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Biomedical subjects

Shaf Keshavjee

Publications and source records attributed to Shaf Keshavjee.

At least 73 records · Page 4Linked to original sources
PubMed2003

Lung transplantation. Lung preservation.

Over the past decade, improvements in the technique of lung preservation have led to significant reduction in the incidence of ischemia-reperfusion-induced lung injury after lung transplantation. The challenge remains to improve the number of donor lungs available for transplantation. While the number of patients on the waiting list is constantly increasing, only 10% to 30% of donor lungs are currently being used for transplantation. Hence, the development of new strategies to assess, repair, and improve the quality of the lungs could have a tremendous impact on the number of transplants performed. In addition, an improved understanding of the mechanisms involved in lung preservation might help elucidate the potential link between acute lung injury and chronic graft dysfunction. In the future, genetic analysis using novel technologies such as microarray analysis will help researchers determine which genes control the injury seen in the transplantation process. Hopefully, this information will provide new insights into the mechanisms of injury and reveal potential new strategies and targets for therapies to improve lung preservation.

Graft Rejection↗
PubMed2003

Ischemia-reperfusion decreases protein tyrosine phosphorylation and p38 mitogen-activated protein kinase phosphorylation in rat lung transplants.

BACKGROUND: Dramatic alterations of protein tyrosine phosphorylation have been found during the ischemia-reperfusion (IR) period of human lung transplantation. IR also induces activation of p38 mitogen-activated protein kinase (p38) in the heart and kidney. The objective of the present study was to determine whether these changes exist in a rat single-lung transplant model for further mechanistic investigations. METHODS: Isogeneic lung transplantation was performed from Lewis (LEW) to LEW rats, whereas allogeneic transplantation was from LEW to Brown Norway (BN) rats. Blood gases and peak airway pressure were monitored. Lung tissues were collected after 6 hours of cold ischemic preservation, after 30 minutes of warm ischemia for lung implantation, and after 2 hours of reperfusion. Protein tyrosine kinase (PTK) and phosphatase (PTP) activities were measured. Protein tyrosine phosphorylation, Src PTK and p38 expression and p38 phosphorylation were examined by western blotting. RESULTS: In both iso- and allografts, the lung function of transplants was very well preserved. Protein tyrosine phosphorylation, PTK and PTP activities were decreased significantly after 2 hours of reperfusion. Src protein level and phosphorylation of p38 were reduced after 2 hours of reperfusion. CONCLUSIONS: During the early IR period of lung transplantation, decreased protein tyrosine phosphorylation may be involved in apoptosis and other biologic changes. The lack of p38 activation suggests that activity of mitogen-activated protein kinase pathways in the lung transplantation setting may be different from other IR processes.

Animals↗
PubMed2003

De novo pulmonary capillary hemangiomatosis occurring rapidly after bilateral lung transplantation.

A 45-year-old woman experienced diffuse bilateral pulmonary capillary hemangiomatosis within 3 months after bilateral lung transplantation. The donor was a 41-year-old man with excellent lung function and without histologic or macroscopic pulmonary lesions at the time of retrieval. This case supports the theory that persistent infection or inflammation may be an inciting factor in uncontrolled angiogenesis, leading ultimately to diffuse pulmonary capillary hemangiomatosis.

Adult↗
PubMed2003

Impact of human interleukin-10 on vector-induced inflammation and early graft function in rat lung transplantation.

This study was undertaken to examine the time course of human interleukin (hIL)-10 gene expression after transtracheal administration of adenoviral (Ad)hIL-10 and its effect on the early adenoviral proinflammatory cytokine response and on post-transplant lung function. Using a rat lung transplant model, we observed that lungs retrieved 12 h after the administration of AdhIL-10 were associated with significant improvement in post-transplant lung function. Shorter periods of transfection were associated with significantly elevated levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in lung tissue, leading to an increased degree of injury. The release of proinflammatory cytokines secondary to the adenoviral vector was reduced by high-dose methylprednisolone (30 mg/kg) administered 3 h before transfection. Reduction in the early adenoviral inflammatory response was associated with significant improvement in post-transplant lung function when lungs were retrieved 6 or 12 h after transtracheal administration of AdhIL-10. Transtracheal administration of adenoviral-mediated hIL-10 to donor lungs is associated with a significant early inflammatory response that may enhance ischemia-reperfusion injury if insufficient hIL-10 is expressed in lung tissue before retrieval. The period between delivery of AdhIL-10 and lung retrieval can be reduced if the early inflammatory response is suppressed with methylprednisolone.

Adenoviridae↗
PubMed2003

GI complications after lung transplantation in patients with cystic fibrosis.

