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Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis., Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD., Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis., Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis., Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.

Introduction: Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD., Methods: We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE)., Results: There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9)., Conclusions: Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.

Background: Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined., Methods: Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database., Results: When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24)., Conclusions: Routine use of clarithromycin does not delay development of BOS or improve survival., (© 2011 John Wiley & Sons A/S.)

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted., (©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR; Atlanta, GA, USA) investigated lung disease in those exposed to the tremolite-contaminated vermiculite mine in Libby, MT, USA. Previously unreported spirometric results are presented here in relation to exposure and radiographic findings. 4,524 study participants were assigned to one of seven mutually exclusive exposure categories. Associations among radiographic findings, spirometric results and exposure were investigated, along with the effect of a reduction in exposure potential when production was moved to a wet process mill in the mid 1970s. Spirometry data for the total population by smoking status and age were within the normal range. Prevalence of pleural plaque increased with age, but was lowest in the environmentally exposed group (0.42-12.74%) and greatest in the W.R. Grace & Co. mineworkers (20-45.68%). For males, there was a significant (4.5%) effect of pleural plaques on forced vital capacity. For W.R. Grace & Co. workers and household contacts, a reduction in plaque (0.11 versus 1.64%) and in diffuse pleural thickening or costophrenic angle obliteration (1.94 and 0.13%) was noted for those exposed after 1976. These analyses do not support a clinically important reduction in spirometry of this cohort. The 1976 reductions in exposure have led to decrease in radiographic changes.

Background: Racial and ethnic disparities are well documented in many areas of health care, but have not been comprehensively evaluated among recipients of heart transplants., Methods and Results: We performed a retrospective cohort study of 39075 adult primary heart transplant recipients from 1987 to 2009 using national data from the United Network of Organ Sharing and compared mortality for nonwhite and white patients using the Cox proportional hazards model. During the study period, 8082 nonwhite and 30 993 white patients underwent heart transplantation. Nonwhite heart transplant recipients increased over time, comprising nearly 30% of transplantations since 2005. Nonwhite recipients had a higher clinical risk profile than white recipients at the time of transplantation, but had significantly higher posttransplantation mortality even after adjustment for baseline risk. Among the nonwhite group, only black recipients had an increased risk of death compared with white recipients after multivariable adjustment for recipient, transplant, and socioeconomic factors (hazard ratio, 1.34; 95% confidence interval, 1.21 to 1.47; P<0.001). Five-year mortality was 35.7% (95% confidence interval, 35.2 to 38.3) among black and 26.5% (95% confidence interval, 26.0 to 27.0) among white recipients. Black patients were more likely to die of graft failure or a cardiovascular cause than white patients, but less likely to die of infection or malignancy. Although mortality decreased over time for all transplant recipients, the disparity in mortality between blacks and whites remained essentially unchanged., Conclusions: Black heart transplant recipients have had persistently higher mortality than whites recipients over the past 2 decades, perhaps because of a higher rate of graft failure.

Context: Racial disparities have not been comprehensively evaluated among recipients of lung transplantation., Objectives: To describe the association between race and lung transplant survival and to determine whether racial disparities have changed in the modern (2001-2009) compared with the historical (1987-2000) transplant eras., Design, Setting, and Patients: A retrospective cohort study of 16 875 adults who received primary lung transplants from October 16, 1987, to February 19, 2009, was conducted using data from the United Network of Organ Sharing., Main Outcome Measures: We measured the risk of death after lung transplant for nonwhites compared with whites using time-to-event analysis., Results: During the study period, 14 858 white and 2017 nonwhite patients underwent a lung transplant; they differed significantly at baseline. The percentage of nonwhite transplant recipients increased from 8.8% (before 1996) to 15.0% (2005-2009). In the historical era, 5-year survival was lower for nonwhites than whites (40.9% vs 46.9%). Nonwhites were at an increased risk of death independent of age, health and socioeconomic status, diagnosis, geographic region, donor organ characteristics, and operative factors (hazard ratio, 1.15; 95% confidence interval, 1.01-1.30). In subgroup analysis of the historical era, blacks had worsened 5-year survival compared with whites (39.0% vs 46.9%) and black women had worsened survival compared with white women (36.9% vs 48.9%). In the modern transplant era, survival improved for all patients. However, a greater improvement among nonwhites has eliminated the disparities in survival between the races (5-year survival, 52.5% vs 51.6%)., Conclusion: In contrast to the historical era, there was no significant difference in lung transplant survival in the modern era between whites and nonwhites.

