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Biomedical subjects

Shaf Keshavjee

Publications and source records attributed to Shaf Keshavjee.

At least 19 recordsLinked to original sources
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

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↗
PubMed2004

Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease.

PURPOSE: To determine the role of lung transplantation in the treatment of patients presenting with bronchogenic carcinoma and end-stage lung disease. METHODS: An international survey was conducted to determine the outcome of patients with bronchogenic carcinoma in the explanted lung at the time of transplantation. A group of 69 patients was collected from 33 centers. RESULTS: Twenty-six patients underwent 29 lung transplantations for advanced multifocal bronchioloalveolar carcinoma (BAC) as the primary indication for transplantation, and 13 developed a recurrence, with an overall 5-year actuarial survival of 39%. Incidental bronchogenic carcinomas classified as stage I (n = 22), II (n = 12), and III (n = 2), or as incidental multifocal BAC (n = 7), were found in the explanted lung of the remaining 43 patients. The 5-year actuarial survival was 51% in patients with stage I carcinomas, and was significantly better than for patients with stage II and III carcinomas (survival of 14%) or with incidental multifocal BAC (survival of 23%). Time from transplantation to recurrence and from recurrence to death was significantly longer in patients with multifocal BAC than in patients with other types of bronchogenic carcinoma. In addition, the site of recurrence was limited to the transplanted lung in 88% of the patients with multifocal BAC, whereas it was always widespread in patients with other types of bronchogenic carcinoma. CONCLUSION: This study demonstrates that long-term survival can be achieved after lung transplantation in patients with stage I bronchogenic carcinoma or with advanced multifocal BAC.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Conversion of mechanical force into biochemical signaling.

Physical forces play important roles in regulating cell proliferation, differentiation, and death by activating intracellular signal transduction pathways. How cells sense mechanical stimulation, however, is largely unknown. Most studies focus on cellular membrane proteins such as ion channels, integrins, and receptors for growth factors as mechanosensory units. Here we show that mechanical stretch-induced c-Src protein tyrosine kinase activation is mediated through the actin filament-associated protein (AFAP). Distributed along the actin filaments, AFAP can directly active c-Src through binding to its Src homology 3 and/or 2 domains. Mutations at these specific binding sites on AFAP blocked mechanical stretch-induced c-Src activation. Therefore, mechanical force can be transmitted along the cytoskeleton, and interaction between cytoskeletal associated proteins and enzymes related to signal transduction may convert physical forces into biochemical reactions. Cytoskeleton deformation-induced protein-protein interaction via specific binding sites may represent a novel intracellular mechanism for cells to sense mechanical stimulation.

Animals↗
PubMed2004

KCl evokes contraction of airway smooth muscle via activation of RhoA and Rho-kinase.

Airway smooth muscle (ASM) cells express voltage-dependent Ca2+ channels, primarily of the L-subtype. These may play a role in excitation-contraction coupling of ASM, although other signaling pathways may also contribute: one of these includes Rho and its downstream effector molecule Rho-associated kinase (ROCK). Although voltage-dependent Ca2+ influx and Rho/ROCK signaling have traditionally been viewed as entirely separate pathways, recent evidence in vascular smooth muscle suggest differently. In this study, we monitored contractile activity (muscle baths) in bronchial and/or tracheal preparations from the pig, cow, and human, and further examined Rho and ROCK activities (Western blots and kinase assays) and cytosolic levels of Ca2+ (fluo 4-based fluorimetry) in porcine tracheal myocytes. KCl evoked substantial contractions that were suppressed in tracheal preparations by removal of external Ca2+ or using the selective L-type Ca2+ channel blocker nifedipine; porcine bronchial preparations were much less sensitive, and bovine bronchi were essentially unaffected by 1 microM nifedipine. Surprisingly, KCl-evoked contractions were also highly sensitive to two structurally different ROCK inhibitors: Y-27632 and HA-1077. Furthermore, the inhibitory effects of nifedipine and of the ROCK inhibitors were not additive. KCl also caused marked stimulation of Rho and ROCK activities, and both these changes were suppressed by nifedipine or by removal of external Ca2+. KCl-induced elevation of [Ca2+]i was not affected by Y-27632 but was reversed by NiCl2 or by BAPTA-AM. We conclude that KCl acts in part through stimulation of Rho and ROCK, possibly secondary to voltage-dependent Ca2+ influx.

Amides↗
PubMed2004

Bilateral lung transplantation for metastatic leiomyosarcoma.

As increased experience is gained in the field of lung transplantation, novel applications for this life saving therapy will evolve. We have described a case of bilateral lung transplantation in a young patient with respiratory failure secondary to metastatic leiomyosarcoma that was limited to the lungs. While lung transplantation for malignancy remains a controversial area, this case illustrates that lung transplantation can provide improved quality and quantity of life for highly selected patients with malignant disease.