STUDY OBJECTIVE: Lung transplantation is now available for patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the nonpulmonary complications of this systemic disease also continue. We examined the GI complications in a cohort of patients who underwent transplantation. DESIGN: This was a retrospective study of all patients with CF who underwent transplantation between March 1988 and December 1998 in Toronto. Medical records were reviewed, and a short questionnaire was mailed to patients who were alive as of December 1998. RESULTS: There were 80 bilateral lung transplants performed in 75 patients. The questionnaire was distributed to 43 patients, of whom 27 patients (63%) responded. Pancreatic insufficiency requiring enzyme intake was evident in 72 of 75 patients (96%) at the time of surgery. Of three pancreatic-sufficient patients (4%), pancreatic insufficiency was diagnosed in two patients later. Biliary cirrhosis was diagnosed in three patients prior to transplantation. Distal intestinal obstruction syndrome (DIOS) was recorded for 15 patients (20%). Ten patients had a single episode, of which eight episodes occurred early in the postoperative period. Five patients had recurrent episodes. All were medically treated, except for two patients who underwent surgery. Other complications included cholecystitis (n = 3), mucocele of the appendix (n = 1), peptic ulcer disease (n = 3), and colonic carcinoma (n = 1). CONCLUSION: GI complications after lung transplantation are common in patients with CF, and attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended.

Adult↗
PubMed2002

Molecular profiling of non-small cell lung cancer and correlation with disease-free survival.

Recent studies have suggested that information from gene expression profiles could be used to develop molecular classifications of cancer. We hypothesized that expression levels of specific genes in operative specimens could be correlated to recurrence risk in non-small cell lung cancer (NSCLC). We performed expression profiling using 19.2 K cDNA microarrays on tumor specimens from a total of 39 NSCLC patients with known clinical follow-up information. Statistical analysis and clustering approaches were used to determine patterns of gene expression segregating with clinical outcome. The results provide evidence that molecular subtyping of NSCLC can identify distinct profiles of gene expression correlating with disease-free survival.

Adult↗
PubMed2002

Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans.

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.

Animals↗
PubMed2002

Interleukin-8 release during early reperfusion predicts graft function in human lung transplantation.

Cytokines have been shown to play an important role in promoting inflammation in the setting of ischemia-reperfusion injury. However, their role in human lung transplantation has not been systematically explored. This study was undertaken to examine the kinetics of cytokine release in 18 consecutive human lung transplantation procedures and to examine the relationships between their levels and donor factors, length of ischemic time, and allograft function. TNF-alpha, IFN-gamma, IL-10, IL-12, and IL-18 were found at higher levels during the ischemic time, whereas IL-8 predominantly increased after reperfusion. IL-8 levels after 2 h of reperfusion correlated with lung function assessed by the Pa(O2 )/FI(O(2)) ratio, the mean airway pressure, and the APACHE score during the first 24 postoperative hours. The length of ICU stay also correlated with IL-8 levels after 2 h of reperfusion. Longer ischemic time was associated with significantly higher levels of IL-18 before reperfusion, and older donors had significantly lower levels of IL-10 after reperfusion. We have demonstrated the importance of IL-8 in predicting early graft function after human lung transplantation. In addition, we showed that donor age and ischemic time may influence release of specific cytokines during ischemia-reperfusion.

APACHE↗
PubMed2002

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome.

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome is a rare disease. Recent evidence suggests that these tumors form part of a continuous spectrum ranging from well-differentiated carcinomas to small cell carcinomas. We report two new cases and review the 23 cases reported in the literature since 1972. The different diagnostic modalities are discussed, and an algorithm for the diagnosis of ectopic secretion of adrenocorticotropin (ACTH) is presented. In the future, the advent of radiologic and nuclear imaging as well as more accurate workup should help to diagnose these tumors at an earlier stage and improve the long-term outcome.

ACTH Syndrome, Ectopic↗
PubMed2002

Bilateral lung transplantation using a donor with a tracheal right upper lobe bronchus.

We report on a case of successful bilateral sequential lung transplantation using a donor with the right upper lobe bronchus arising from the trachea. After en-bloc donor lung retrieval, the right bronchial stump was fashioned to create one lumen including the bronchus intermedius and the aberrant right upper lobe bronchus. A carinoplasty was performed in the recipient with resection of a portion of the lateral wall of trachea. The anastomosis was completed using a telescoping technique without any complication. This case demonstrates the possibility of successfully using donor lungs with such anatomic abnormality for transplantation.

Adult↗
PubMed2002

Solitary fibrous tumors of the pleura.

Solitary fibrous tumor of the pleura is a mesenchymal tumor that has been increasingly recognized over the past few years. The tumor was initially described in the pleura, but it has been reported in many other sites lately. Although the majority of these tumors have a benign course, the malignant form still remains enigmatic. Indeed, the behavior of these tumors is often unpredictable and does not always correlate with histologic findings. In addition, benign tumors may remain unproblematic for several years before changing into a malignant form. In order to define more precisely the clinical behavior of solitary fibrous tumors of the pleura, we reviewed the literature with particular attention to the clinical presentation, histopathologic characteristics, and cytogenetic differentiation of these tumors. A staging system and an algorithm for the management and follow-up of these patients are proposed.

