was inhibited in the latter condition. In acute vascular rejection, heparan sulfate and syndecan-4-phosphate, which can aid in complement control, were nearly absent, whereas in accommodation these were present in heightened amounts. Conclusion. These findings suggest that control of complement may underlie accommodation, at least in part, and raise the possibility that this control and possibly other protective mechanisms could be exerted by heparan sulfate.

Coronary artery disease has a high prevalence among lung transplant recipients and has historically been a contraindication to transplant at many institutions. In patients with mild-to-moderate coronary artery disease (Mod-CAD) undergoing lung transplant, outcomes are not well defined.All patients who underwent pulmonary transplantation from January 1996 through November 2010 with pretransplant coronary angiogram were included in our study. Recipients of multivisceral, redo, and lobar lung transplants and those who underwent pretransplant coronary revascularization were excluded. Patients were grouped into Mod-CAD or no-coronary artery disease group (No-CAD). Primary end point was overall survival. Secondary end points were 30-day events and the need for posttransplant coronary revascularization.Approximately 539 patients were included in the study: 362 in the No-CAD, 177 in the Mod-CAD group. Patients with Mod-CAD were predominantly male, older, and had a higher body mass index. No difference in either perioperative morbidity and mortality (Mod-CAD, 4.2% vs. No-CAD 3.3%, P=0.705) or late overall mortality was shown between groups. Mod-CAD patients had a shorter hospitalization (median: 12 days vs. 14 days, P=0.009) and required a higher rate of late coronary revascularization procedures (PCI: Mod-CAD vs. No-CAD, 0.3% vs. 4.0%, P=0.0035; CABG: Mod-CAD vs. No-CAD, 0.3% vs. 2.3%, P=0.0411).Mod-CAD does not appear to be associated with increased perioperative morbidity or decreased survival after transplant. Coronary artery disease may worsen and require coronary revascularization in patients with risk factors for disease progression. In these patients, close follow-up and screening for progression of coronary artery disease may help prevent late cardiac morbidity.

The evidence behind the widely used pre-lung transplant glomerular filtration rate (GFR) cutoff of 50 mL/min per 1.73 m2 is limited. This study reviews data from a large cohort to assess outcomes associated with this historical cutoff and to estimate other possible cutoffs that might be appropriate in lung transplantation.We conducted a retrospective cohort analysis of lung recipients at a single center. Recursive partitioning and receiver operating characteristics analysis were used to estimate other potential GFR cutoffs with 1-year mortality as the outcome. Postoperative outcomes around the various cutoffs, including survival, acute kidney injury, and dialysis, were assessed using χ2, Kaplan-Meier, and Cox regression methods.A total of 794 lung recipients met study inclusion criteria. Compared with 778 patients with GFR 50 mL/min per 1.73 m2 or greater at time of transplant, 16 patients with GFR below this cutoff were older and more likely to have restrictive disease. One-year mortality below the cutoff was 31.3% compared with 15.1% above the cutoff (p=0.021). Recursive partitioning estimated potential GFR cutoff values between 46 and 61 mL/min per 1.73 m2. Patients with GFR below these cutoffs were at significantly higher risk for adverse outcomes (p0.05). Receiver operating characteristics analysis was less successful at identifying meaningful cutoff values with areas under the curve approximately 0.5.Study results support the practice of requiring candidate GFR 50 mL/min per 1.73 m2 or greater for lung transplantation. Future work should focus on reproducing the analysis in a larger cohort of patients including more individuals with low GFR.