Rationale: Chronic rejection, manifested pathologically as airway fibrosis, is the major problem limiting long-term survival in lung transplant recipients. Airway hypoxia and ischemia, resulting from a failure to restore the bronchial artery (BA) circulation at the time of transplantation, may predispose patients to chronic rejection. To address this possibility, clinical information is needed describing the status of lung perfusion and airway oxygenation after transplantation., Objectives: To determine the relative pulmonary arterial blood flow, airway tissue oxygenation and BA anatomy in the transplanted lung was compared with the contralateral native lung in lung allograft recipients., Methods: Routine perfusion scans were evaluated at 3 and 12 months after transplantation in 15 single transplant recipients. Next, airway tissue oximetry was performed in 12 patients during surveillance bronchoscopies in the first year after transplant and in 4 control subjects. Finally, computed tomography (CT)-angiography studies on 11 recipients were reconstructed to evaluate the post-transplant anatomy of the BAs., Measurements and Main Results: By 3 months after transplantation, deoxygenated pulmonary arterial blood is shunted away from the native lung to the transplanted lung. In the first year, healthy lung transplant recipients exhibit significant airway hypoxia distal to the graft anastomosis. CT-angiography studies demonstrate that BAs are abbreviated, generally stopping at or before the anastomosis, in transplant airways., Conclusions: Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.

Long-term survival after heart-lung transplantation was first achieved in 1981 at Stanford and a total of 217 heart-lung transplantations had been performed by June 2008. This review summarizes Stanford's cumulative experience with heart-lung transplantation, demonstrates the progress that has been made, and discusses past and persistent problems. Diagnostic tools and treatment options for infectious diseases and rejection have changed and patient survival markedly improved over the almost three decades. Eight patients lived longer than 20 years. Further options to treat infections and strategies to control bronchiolitis obliterans syndrome, the main causes of early and long-term mortality, respectively, are required to achieve routine long-term survival., (Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

ABSTRACT The purposes of this study were to compare dexterity, visual perception, and abilities to carry out activities of daily living (ADL) in persons with different multiple sclerosis (MS) subtypes and to determine what relationships exist between the three variables. Fifty-six persons with MS were administered tests of dexterity, visual perception, and ADL ability. Demographic variables and scores on Kurtzke's Expanded Disability Status Scale were also collected. Scores from the chronic-progressive group were significantly higher than those of the benign and progressive-relapsing groups for the Nine-Hole Peg Test-Left Hand, Grooved Peg Test, and Functional Status Index (except Functional Status Index-Pain). There were no differences between the MS groups for any demographic variables except on the Expanded Disability Status Scale. Visual perception did not correlate with dexterity or ADL ability, and only dexterity scores for the left hand correlated with ADL ability. Persons with the severer subtype of MS were significantly impaired compared with the least severe group for dexterity and ADL ability. Decreased dexterity was associated with needing more assistance and having more perceived difficulty with ADL.

Implemented in 2005, the lung allocation score (LAS) aims to distribute donor organs based on overall survival benefits for all potential recipients, rather than on waiting list time accrued. While prior work has shown that patients with scores greater than 46 are at increased risk of death, it is not known whether that risk is equivalent among such patients when stratified by LAS score and diagnosis. We retrospectively evaluated 5331 adult lung transplant recipients from May 2005 to February 2009 to determine the association of LAS (groups based on scores of < or =46, 47-59, 60-79 and > or =80) and posttransplant survival. When compared with patients with LAS < or = 46, only those with LAS > or = 60 had an increased risk of death (LAS 60-79: hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.21-1.90; LAS > or = 80: HR, 2.03; CI, 1.61-2.55; p < 0.001) despite shorter median waiting list times. This risk persisted after adjusting for age, diagnosis, transplant center volume and donor characteristics. By specific diagnosis, an increased hazard was observed in patients with COPD with LAS > or = 80, as well as those with IPF with LAS > or = 60.

Idiopathic pulmonary fibrosis (IPF) is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in IPF patients, we isolated fibroblasts from patients with IPF and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in IPF. We found that IPF fibroblasts constitutively expressed increased basal levels of SPARC, plasminogen activator inhibitor-1 (PAI-1), and active beta-catenin compared with control cells. Control of basal PAI-1 expression in IPF fibroblasts was regulated by SPARC-mediated activation of Akt, leading to inhibition of glycogen synthase kinase-3beta and activation of beta-catenin. Additionally, IPF fibroblasts (but not control fibroblasts) were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of SPARC or beta-catenin. These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated SPARC, giving rise to activated beta-catenin, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosis-resistant phenotype. Disruption of this pathway may represent a novel therapeutic target in IPF.

