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Biomedical subjects

Shaf Keshavjee

Publications and source records attributed to Shaf Keshavjee.

At least 37 records · Page 2Linked to original sources
PubMed2005

Surfactant palmitoylmyristoylphosphatidylcholine is a marker for alveolar size during disease.

Two common lung-related complications in the neonate are respiratory distress syndrome, which is associated with a failure to generate low surface tension at the air-liquid interface because of pulmonary surfactant insufficiency, and bronchopulmonary dysplasia (BPD), a chronic lung injury with reduced alveolarization. Surfactant phosphatidylcholine (PC) molecular species composition during alveolarization has not been examined. Mass spectrometry analysis of bronchoalveolar lavage fluid of rodents and humans revealed significant changes in surfactant PC during alveolar development and BPD. In rats, total PC content rose during alveolarization, which was caused by an increase in palmitoylmyristoyl-PC (16:0/14:0PC) concentration. Furthermore, two animal models of BPD exhibited a specific reduction in 16:0/14:0PC content. In humans, 16:0/14:0PC content was specifically decreased in patients with BPD and emphysema compared with patients without alveolar pathology. Palmitoylmyristoyl-PC content increased with increasing intrinsic surfactant curvature, suggesting that it affects surfactant function in the septating lung. The changes in acyl composition of PC were attributed to type II cells producing an altered surfactant during alveolar development. These data are compatible with extracellular surfactant 16:0/14:0PC content being an indicator of alveolar architecture of the lung.

Aging↗
PubMed2005

Does the incidence and outcome of brain metastases in locally advanced non-small cell lung cancer justify prophylactic cranial irradiation or early detection?

OBJECTIVE: The radical treatment of locally advanced non-small cell lung cancer (LA-NSCLC) currently involves combined modality therapy (CMT) with the use of chemotherapy in addition to radiation therapy and/or surgery. Chemotherapy has been shown to improve survival, but does not alter brain relapse. We reviewed the outcomes of Stage IIIA and IIIB LA-NSCLC patients treated with CMT at our institution. We assessed the incidence of brain metastases and the management and outcome of these patients. METHODS: Using our radiation-planning database (RSTS), we identified 230 consecutive patients from the years 1999 and 2000 who received radical radiation therapy to the lung. Extracting data from the chart, we identified 83 patients who were treated radically with chemotherapy, radiation and possibly surgery. These patients form the basis of this study. RESULTS: At 2 years, the actuarial rates for any brain failure, first failure in the brain and sole failure in the brain were 34.2%, 24.6% and 11.0%, respectively. Age was the only factor among sex, histology, stage, weight loss and the timing of chemotherapy and radiation that predicted for an increased risk of first failure in the brain. Patients less than age 60 had a risk of 25.6% versus 11.4% for those greater than 60 (p = 0.022). Among the patients who failed first in the brain, those who had aggressive management of their brain metastases with surgical resection in addition to whole brain radiotherapy had a median survival of 26.3 months compared with 3.3 months for those treated with palliative whole brain radiotherapy alone. CONCLUSION: Brain metastases are common in patients with LA-NSCLC treated with CMT. These patients may benefit from either prophylactic cranial irradiation or early detection and aggressive treatment of brain metastases.

Aged↗
PubMed2005

Independent ventilation of the graft and native lungs in vivo after rat lung transplantation.

Rat lung transplantation is a proven experimental technique for the study of lung injury following lung transplantation. We have modified the surgical and ventilatory techniques to allow for independent ventilation in vivo of the transplanted graft and native lungs. This will provide additional data on the physiology and function of the transplanted graft and ameliorate the problem of progressive graft lung collapse and thereby allow for an improved model of ischemia-reperfusion injury and ventilator-induced lung injury in the setting of lung transplantation.

Animals↗
PubMed2005

Risk of a right pneumonectomy: role of bronchopleural fistula.