Algorithms↗
PubMed2002

Everting mattress running suture: an improved technique of atrial anastomosis in human lung transplantation.

Significant complications related to the venous anastomosis have been reported in clinical lung transplantation, and it has been suggested that the incidence of pulmonary vein complications may have been previously underestimated. In our institution, we have adopted the horizontal everting mattress running suture as standard practice for the venous anastomosis in human lung transplantation. This technique is easier to perform than the regular over-and-over sutures, and allows suturing of the donor and recipient atrial cuffs in a straight line, opposing endothelium to endothelium, thus limiting the presence of redundant and potentially thrombogenic tissue in the lumen. This technique should help reduce the risk of venous anastomotic complications.

Anastomosis, Surgical↗
PubMed2002

Effect of ventilator-induced lung injury on the development of reperfusion injury in a rat lung transplant model.

OBJECTIVE: Although mechanical ventilation can potentially worsen preexisting lung injury, its importance in the setting of lung transplantation has not been explored. This study was undertaken to examine the effect of 2 ventilatory strategies on the development of ischemia-reperfusion injury after lung transplantation. METHODS: In a rat lung transplant model animals were randomized into 2 groups defined by the ventilatory strategy during the early reperfusion period. In conventional mechanical ventilation the transplanted lung was ventilated with a tidal volume equal to 50% of the inspiratory capacity of the left lung and a low positive end-expiratory pressure. In minimal mechanical stress ventilation the transplanted lung was ventilated with a tidal volume equal to 20% of the inspiratory capacity of the left lung, and positive end-expiratory pressure was adjusted according to the shape of the pressure-time curve to minimize pulmonary stress. RESULTS: After 3 hours of reperfusion, oxygenation from the transplanted lung was significantly higher with minimal mechanical stress ventilation than with conventional ventilation. In addition, elastance, cytokine levels, and morphologic signs of injury were significantly lower in the group with minimal mechanical stress ventilation. CONCLUSIONS: This study demonstrates that the mode of mechanical ventilation used in the early phase of reperfusion of the transplanted lung can influence ischemia-reperfusion injury, and a protective ventilatory strategy on the basis of minimizing pulmonary mechanical stress can lead to improved lung function after lung transplantation.

Animals↗
PubMed2002

Molecular cloning of actin filament-associated protein: a putative adaptor in stretch-induced Src activation.

Mechanical stretch-induced activation of c-Src is an important step for signal transduction of stretch-induced fetal rat lung cell proliferation. This process appears to be mediated through actin filament-associated protein (AFAP), encoded by a gene originally cloned from the chicken. In the present study, we cloned the rat AFAP gene from fetal rat lungs. Its mRNA and protein are differentially expressed among various tissues. The protein is colocalized with actin filaments in fetal rat lung epithelial cells and fibroblasts. Mechanical stretch increased tyrosine phosphorylation of rat AFAP and its binding to c-Src within the initial several minutes. Src SH2 and SH3 binding motifs are highly conserved in the AFAP proteins (from chicken, rat to human). On the basis of the molecular structure of AFAP protein, we speculate that it is an adaptor in mechanical stretch-induced activation of c-Src. A novel model of mechanoreception is proposed.

Actins↗
PubMed2002

Thixotropic solutions enhance viral-mediated gene transfer to airway epithelia.

Adenovirus-mediated gene transfer to airway epithelia is inefficient in part because its receptor is absent on the apical surface of the airways. Targeting adenovirus to other receptors, increasing the viral concentration, and even prolonging the incubation time with adenovirus vectors can partially overcome the lack of receptors and facilitate gene transfer. Unfortunately, mucociliary clearance would prevent prolonged incubation time in vivo. Thixotropic solutions (TS) are gels that upon a vigorous shearing force reversibly become liquid. We hypothesized that formulating recombinant adenoviruses in TS would decrease virus clearance and thus enhance gene transfer to the airway epithelia. We found that clearance of virus-sized fluorescent beads by human airway epithelia in vitro and by monkey trachea in vivo were markedly decreased when the beads were formulated in TS compared with phosphate-buffered saline (PBS). Adenovirus formulated in TS significantly increased adenovirus-mediated gene transfer of a reporter gene in human airway epithelia in vitro and in murine airway epithelia in vivo. Furthermore, an adenovirus encoding the cystic fibrosis transmembrane regulator (CFTR) gene (AdCFTR) formulated in TS was more efficient in correcting the chloride transport defect in cystic fibrosis airway epithelia than AdCFTR formulated in PBS. These data indicate a novel strategy to augment the efficiency of gene transfer to the airways that may be applicable to a number of different gene transfer vectors and could be of value in gene transfer to cystic fibrosis (CF) airway epithelia in vivo.

Adenoviridae↗