Background: Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can cause significant morbidity and mortality in lung and heart-lung transplant recipients. We evaluated the utility of a multi-drug protocol for the treatment of RSV- and PIV-related infections., Patients and Methods: RSV or PIV was identified in 25 patients with a total of 29 infectious episodes between January 2006 and December 2007. The study included 20 women and 5 men, mean age 42 +/- 13 years. Fifteen patients had received bilateral lung transplant and the remainder either received single lung or heart-lung transplant. Mean time from transplant to infection was 1192 days. RSV was identified in 23 cases, PIV in 7 cases. Patients underwent treatment with inhaled ribavirin, methylprednisolone, and intravenous immunoglobulin (IVIG). RSV-positive patients were also treated with palivizumab. We retrospectively evaluated their clinical status and pulmonary function for a 1-year interval before and after the date of infection., Results: Average baseline forced expiratory volume in 1 s (FEV(1)) before infection was 2.14 +/- 0.68 L/min. Average decline in FEV(1) was 5.7% at the time of infection. Average FEV(1) during post-treatment follow-up was not significantly different than baseline (2.16 +/- 0.80 L/min). Among patients with bronchiolitis obliterans syndrome (BOS) stages 1, 2, or 3 at the time of infection, average FEV(1) declined by 14.8% and remained lower at 9.1% during follow-up when compared with patients with BOS stages 0 or 0p. No complications resulted from treatment. One patient died during follow-up as a result of pre-existing liver failure., Conclusions: This study of lung and heart-lung transplant recipients infected with RSV and PIV shows that a multi-drug regimen including inhaled ribavirin, corticosteroids, and IVIG (with or without palivizumab) is safe and effective. Prompt diagnosis and therapy for patients with RSV or PIV infections are critical for maintaining lung function.

Background: The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients., Methods: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs., Results: We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant., Conclusions: Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.

Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections.

Purpose: To perform a critical review of a series of journal articles and Health Hazard Evaluation Reports (HHER) by the National Institute for Occupational Safety and Health (NIOSH), where they have described the incidence of fixed obstructive pulmonary disease in a population of workers exposed to butter flavorings., Methods: The clinical presentations, diagnostic modalities frequently employed and a review of the pertinent clinical literature are discussed for constrictive bronchiolitis and bronchiolitis obliterans with intraluminal polyps; two distinct forms of bronchiolitis obliterans (BO). An analysis of the NIOSH reports and scientific articles is provided, followed by suggestions for evaluating this public and occupational health concern moving forward., Findings: Cases of lung disease in the food flavorings industry discussed in the literature have not been sufficiently documented to allow the conclusion that BO has been caused by diacetyl or butter flavoring. Further research is required to establish the causative agent(s)., Conclusion: The diagnosis of bronchiolitis obliterans should be reserved for those individuals who have diagnostic lung biopsy findings, obtained and interpreted by clinicians who are experienced with this complex disorder.

Background: Among the many potential risk factors influencing the development of bronchiolitis obliterans syndrome (BOS), acute cellular rejection is the most frequently identified. Despite the unique susceptibility of the lung allograft to pathogens, the association with respiratory tract infections remains unclear. In this study we analyze the role respiratory tract infections have on the development of BOS after lung transplantation., Methods: Data from a single center were analyzed from 161 lung recipients transplanted from November 1990 to November 2005, and who survived >180 days. Univariate and multivariate Cox regression analyses were performed using BOS development and the time-scale was reported with hazard ratios (HRs) and confidence intervals (CIs)., Results: Significant findings by univariate analysis per 100 patient-days prior to BOS onset included acute rejection, cytomegalovirus (CMV) pneumonitis, Gram-negative respiratory tract infections, Gram-positive respiratory tract infections and fungal pneumonias. Multivariate analysis indicated acute rejection, Gram-negative, Gram-positive and fungal pneumonias with HRs (CI) of 84 (23 to 309), 6.6 (1.2 to 37), 6,371 (84 to 485,000) and 314 (53 to 1,856) to be associated with BOS, respectively. Acute rejection, CMV pneumonitis, Gram-positive pneumonia and fungal pneumonitis in the first 100 days had HRs (CI) of 1.8 (1.1 to 3.2), 3.1 (1.3 to 6.9), 3.8 (1.5 to 9.4) and 2.1 (1.1 to 4.0), respectively, and acute rejection and fungal pneumonitis in the late post-operative period with HRs (CI) of 2.3 (1.2 to 4.4) and 1.5 (1.1 to 1.9), respectively., Conclusions: In addition to acute rejection, pneumonias with GP, GN and fungal pathogens occurring prior to BOS are independent determinants of chronic allograft dysfunction. Early recognition and treatment of these pathogens in lung transplant recipients may improve long-term outcomes after transplantation.

Background: Many lung transplant physicians advocate surveillance bronchoscopy with transbronchial lung biopsy and bronchoalveolar lavage (TBB/BAL) to monitor lung recipients despite limited evidence this strategy improves outcomes. This report compares rates of infection (INF), acute rejection (AR), bronchiolitis obliterans syndrome (BOS) and survival in lung allograft recipients managed with surveillance TBB/BAL (SB) versus those with clinically indicated TBB/BAL (CIB)., Methods: We reviewed 47 consecutive recipients transplanted between March 2002 and August 2005. Of these recipients, 24 consented to a multi-center trial requiring SB and 23 were managed by our usual practice of CIB. Rates of freedom from INF, AR, BOS and survival were compared. BOS and AR were diagnosed according to published guidelines from the International Society for Heart and Lung Transplantation., Results: A total of 240 TBB/BALs were performed. CIB and SB groups underwent 84 (3.7 +/- 3.4/patient) and 156 (6.5 +/- 2.0/patient) TBB/BALs, respectively. In the SB group, 54 (2.2 +/- 1.6/patient) TBB/BALs were true surveillance procedures, whereas 102 (4.2 +/- 2.3/patient) were clinically indicated. No AR episode requiring treatment was detected by true surveillance. Freedom from respiratory INF, AR, BOS and survival in the SB and CIB groups showed no significant differences. Five patients in the CIB group remained stable without requiring TBB/BAL. In the SB group, 4 previously asymptomatic patients developed pneumonia within 2 weeks of surveillance TBB/BAL., Conclusions: With no obvious advantage identified, surveillance bronchoscopy may pose a risk to stable lung transplant recipients. A multi-center, controlled trial is required to validate the utility and safety of surveillance bronchoscopy in lung transplantation.