BACKGROUND: The purpose of this study is to compare the morbidity and mortality of right versus left pneumonectomy. METHODS: We used a retrospective review of pneumonectomies performed during the period 1990 to 2000 and included a meta-analysis of relevant literature. RESULTS: There were 187 pneumonectomies: 68 right, 119 left. The primary study end point was in-hospital death. There were 11 deaths: 7 (10.3%) right, 4 (3.3%) left (p = 0.10). Six deaths were attributable to bronchopleural fistula and its subsequent complications. The risk of bronchopleural fistula was higher on the right (9 [13.2%]) versus left (6 [5.0%]; p = 0.0472), as was the mortality associated with bronchopleural fistula (4 of 9 [44%] right versus 2 of 6 [33%] left). Right pneumonectomies were more likely to require an intrapericardial or extended dissection (p = 0.003), hand-sewn bronchial closure (p < 0.0001), or the closure buttressed (p < 0.0001). By univariate analysis, factors associated with an increased mortality were bronchopleural fistula (p < 0.0001), hand-sewn closure (p = 0.001), and a history of smoking (p = 0.01). By multivariate analysis, the most important factor was bronchopleural fistula (odds ratio, 43.3; 95% confidence limits, 4.2 to 441.9; p = 0.002). A meta-analysis combining our results with those from the literature found increased mortality of right pneumonectomy with a relative risk of 3.39 (95% confidence limits, 2.10 to 5.48; p < 0.00001). CONCLUSIONS: Right pneumonectomy is associated with a higher mortality even in the absence of induction therapy. This is primarily related to the increased risk of bronchopleural fistula on the right. The increased number of bronchopleural fistulas on the right may be attributable to more extensive resection. Addressing technical factors that contribute to early bronchopleural fistula may reduce the mortality of right pneumonectomy.

Adult↗
PubMed2005

Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant.

BACKGROUND: Aspiration secondary to gastroesophageal reflux has been postulated to be a contributing factor in bronchiolitis obliterans after lung transplantation. It is not clear whether gastroesophageal reflux is a preexisting condition or secondary to intraoperative vagal injury or drug-induced prolonged gastric emptying. METHODS: The prevalence of gastroesophageal reflux was examined in 78 consecutive end-stage lung disease patients assessed for lung transplantation: emphysema, 21; cystic fibrosis, 5; idiopathic pulmonary fibrosis, 26; scleroderma, 10; and miscellaneous diseases, 16. All underwent esophageal manometry. Two-channel esophageal 24-hour pH testing was completed in 76 patients. Gastric emptying studies were conducted in 36 patients. RESULTS: Typical gastroesophageal reflux symptoms were documented in 63% of patients. The lower esophageal sphincter was hypotensive in 72% of patients, and 33% had esophageal body dysmotility. Prolonged gastric emptying was documented in 44%, and 38% had abnormal pH testing. The overall DeMeester score was above normal in 32% of patients, and 20% had abnormal proximal pH probe readings. CONCLUSIONS: Gastroesophageal reflux is highly prevalent in end-stage lung disease patients who are candidates for lung transplantation. Further investigation is needed to study the prevalence of gastroesophageal reflux after lung transplantation and its contribution to chronic allograft dysfunction.

Adult↗
PubMed2005

Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study.

BACKGROUND: The presence of antibodies to human leukocyte antigens (HLA) prior to transplantation has been linked to worse post-transplant outcomes in many solid organ transplants. The effect of these antibodies is less clear in lung transplant recipients, although previous studies have suggested an increased incidence of allograft dysfunction. METHODS: A retrospective study of all first lung transplant recipients from the University of Toronto (November 1983-July 2001, n = 380) and Duke University (April 1992-June 2000, n = 276) was performed. Demographic data, survival information, and level of last pre-transplant panel reactive antibody (PRA) were collected. PRA level was measured by the complement-dependent cell cytotoxicity assay at both centers. Survival analysis was performed using the Kaplan-Meier method, and groups were compared with the Wilcoxon rank sum test. RESULTS: Of 656 lung transplant recipients, 101 (15.4%) had a PRA greater than 0, 37 (5.6%) had a PRA greater than 10%, and 20 (3.0%) had a PRA greater than 25%. Patients with a PRA greater than 25% had decreased median survival than did the rest of the patients (1.5 vs 5.2 years) and at 1 month (70% vs 90%), 1 year (65% vs 76%), and 5 years (31% vs 50%), respectively (p = 0.006, Wilcoxon's rank sum test) test). CONCLUSION: Significant elevation of PRA prior to lung transplantation is associated with worse survival, especially in the early post-transplant period. This may be due to a direct effect of anti-HLA antibodies on the allograft. The effectiveness of treatments such as plasmapheresis and intravenous immunoglobulin prior to transplantation needs to be evaluated.