Adult↗
PubMed2004

A novel model to study bacterial adherence to the transplanted airway: inhibition of Burkholderia cepacia adherence to human airway by dextran and xylitol.

BACKGROUND: Lung infection with Burkholderia cepacia complex before lung transplantation in patients with cystic fibrosis is a major risk factor for decreased post-operative survival rates compared with those of patients colonized with the more common opportunistic pathogen Pseudomonas aeruginosa. Because adherence to mucosal surfaces is an important initial step in infection, we investigated the use of non-toxic neutral polysaccharides and a sugar alcohol to prevent adherence of B cepacia complex to allograft airway epithelium. METHODS: We used human airway explants prepared from donor tracheobronchial tissue to test the effect of dextrans and xylitol in inhibiting the binding of Burkholderia cepacia complex. We used immunofluorescence and electron microscopy to determine the distribution of bacteria in the explants. RESULTS: Burkholderia cepacia complex bound to the explants and was found only in the surface mucus layer. Dextran 40 kd applied before adding the bacteria decreased the number of bound organisms by 80% to 99%. Smaller molecular mass dextrans (4 and 20 kd) were ineffective. Xylitol inhibited bacterial binding by 67% to 85%. Both agents seemed to decrease the thickness of the surface mucus, suggesting that they may indirectly inhibit bacterial binding by removing adherent surface mucus. CONCLUSIONS: Treating donor lungs with dextran 40 kd or xylitol before (and possibly after) surgery may inhibit the adherence of Burkholderia cepacia complex to airways and may prevent or decrease subsequent infection of the allografts.

Bacterial Adhesion↗
PubMed2004

Twenty-year experience of lung transplantation at a single center: Influence of recipient diagnosis on long-term survival.

OBJECTIVES: The objective of this study was to examine the long-term patient outcomes of lung transplantation in a single center. METHODS: Between 1983 and 2003, 521 lung transplants were performed in 501 patients. Major indications were cystic fibrosis (n = 124), chronic obstructive pulmonary disease (n = 88), alpha-1 antitrypsin deficiency (n = 63), pulmonary fibrosis (n = 97), primary pulmonary hypertension (n = 35), Eisenmenger syndrome (n = 21), and miscellaneous end-stage lung diseases (n = 93). RESULTS: The 5-, 10-, and 15-year survivals for all recipients were 55.1% (95% confidence interval: +/-5%), 35.3% (+/-6%), and 26.5% (+/-11%), respectively. The most common causes of death were sepsis and bronchiolitis obliterans syndrome. Despite an increased postoperative mortality rate, patients with primary pulmonary hypertension achieved the best long-term survival (10-year survival: 59%). Recipients with cystic fibrosis without Burkholderia cepacia infection achieved significantly better long-term survival (10-year survival: 52%) than those with Burkholderia cepacia infection (10-year survival: 15%). The 10-year survival was also significantly better in recipients with chronic obstructive pulmonary disease (43%) than in recipients with alpha-1 antitrypsin deficiency (23%). Although the incidence of bronchiolitis obliterans syndrome was similar between recipients with chronic obstructive pulmonary disease (39%) and alpha-1 antitrypsin deficiency (46%), recipients with alpha-1 antitrypsin deficiency died of sepsis more frequently than recipients with chronic obstructive pulmonary disease (27% vs 6%, respectively; P =.0003). CONCLUSIONS: Although bronchiolitis obliterans syndrome and sepsis still limit the durability of the benefit, lung transplantation returns many patients with end-stage lung disease to active and productive lives. Differences in the complications and long-term survival show the important contribution of the recipient diagnosis to the success of lung transplantation.

Adolescent↗
PubMed2004

15 years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer.

OBJECTIVES: To examine our results with surgery for locally advanced non-small cell lung cancer (NSCLC) invading the superior vena cava (SVC). METHODS: A retrospective analysis of patients who underwent resection between 1988 and 2003 was performed. Postoperative morbidity, long-term survival, including risk factors for overall and disease-free survival were examined. RESULTS: Median age of the 15 operated patients was 60 years (28-78). All had direct SVC invasion by tumor. All underwent mediastinoscopy. Seven patients with N2 disease, and one with a bulky right upper lobe tumor received induction therapy. Eight underwent lobectomy (three sleeve), and seven had pneumonectomy (two carinal). The SVC was replaced by interposition graft in nine patients, whereas six had partial resection. There were two postoperative deaths (14%) and three major morbidities (23%). There was one late graft thrombosis. Mean follow-up was 25 months (3-132, median 11). Overall 1 and 3-year survival was 68 and 57% and disease-free survival was 55 and 27%, respectively. All late deaths were due to recurrence. Survival of patients with N2 disease was not significantly worse than those with localized (N0/N1) nodal disease. There was a trend towards later recurrence in patients who had induction therapy (median disease-free interval of 29 months versus 5 months in the untreated group, P = 0.3), but there was no significant effect on overall survival. The extent of lung resection and type of SVC procedure did not influence long-term survival. CONCLUSIONS: Carefully selected patients with NSCLC and SVC involvement can be operated upon with acceptable postoperative morbidity and mortality. Induction therapy appears to delay recurrence.