Background: Universal ganciclovir (GCV) prophylaxis is a strategy aimed at reducing cytomegalovirus (CMV) infection and delaying the development of bronchiolitis obliterans syndrome (BOS). However, the optimal duration of GCV prophylaxis remains unclear. We report our experience with GCV prophylaxis administered indefinitely and its effect on CMV pneumonitis, BOS and survival after lung transplantation (LT)., Methods: One hundred fifty-one patients surviving >100 days after LT were analyzed. GCV was given to 130 CMV donor- or recipient-seropositive patients. Data from 90 patients who received indefinite GCV prophylaxis (IND) and 40 patients who discontinued their GCV prophylaxis (STOP) were compared., Results: CMV pneumonitis occurred in 16%, 8%, 17% and 19% of patients in the D+R+, D-R+, D+R- and D-R- groups, respectively. In the STOP cohort, 15 of 40 patients developed CMV pneumonitis (median time 79 days) after GCV was stopped. Ten of these 15 patients developed BOS (median time 116 days) after discontinuing GCV. The risk of CMV pneumonitis in the STOP cohort was significantly higher when GCV prophylaxis was discontinued within the first year. Cumulative incidence of CMV pneumonitis in the IND and STOP groups at 5 years was 2% and 57%, respectively (p < 0.001). BOS-free survival and survival were similar across both groups., Conclusions: Indefinite GCV prophylaxis prevents CMV pneumonitis in 98% of LT recipients. Thirty-eight percent of patients discontinuing prophylaxis developed CMV pneumonitis, 50% of whom progressed to BOS within 1 year. Continuing ganciclovir prophylaxis indefinitely after lung transplantation should be considered.

This article highlights trends in heart and lung transplantation between 1997 and 2006, drawing on data from the OPTN and SRTR. The total number of candidates actively awaiting heart transplantation declined by 45% over the last decade, dropping from 2414 patients in 1997 to 1327 patients in 2006. The overall death rates among patients awaiting heart transplantation declined over the same period. The distribution of recipients among the different status groups at the time of heart transplantation changed little between the inception of the new classification system in 1999 and 2005. Deaths in the first year after heart transplantation have steadily decreased. At the end of 2006, 2885 candidates were awaiting a lung transplant, up 10% from the 1997 count. The median time-to-transplant for listed patients decreased by 87% over the decade, dropping from 1053 days in 1997 to 132 days in 2006. Selection for listing and transplantation has shifted toward more urgent patients since the May 2005 implementation of a new lung allocation system based on survival benefit and urgency rather than waiting time. Only 31 heart-lung transplants were performed in 2006, down from a high of 62 in 1997.

Background: In cystic fibrosis (CF) patients who are candidates for lung transplant, pretransplant sinus surgery has been advocated to avoid bacterial seeding of the transplanted lungs. This study reviews the 17-year experience of pretransplant sinus surgery among CF patients at a major transplant center., Methods: Retrospective chart review was performed in all CF patients who underwent heart-lung or lung transplantation at Stanford Medical Center between 1988 and 2005. Postoperative culture data from bronchoalveolar lavage (BAL) and sinus aspirates were evaluated, in addition to survival data., Results: Eighty-seven CF transplant recipients underwent pretransplant sinus surgery; 87% (n=59/68) of patients showed recolonization of the lung grafts with Pseudomonas on BAL cultures. The median postoperative time to recolonization was 19 days. Bacterial floras cultured from sinuses were similar in type and prevalence as the floras cultured from BAL. When compared with published series of comparable cohorts in which pretransplant sinus surgery was not performed, there was no statistically significant difference in the prevalence of Pseudomonas recolonization. Times to recolonization also were similar. Survival rates in our cohort were similar to national survival rates for CF lung transplant recipients., Conclusion: Despite pretransplant sinus surgery, recolonization of lung grafts occurs commonly and rapidly with a spectrum of flora that mimics the sinus flora. Survival rates of CF patients who undergo prophylactic sinus surgery are similar to those from centers where prophylactic sinus surgery is not performed routinely. Pretransplant sinus surgery does not appear to prevent lung graft recolonization and is not associated with overall survival benefit.