Adult↗
PubMed2005

Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.

BACKGROUND: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction. METHODS: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis. RESULTS: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure. CONCLUSION: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.

Adult↗
PubMed2005

Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation.

BACKGROUND: Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS. MATERIALS AND METHODS: Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L). RESULTS: Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001). CONCLUSIONS: Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

Actuarial Analysis↗
PubMed2005

Lung transplantation: donor and recipient critical care aspects.

PURPOSE OF REVIEW: The purpose of this paper is to highlight new developments in donor and recipient lung transplant issues for the critical care physician. RECENT FINDINGS: A shortage of suitable lung donors has led to the use of extended donors and the development of novel techniques such as live-donor lung transplantation and the use of non-heart-beating donors. The increased experience and success with lung transplantation has also resulted in the extension of this therapy to patients previously considered unsuitable for transplantation. Postoperative outcomes can be affected by many of these recent donor and recipient changes. Improved preservation solutions and techniques to reduce reperfusion injury may be able to ameliorate some of the new perioperative graft dysfunction, but morbidity is still potentially significant, and extraordinary interventions such as extracorporeal membrane oxygenation may be required in selected cases. SUMMARY: Patients undergoing lung transplantation continue to be very challenging in the intensive care unit. A multidisciplinary approach to care, and early recognition of serious problems, will help improve outcomes.

Body Size↗
PubMed2005

Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.

Cystic fibrosis (CF) related diabetes mellitus (DM) occurs in 15% of adult pancreatic insufficient CF patients. Lung transplantation is a treatment option for end-stage CF. We hypothesized that the prevalence of DM increases after lung transplantation. The study population included adult patients undergoing lung transplantation from March 1988 to March 2002 for end-stage CF at the University of Toronto. Demographic data, exocrine pancreatic function, presence of DM before and after transplant, as well as timing of its development after transplant were collected. Eighty-six patients met the study criteria; 77 of 86 (89.5%) of patients were pancreatic insufficient and were further analyzed. Median follow-up post-transplant was 3.3 yr (interquartile range: 1.2-7.2). Their mean age was 29.7 +/- 8.1 yr and 46 of 77 (59.7%) were male. The prevalence of DM increased from 22 of 77 (28.6%) before transplant to 38 of 77 (49.4%) after transplant (p = 0.008). The median time of DM development after transplant was 80 d (range: 13-4352). Sixteen of 55 (29.1%) of pancreatic insufficient patients who were non-diabetic prior to transplant, developed DM after transplant. DM is common in CF patients undergoing lung transplantation and the prevalence increases after transplant.

Adult↗
PubMed2005

A novel model for post-transplant obliterative airway disease reveals angiogenesis from the pulmonary circulation.

We present a novel animal model for post-transplant obliterative airway disease in which the donor trachea is implanted into the recipient's lung parenchyma. Although this procedure is technically more challenging than the heterotopic model of implantation into a subcutaneous pouch, it has several important advantages some of which are the appropriate local environment and the possibility of local immunosuppressive therapy after transtracheal gene, cell or drug delivery. This model has revealed new insights into angiogenic potential of the pulmonary circulation.

Animals↗
PubMed2005

Caspase inhibition improves ischemia-reperfusion injury after lung transplantation.

Ischemia-reperfusion injury is associated with cell death in many organ systems. The role of programmed cell death (PCD) pathways and the ultimate clinical relevance of PCD in the context of lung transplantation (LTx) are unknown. In randomized and blinded studies, rat single LTx was performed in the presence of caspase inhibitors after 'short' (6 h) and 'long' (18 h) periods of cold ischemic storage. Lung function, electron microscopic morphology, caspase 3, 8 and 9 activities and TUNEL assays were evaluated. Endothelial cells and lymphocytes were observed undergoing apoptotic cell death with electron microscopy. Caspase activities were significantly up-regulated immediately after the initial flush and increased further during short periods of cold ischemic storage. A significant amount of apoptotic cell death was observed after LTx and reperfusion. Caspase inhibition virtually eliminated apoptotic cell death and led to improved lung function after LTx and reperfusion. Activation of caspases during cold ischemia contributes significantly to cell death in LTx. Suppression of caspase activity appears to decrease apoptosis and improve lung function. Clearly, this needs to be investigated further with more experiments to validate the potential role of caspase inhibition as a therapeutic modality in ischemia-reperfusion-induced lung injury.