Adult↗
PubMed2004

Validating the prognostic value of marker genes derived from a non-small cell lung cancer microarray study.

We previously reported that our cDNA microarray analysis of primary non-small cell lung carcinoma (NSCLC) could predict for patients at increased risk of cancer recurrence. From the result of this analysis, we selected 11 genes that were considered candidate prognostic marker genes and used the realtime reverse transcription polymerase chain reaction (RT-PCR) to investigate their expression in the same set of NSCLC cases used in the microarray study. Cluster analysis of the realtime RT-PCR data separated these patients into two groups with significantly different disease-free survivals (log-rank test, P < 0.017). In contrast, cluster analysis failed to confirm the prognostic significance of the realtime RT-PCR results for these 11 genes in a validation series of 92 NSCLC cases. In univariate analysis, hypoxia inducible factor 1alpha, Rho-GDP dissociation inhibitor (GDI) alpha (RhoGDI) and Citron/rho-interacting serine-threonine kinase 21 (Citron K21) were significant prognostic factors for disease-free survival in the entire cohort of 130 NSCLC patients, but none were significant in multivariate analysis. The results demonstrate that the prognostic significance of microarray (SAM) results can be partially validated using realtime RT-PCR, but secondary validation using larger and independent series of tumors is necessary to identify true prognostic marker genes.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters.

BACKGROUND: Because there is no reliable evaluation system of recipient acuity after lung transplantation, comparing patients among centers is difficult. The purpose of our study was to identify risk factors for 30-day mortality and prolonged intensive care unit stay and to develop a scoring system to evaluate the severity of impairment and to predict surgical outcomes. METHODS: We prospectively collected data from 122 lung transplant recipients and from 119 donors from January 1997 to June 2000. We assessed donor, recipient, and operative factors; ischemic time; and immediate post-operative physiologic parameters to identify risk factors for 30-day mortality and prolonged intensive care unit stay. Furthermore, we sub-classified these factors into grades to develop a scoring system for predicting surgical outcomes. RESULTS: Cardiopulmonary bypass use, body mass index >25 kg/m2, immediate post-operative systolic pulmonary arterial pressure, trend of oxygenation index from 12 to 24 hours after transplantation, and the Acute Physiology and Chronic Health Evaluation II score correlated significantly with outcomes, and the sum of these 5 scores correlated strongly with outcomes (p < 0.0001). CONCLUSIONS: We conclude that the total score of these 5 risk factors could be used to predict 30-day mortality and prolonged intensive care unit stay. This scoring system also will facilitate standardization among transplant centers in evaluating post-transplant severity of illness.

Female↗
PubMed2004

Lung preservation.

Better understanding of the mechanisms of ischemia-reperfusion injury, improvement in the technique of lung preservation, and the recent introduction of a new preservation solution specifically developed for the lungs have helped to reduce the incidence of primary graft dysfunction after lung transplantation. Currently, the limitation in extending the ischemic time is more often related to the increasing use of non-ideal lung donors rather than to poor lung preservation. In this review, we have focused our attention on the experimental and clinical work performed to optimize the methods of lung preservation from the time of retrieval to the period of reperfusion after graft implantation.

Graft Survival↗
PubMed2004

Responses of well-differentiated airway epithelial cell cultures from healthy donors and patients with cystic fibrosis to Burkholderia cenocepacia infection.

Well-differentiated cultures established from airway epithelia of patients with cystic fibrosis (CF cultures) exhibited goblet cell hyperplasia, increased secretion of mucus, and higher basal levels of interleukin-8 than similarly cultured cells from healthy donors. Upon apical infection with low doses (10(4) to 10(5) CFU) of Burkholderia cenocepacia isolate BC7, the two cultures gave different responses. While normal cultures trapped the added bacteria in the mucus layer, killed and/or inhibited bacterial replication, and prevented bacterial invasion of the cells, CF cultures failed to kill and/or supported the growth of bacteria, leading to invasion of underlying epithelial cells, compromised transepithelial permeability, and cell damage. Depletion of the surface mucus layer prior to bacterial infection rendered the normal cultures susceptible to bacterial invasion, but the invading bacteria were mainly confined to vacuoles within the cells and appeared to be nonviable. In contrast, bacteria that invaded cells in CF cultures were found free in the cytoplasm surrounded by intermediate filaments and also between cells. Cultured CF airway epithelium was therefore more susceptible to infection than normal epithelium. This mimics CF tissue in vivo and illustrates differences in the way epithelia in CF patients and normal subjects handle bacterial infection. In addition, we found that the CF and normal cell cultures responded differently not only to isolate BC7 but also to isolates of other B. cepacia complex species. We therefore conclude that this cell culture model is suitable for investigation of B. cepacia complex pathogenesis in CF patients.