The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical syndrome characterized by dyspnea, hypoxemia, abnormal chest X-ray, and a decrease in forced expiratory volume in 1 second (FEV1); 25% presented with hemoptysis, and 18% with fulminant respiratory failure. Therapy with intravenous corticosteroids resulted in clinical improvement in 17 cases (43%). A response to plasmapheresis was seen in 12 (67%) of 18 cases refractory to corticosteroids. There were 5 deaths within 3 months of diagnosis. Nine (82%) of 11 lung transplant recipients who presented with capillaritis within 4 weeks post-transplant were alive at 1 year; all but 1 patient achieved expected percent predicted FEV1 values. Only 3 (14%) of 21 who presented with capillaritis > 1 month after transplant had a >20% decrease in the FEV1 after 12 months. These results suggest that post-transplant pulmonary capillaritis is (1) likely a form of acute allograft rejection clinically and histologically distinct from typical acute rejection, (2) less responsive to corticosteroid therapy than typical acute rejection, and (3) not associated with long-term adverse effects on allograft function.

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at-risk (donor positive/recipient negative [D+/R-] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV-IVIG) followed by valganciclovir (450 mg twice-daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high-dose oral acyclovir following i.v. GCV and CMV-IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100-179 days (64%) or < 100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV-IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at-risk lung transplant recipients. The required length of prophylaxis was at least 180 days.

Background: The role of surveillance bronchoscopy in the care of lung transplant recipients remains controversial. Although there are no controlled studies to suggest a survival advantage, many transplant physicians support the practice. The procedure is generally safe but is associated with some complications. A review of practices at our institution revealed significant variation in patient preparation, management of risk related to the procedure, and in the technical aspects of the bronchoscopy itself. In an effort to minimize these differences and potentially improve outcomes, a standard set of procedural guidelines for all bronchoscopies was adopted in January 2000., Methods: Reports from 1028 surveillance bronchoscopies performed in our outpatient facility from January 1999 to December 2001 were reviewed. Baseline patient data and procedure-related complications were identified. Specific complications recorded included oversedation, the need for prolonged supplemental oxygen, major and minor bleeding, pneumothorax, bronchospasm, vomiting, arrhythmia, hypotension and death. Differences between groups were analyzed using chi-square or Student's t-tests as appropriate., Results: The incidence of complications after the introduction of the guidelines (2000 and 2001) was significantly lower than in the year prior (1999) (1.95% vs 6.45%, p < 0.001). The lower rate of adverse events was mainly a result of a reduction in the incidence of minor bleeding (0.28% vs 2.26% p = 0.006) and of sedation-related complications (0.97% vs 2.90%, p = 0.04)., Conclusions: The use of a standardized set of guidelines for surveillance fiber-optic bronchoscopy reduces complication rates. Similar guidelines should be considered by transplant centers performing the procedure.

Despite the serious direct and indirect deleterious effects caused by cytomegalovirus (CMV), the optimal prophylactic strategy remains unknown. We sought to determine whether combination prophylaxis using intravenous ganciclovir (GCV) and CMV-IVIG reduced the incidence of CMV compared to GCV alone. Donor CMV positive/recipient negative (D+/R-) patients received GCV (6 weeks i.v. + 6 weeks oral) and CMV-IVIG (every 2 weeks for 7 doses), while R+ patients received GCV (2 weeks i.v. + 4 weeks oral) and CMV-IVIG (every 2 weeks for 3 doses). The group receiving combination prophylaxis (GpA) was compared to a historical, case-controlled group receiving GCV alone (GpB). Groups were matched by CMV donor/recipient serology, pretransplant diagnosis, age, and sex in reverse chronological order. Cyclosporine, azathioprine, and prednisone were used in both groups. Additionally, GpA received daclizumab induction therapy. Groups were compared as to the incidence of CMV disease, CMV infection, and acute rejection (AR). In GpA, 38 patients were evaluable and matched to 48 patients in GpB. Three GpA patients (8%) (2 D+/R-) developed CMV disease vs. 16 patients (33%) in GpB, p = 0.0077, Fisher's exact. There was also a trend toward a delay in CMV onset (148 days in GpA vs. 92 days in GpB, p = 0.07, Mann-Whitney). CMV infection did not occur in GpA, and one case occurred in GpB. There was no difference in the incidence of AR (66% in GpA vs. 79% in GpB, p = 0.22, Fisher's exact) or the need for cytolytic therapy between groups. Despite the use of daclizumab induction therapy, combination prophylaxis with GCV and CMV-IVIG reduced the incidence and probably delayed the onset of CMV infection compared to GCV alone. Longer follow-up will be needed to evaluate the impact of combination therapy on the incidence of bronchiolitis obliterans syndrome (BOS).