Animals↗
PubMed2005

Innate immunity and organ transplantation: the potential role of toll-like receptors.

Traditionally, the recognition and tolerance of transplanted grafts has been considered to be within the realm of the adaptive immune system. Innate immunity, on the other hand, as the first line of host defense, plays a role in fighting against invading microorganisms. Recently, with the discovery of the Toll-like receptors (TLRs), the role of innate immune responses in the control of adaptive immunity has become a new area of interest. Emerging evidence suggests that in addition to responding to pathogen-associated molecular patterns of microorganisms, TLRs can be activated by endogenous ligands, expressed by mammalian cells. These 'danger signals' may participate in ischemia-reperfusion related organ damage and subsequently influence function and survival of transplanted grafts. Furthermore, it has been suggested that adaptive immune responses can enhance the acute inflammatory responses controlled by innate immunity in organ transplantation. This review addresses the potential involvement of TLRs in different stages of organ transplantation. Intriguing and controversial findings are presented and discussed in order to stimulate more attention to this emerging and potentially important area of research in organ transplantation.

Animals↗
PubMed2005

Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant.

Community-acquired viral respiratory tract infections (RTI) in lung transplant recipients may have a high rate of progression to pneumonia and can be a trigger for immunologically mediated detrimental effects on lung function. A cohort of 100 patients was enrolled from 2001 to 2003 in which 50 patients had clinically diagnosed viral RTI and 50 were asymptomatic. All patients had nasopharyngeal and throat swabs taken for respiratory virus antigen detection, culture and RT-PCR. All patients had pulmonary function tests at regular intervals for 12 months. Rates of rejection, decline in forced expiratory volume (L) in 1 s (FEV-1) and bacterial and fungal superinfection were compared at the 3-month primary endpoint. In the 50 patients with RTI, a microbial etiology was identified in 33 of 50 (66%) and included rhinovirus (9), coronavirus (8), RSV (6), influenza A (5), parainfluenza (4) and human metapneumovirus (1). During the 3-month primary endpoint, 8 of 50 (16%) RTI patients had acute rejection versus 0 of 50 non-RTI patients (p=0.006). The number of patients experiencing a 20% or more decline in FEV-1 by 3 months was 9 of 50 (18%) RTI versus 0 of 50 non-RTI (0%) (p=0.003). In six of these nine patients, the decline in FEV-1 was sustained over a 1-year period consistent with bronchiolitis obliterans syndrome (BOS). Community-acquired respiratory viruses may be associated with the development of acute rejection and BOS.

Bronchiolitis Obliterans↗
PubMed2005

Reperfusion-induced gene expression profiles in rat lung transplantation.

Ischemia-Reperfusion (I/R) injury after lung transplantation (LTx) can lead to significant morbidity and mortality in recipients. In an attempt to improve our understanding of molecular mechanisms of I/R injury, we examined the changes in gene expression levels in a rat lung transplant model using oligonucleotide microarrays. Lewis rat lung grafts were stored for 6 or 24 h followed by transplantation and reperfusion for 2 h. Lung tissues were taken before and after flushing the grafts, before implantation, and after 2 h of reperfusion. RNA samples were examined with Affymetrix rat microarray chips and RT-PCR was performed to validate significant changes in gene expression. Microarray analysis showed 404 genes that were up-regulated more than 2-fold after reperfusion compared to cold ischemic lungs, and 187 genes that were down-regulated. Using RT-PCR, we confirmed the response pattern of several specific gene transcripts from the microarray analysis. Among these, up-regulation in transcripts of transcription factors, adhesion molecules, pro-coagulant factors and pro-inflammatory cytokines were identified. The differential gene regulation during the I/R process can be considered as molecular signatures for the changes of cellular metabolism, functions and injury. Reperfusion-induced genes related to inflammatory response may contribute to graft dysfunction in LTx.

Animals↗