Burkholderia↗
PubMed2003

Recipient T cells mediate reperfusion injury after lung transplantation in the rat.

Leukocytes have been implicated in ischemia-reperfusion (IR) injury of the lung, but the individual role of T cells has not been explored. Recent evidence in mice suggests that T cells may play a role in IR injury. Using a syngeneic (Lewis to Lewis) rat lung transplant model, we observed that recipient CD4(+) T cells infiltrated lung grafts within 1 h of reperfusion and up-regulated the expression of CD25 over the ensuing 12 h. Nude rats (rnu/rnu) and heterozygous rats (rnu/+) were used to determine the role of T cells in IR injury. No significant difference in lung function was observed between nude and heterozygous recipient rats after 2 h of reperfusion. However, after 12 h of reperfusion, recipient nude rats had significantly higher oxygenation and lower peak airway pressure than recipient heterozygous rats. This was associated with significantly lower levels of IFN-gamma in transplanted lung tissue of recipient nude rats. Reconstitution of recipient nude rats with T cells from heterozygous rats restored IR injury after 12 h of reperfusion. The effect of T cells was independent of neutrophil recruitment and activation in the transplanted lung. These results demonstrate that recipient T cells are activated and mediate IR injury during lung transplantation in rats.

Adoptive Transfer↗
PubMed2003

Accommodation after lung xenografting from hamster to rat.

BACKGROUND: Long-term xenograft survival can be achieved in hamster hearts transplanted into rats treated with cobra venom factor (CVF) and cyclosporine A (CsA). This phenomenon of "accommodation" is associated with expression of protective genes such as bcl-2, bcl-X(L), and heme-oxygenase-1. We examined whether accommodation could be induced in hamster-to-rat lung xenografts and whether the pattern of protective genes is similar to cardiac xenografts. METHODS: We used hamster-to-rat cardiac and lung xenotransplantation models. Cardiac xenotransplants were treated with CVF+CsA and compared with untreated controls. Lung xenotransplants were treated with either CVF+CsA or FK506 and cyclophosphamide (Cp) and compared with untreated controls. All recipients were killed by 21 days after transplantation. We examined graft survival and protein expression of protective genes, and we performed histologic and immunohistologic analyses. RESULTS: Rejection occurred rapidly in untreated rats. CVF+CsA or FK506+Cp treatment significantly influenced graft survival. Eight of 12 CVF+CsA-treated heart transplants survived 21 days. Seven of 16 CVF+CsA-treated lung grafts and five of 12 FK506+Cp-treated lung xenografts survived 21 days. We observed significant protein expression of bcl-2, bcl-X(L), and heme-oxygenase-1 in cardiac xenografts treated with CVF+CsA at 2, 14, and 21 days after transplantation, compared with normal hamster hearts. We also observed significant expression of these proteins in lung xenografts treated with either CVF+CsA or FK506+Cp at 21 days after transplantation, compared with normal lungs. CONCLUSIONS: Accommodation may be a general phenomenon for all organs, mediated through protective genes. Induction of accommodation does not require disruption of the complement system.

Adaptation, Physiological↗
PubMed2003

Ischemia-reperfusion-induced lung injury.

Ischemia-reperfusion-induced lung injury is characterized by nonspecific alveolar damage, lung edema, and hypoxemia occurring within 72 hours after lung transplantation. The most severe form may lead to primary graft failure and remains a significant cause of morbidity and mortality after lung transplantation. Over the past decade, better understanding of the mechanisms of ischemia-reperfusion injury, improvements in the technique of lung preservation, and the development of a new preservation solution specifically for the lung have been associated with a reduction in the incidence of primary graft failure from approximately 30 to 15% or less. Several strategies have also been introduced into clinical practice for the prevention and treatment of ischemia-reperfusion-induced lung injury with various degrees of success. However, only three randomized, double-blinded, placebo-controlled trials on ischemia-reperfusion-induced lung injury have been reported in the literature. In the future, the development of new agents and their application in prospective clinical trials are to be expected to prevent the occurrence of this potentially devastating complication and to further improve the success of lung transplantation.

Graft Rejection↗