Background: No effective therapy is currently available for the diffuse stage of bronchioloalveolar carcinoma., Objective: We tested the hypothesis that total lung replacement with standard lung transplantation techniques would provide curative therapy., Methods: Nine patients aged 31 to 58 years with bronchioloalveolar carcinoma were entered in the study. Five patients initially had bilateral diffuse tumor. Four patients had recurrence in the contralateral lung after pulmonary resection., Results: Between 1993 and 1998, all 9 patients underwent transplantation (2 single-lung and 7 bilateral transplants, 1 reoperative single-lung transplant, and 1 reoperative bilateral transplant). Two patients had mediastinal node metastasis (level 7) at the time of transplantation, and 1 of these had a frankly invasive adenocarcinoma. Of the 8 patients with pure bronchioloalveolar carcinoma, 6 had recurrent pulmonary tumor after transplantation. In 2 of these patients the tumor was localized and could be resected with left lower lobectomy in one case and left pneumonectomy in the other. One is alive 89 months after transplantation; the other died 82 months after transplantation. Four other patients had a diffuse pattern of pulmonary recurrence. Two died of progressive pulmonary failure; 1 of these had retransplantation with recurrence. A third patient died of cerebral edema shortly after bilateral retransplantation. The other patient is alive with recurrence 39 months after transplantation and has bronchiolitis obliterans. Two patients without recurrence are well with unrestricted performance levels 87 and 76 months after transplantation., Conclusions: Transplantation produces a powerful palliative outcome in patients with advanced bronchioloalveolar carcinoma, but the recurrence rate is high. Transplantation for this indication remains controversial.

The availability of suitable lung donors is the major limitation to increasing the number of lung transplants performed. Donor criteria developed early in the lung transplant era have not been rigorously evaluated. Each of the "standard" lung donor criteria currently in use should be challenged by obtaining, analyzing, and using multicenter data from a well-designed database. Only in this way will our understanding of appropriate lung donor criteria advance and the pool of lungs available for transplantation increase.

Background: Many potential lung donors are excluded on the basis of a positive donor gram stain (DGS). We examined the association between a positive DGS and the probability of post-operative recipient pneumonia in the first 30 days., Methods: Ninety lung transplants (80 with a non-septic pre-transplant diagnosis) from 60 consecutive donors were evaluated for post-operative pneumonia (defined as a compatible clinical syndrome with fever, leukocytosis, chest X-ray abnormalities or histologic evidence obtained by transbronchial biopsy). DGS, white blood cell quantity, CXR and PaO(2)/FIO(2) (P/F) ratio were compared with immediate and 24-hour P/F ratio, length of mechanical ventilation and incidence of pneumonia. All recipients received standard prophylactic anti-bacterial coverage. Patients not surviving 30 days (n = 3) were excluded from this study, but none had evidence of pneumonia either by bronchoalveolar lavage (BAL), transbronchial biopsy or autopsy., Results: Fourteen (16%) of our 87 recipients developed pneumonia in the first 30 days after transplant. Of the 43 patients with a positive DGS, 5 (12%) developed pneumonia, compared to 9 of 44 (20%) with a negative DGS (p = 0.26). The mean post-operative P/F ratio (315 +/- 47 with a positive DGS, p = 0.3) and length of mechanical ventilation (2 days in each group) did not differ significantly between the negative and positive DGS groups., Conclusions: In the current era of lung transplantation, DGS does not predict the development of early post-operative pneumonia and does not affect oxygenation or duration of mechanical ventilation; therefore, its role should be diminished when judging donor lung suitability.

Congenital abnormalities were encountered in three donor lungs. A donor tracheal bronchus was incorporated into the right bronchial anastomosis. Anomalous pulmonary venous return of the right upper lobe to the superior vena cava and the left upper lobe to the innominate vein were managed by bridging the anomalous veins to the left atrial cuff with autologous pericardium and donor iliac vein, respectively.

Cardiac allograft vasculopathy is the most common cause of death and retransplantation following heart transplantation, and about 10% of patients per year have evidence of accelerated vascular disease; 50% at 5 years. Cytomegalovirus (CMV) infection has been associated with accelerated cardiac vasculopathy and decreased 5-year survival. Prophylactic therapy using ganciclovir has reduced the incidence of CMV disease, but not in the group at highest risk, namely the seronegative recipient of an allograft from a seropositive donor (D+/R-). Combination prophylaxis consisting of CMV hyperimmune globulin (CMV-IGIV) plus ganciclovir is associated with decreased intimal thickening, reduced coronary artery disease and obliterative bronchiolitis, and improved survival.

Objective: The objective was to determine the degree of toxicity and antitumor activity following bronchoscopic injection of an adenoviral-mediated p53 gene (Adp53) into tumors causing airway obstruction. DOSING: This was a subset analysis of a phase I dose escalation trial., Setting: Patients were treated in the outpatient clinics at the University of Texas (MD Anderson Cancer Center, Houston, TX) and at Medical City Dallas Hospital (US Oncology, Dallas, TX)., Patients: Twelve patients (median age, 60 years) with advanced endobronchial non-small cell lung cancer (NSCLC) (squamous cell carcinoma, six patients; adenocarcinoma, six patients) were entered into trial. The median tumor area was 5 x 3.2 cm. All patient tumors contained a p53 gene mutation., Interventions: Adp53 (dose range, 1 x 10(6) to 1 x 10(11) plaque-forming units) was administered by bronchoscopic intratumoral injection once every 28 days., Measurements and Results: Toxicity attributed to the Adp53 vector was minimal. Six of the 12 patients had significant improvement in airway obstruction, and 3 patients met the criteria for partial response., Conclusions: Direct bronchoscopic injection of Adp53 into endobronchial NSCLC is safe, with acceptable levels of toxicity. The initial clinical results demonstrating relief of airway obstruction warrant further clinical investigation.

Background: Most pulmonary complications associated with lung transplantation have non-specific clinical characteristics. Furthermore, common diagnostic modalities, including bronchoscopy with transbronchial biopsy (TBB), often do not render a definitive diagnosis. In this study, we reviewed our experience with open lung biopsy (OLB) following lung transplantation, specifically regarding its ability to safely provide clinically relevant information that affects therapeutic decisions., Methods: From October 1989 to March 2000, 202 patients underwent lung transplantation at our institution. We reviewed the clinical course of the 42 patients who received 48 OLBs. Of these patients, we determined the pre-operative clinical condition, preceding TBB histologic information, OLB histology, treatment changes, and procedural complications as a result of the OLB., Results: A new, clinically unsuspected diagnosis was made in 14 biopsies (29% of all OLB), and all of these resulted in therapy changes. Thirty-two biopsies (67% of all OLB) confirmed our clinical suspicions, and new therapy was initiated in 30 of these patients. Two patients (4% of all OLB) had non-diagnostic OLB. Four biopsies (8% of all OLB), including the 2 non-diagnostic OLBs, did not result in any therapy changes or initiation of new therapy. Complications occurred in 3 patients, all of whom had an air leak for >7 days., Conclusion: Open lung biopsy in lung transplant patients renders a new, unsuspected diagnosis in nearly one third of patients and leads to specific, directed therapy in the vast majority of patients. Open-lung biopsy can be performed safely and should be considered when diagnosis is uncertain in clinically deteriorating patients.

Purpose: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay)., Results: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients., Conclusion: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Background: Single-lung transplantation for emphysema may be complicated by acute native lung hyperinflation (ANLH) with hemodynamic and ventilatory compromise. Some groups advocate the routine use of independent lung ventilation, double-lung transplant, or right-lung transplant with or without contralateral lung volume reduction surgery in high-risk patients. The goal of this study was to determine the incidence of ANLH and identify its potential predictors., Methods: We reviewed 51 consecutive single-lung transplants for emphysema. Symptomatic ANLH was defined as mediastinal shift and diaphragmatic flattening on chest x-ray with hemodynamic or respiratory failure requiring cardiopressor agents or independent lung ventilation. Preoperative and postoperative physiologic and hemodynamic data were analyzed from both recipients and donors., Results: Sixteen patients developed radiographic ANLH; 8 were symptomatic, 2 severely so. We could not identify high-risk patients before transplant by pulmonary function tests, predicted donor total lung capacity (TLC)/actual recipient TLC ratio, pulmonary artery pressures, or the side transplanted. There was a trend toward an increased incidence of symptomatic ANLH in patients with bullous emphysema on chest computed tomography, but this was accounted for primarily by patients with alpha1-antitrypsin deficiency (4/13 vs 4/38 with chronic obstructive pulmonary disease, P = 0.10). No patient required cardiopulmonary bypass or inhaled nitric oxide intraoperatively. Patients with acute native lung hyperinflation did not have increased reperfusion edema as measured by chest x-ray score or PaO2/F(I)O2 ratio. Compared to patients without ANLH, symptomatic patients had longer ventilator times (64.9+/-14.6 hours vs 40.4+/-3.9, P = 0.02, ANOVA) and longer lengths of stay (19.3+/-2.1 days vs 13.7+/-1.3, P = 0.07), but 30-day survival was 100%. Two symptomatic patients required independent lung ventilation or inhaled nitric oxide; the others were managed with decreased minute ventilation, early extubation, and cardiopressor agents. No patient required early lung volume reduction surgery or retransplantation. Acute native lung hyperinflation had no effect on FEV1 or 6-minute walk results at 1 year; survival at 1, 2, or 3 years; or the rate of acute rejection, infection, or bronchiolitis obliterans syndrome greater than grade 2., Conclusion: Acute native lung hyperinflation is common radiographically but is rarely clinically severe. Although there was a trend toward an increase in symptomatic ANLH in patients with bullous emphysema, a high-risk group could not be identified preoperatively. Our results do not support the routine use of bilateral lung transplant, the exclusive use of right single-lung transplant, simultaneous lung volume reduction surgery, or independent lung ventilation for patients with emphysema. Management strategies should be employed that limit overdistension of the native lung and lead to early extubation.

Background: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments., Methods: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU., Results: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression., Conclusions: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN-alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN-responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN-alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells.

A wide variety of medications is commonly used following thoracic surgical procedures. All of these medications have associated side effects that may adversely affect the recovery of patients. A complete understanding of the important adverse effects of all the medications used postoperatively can limit or eliminate unwanted medication effects and lead to a more successful outcome. This article will review the important actions and side effects of the most commonly administered medications following thoracic surgical procedures.

Acute rejection after lung transplantation occurs commonly and is usually characterized histologically by a perivascular mononuclear infiltrate. We report five cases of pulmonary capillaritis with a histologic appearance distinct from typical rejection, occurring in patients ranging in age from 18 to 45 years, with a variety of underlying diseases including alpha1 antitrypsin deficiency, pulmonary hypertension, cystic fibrosis, and rheumatoid arthritis. Four of the five patients had alveolar hemorrhage histologically, and two had frank hemoptysis. Time of onset ranged from 3 weeks to many months after transplantation. Three cases were fulminant, and there were two deaths. In only one case, with methicillin-resistant Staphylococcus aureus bronchitis, could infection be established. All were treated with intensification of immunosuppressive therapy. Plasmapheresis was carried out in two cases and coincided with temporary improvement, but its efficacy was questionable because of concurrent immunosuppressive therapy. Two had recurrent biopsy-proven acute rejection within 6 weeks of treatment, and one had recurrent severe pulmonary hemorrhage that abated with total lymphoid irradiation. Our experience suggests that pulmonary capillaritis in lung transplant recipients can be an acute, fatal illness with the potential for recurrence in the survivors. We speculate that it represents a form of acute vascular rejection. Early pathologic diagnosis and aggressive immunosuppressive therapy are recommended. Although a humoral component was not documented, the possible response to plasmapheresis requires continued evaluation.

Circulating xanthine oxidase (XO) can modify adhesive interactions between neutrophils and the vascular endothelium, although the mechanism underlying this effect are not clear. We found that treatment with XO of bovine pulmonary artery endothelial cells (EC), but not neutrophils or plasma, increased adherence, suggesting that XO had its primary effect on EC. The mechanism by which XO increased neutrophil adherence to EC involved binding of XO to EC and production of H2O2. XO also increased platelet-activating factor production by EC by a H2O2-dependent mechanism. Similarly, the platelet-activating factor-receptor antagonist WEB-2086 completely blocked XO-mediated neutrophil EC adherence. In addition, neutrophil adherence was dependent on the beta 2-integrin Mac-1 (CD11b/CD18) but not on leukocyte functional antigen-1 (CD11a/CD18). Treatment of EC with XO for 30 min did not alter intercellular adhesion molecule-1 surface expression but increased expression of P-selectin and release of von Willibrand factor. Antibodies against P-selectin (CD62) did not affect XO-mediated neutrophil adherence under static conditions but decreased both rolling and firm adhesive interactions under conditions of shear. We conclude that extracellular XO associates with the endothelium and promotes neutrophil-endothelial cell interactions through dual intercellular adhesion molecule-1 and P-selectin ligation, by a mechanism that involves platelet-activating factor and H2O2 as intermediates.

Background: Colon perforation has been previously described after solid organ transplantation. Since the inception of the lung transplant program at the University of Colorado 60 isolated lung transplantations have been performed. Four of these patients have suffered spontaneous colonic perforation., Methods: The case history of each lung transplant patient with a colon perforation and the literature were reviewed., Results: An increased incidence of colon perforation in lung transplant patients was identified. Diverticulitis was found to be the predominant cause, and an association with steroids was noted. The two deaths in this series were in patients receiving high-dose steroids in whom invasive Aspergillus infections developed., Conclusions: Careful screening of the gastrointestinal tract before transplantation is advocated. A steroid-sparing immunosuppressive regimen is recommended. All lung transplant patients with abdominal complaints require an aggressive work-up, and surgeons should have a low threshold for laparotomy. Conservative surgical principles, including resection of the perforated segment of colon and proximal end-colostomy rather than primary anastomosis, are necessary for the optimal outcome.

In this work, we present evidence that enriched human peripheral blood T lymphocytes, depleted of contaminating monocytes, rapidly express tumor necrosis factor alpha (TNF-alpha) mRNA when exposed to low doses of gamma-irradiation. In total PBL, TNF-alpha mRNA accumulation increased threefold as early as 30 minutes following exposure to 4 Gy and then declined to the baseline level by 3-5 h, as measured by the reverse transcriptase-polymerase chain reaction (RT-PCR). The increase in TNF-alpha mRNA was also observed in populations of enriched T cells and decreased when the dose of irradiation was increased to 10 Gy, strongly suggesting that T lymphocytes, the most radiosensitive cells of the body, contributed directly to the increase of TNF-alpha mRNA. A good correlation was found between mRNA expression and TNF-alpha protein secretion. Interestingly, a eightfold increase in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA accumulation was also detected in both PBL and enriched T cells irradiated at 4 Gy for 3 h compared with unirradiated cells. This irradiation effect was almost completely abolished, however, following exposure to 10 Gy. Together these data suggest that T cells are responsible for the irradiation-induced expression of TNF-alpha and GAPDH.