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Biomedical subjects

G L Zorn

Publications and source records attributed to G L Zorn.

At least 19 recordsLinked to original sources
PubMed2003

Hyperacute lung rejection in the pig-to-human model. 2. Synergy between soluble and membrane complement inhibition.

BACKGROUND: The role of complement in hyperacute lung xenograft rejection has not been elucidated. The present study evaluates the effect of complement (C) C3/C5 convertase inhibition on hyperacute rejection of pig lung by human blood. METHODS: In an established ex-vivo model, lungs from pigs heterozygous for human decay accelerating factor (hDAF), non-transgenic littermate control pigs, or farm-bred pigs were perfused with fresh human blood that was either unmodified or treated with soluble complement receptor type 1 (sCR1: TP10, 100 microg/ml). RESULTS: Non-transgenic lungs from littermate controls had a median survival time of 35 min (range 5 to 210; P = 0.25 vs. farm-bred piglets: median 5 min, range 5 to 10). Lungs expressing hDAF survived for a median of 90 min (range 10 to 161; P = 0.5 and 0.01 vs. littermate and farm-bred controls, respectively), with sCR1, whereas hDAF (-) lungs failed by 35 min (range 6 to 307), hDAF (+) lungs survived for 330 min (range 39 to 577) [P = 0.002 vs. farm-bred; P = 0.08 vs. hDAF (-); P = 0.17 vs. sCR1/hDAF (-)]. The rise in pulmonary vascular resistance (PVR) at 5 min was blunted only by hDAF (+) with sCR1 (0.26 +/- 0.2 vs. 0.5 to 0.7 mmHg/ml/min for other groups). Plasma C3a and sC5b-9 and tissue deposition of C5b-9 were dramatically diminished using sCR1, and further decreased in association with hDAF. Histamine and thromboxane were produced rapidly in all groups. CONCLUSION: Complement plays an important role in lung HAR. However, even potent inhibition of C3/C5 convertase, both membrane bound in lung and by a soluble-phase inhibitor in the blood, does not prevent activation of inflammatory responses known to be particularly injurious to the lung. Our findings implicate a role for innate immune pathways resistant to efficient complement regulation. The role of anti-species antibody, coagulation pathway dysregulation, and additional environmental or genetic influences remain to be defined.

Acute Disease↗
PubMed2001

Role of anti-Gal alpha13Gal and anti-platelet antibodies in hyperacute rejection of pig lung by human blood.

BACKGROUND: Previous work has shown that antibodies against porcine antigens are an important trigger of hyperacute lung rejection (HALR). The relative importance of Gal alpha1,3Gal epitopes and other antigens, such as those expressed on pig platelet membranes or lung itself, has not been defined. This study compares the efficiency of three anti-pig antibody depletion strategies, and their efficacy with regard to attenuation of HALR. METHODS: Plasma pooled from three human donors was adsorbed against Gal alpha1,3Gal disaccharide or porcine platelet extract (PPE), or passed through pig lung vasculature. Whole blood reconstituted using adsorbed plasma was then used to perfuse piglet lung, and results were compared with unmodified human blood. RESULTS: Depletion of lung-reactive anti-Gal alpha1-3Gal antibodies was most efficient with the alphaGal column (99% +/- 0.5% vs 87% to 93% +/- 11% for PPE and 92% to 95% +/- 8% for lung, p < 0.01 vs alphaGal column). PPE column tended to be more efficient (77% to 84% +/- 12%) in removing anti-PPE antibodies than pig lung (66% to 70% +/- 14%) or the alphaGal column (56% to 63% +/- 16%, p < 0.05). Lung survival and function with each antibody depletion strategy was improved relative to unmodified controls (mean survival > or = 146 minutes vs 8 minutes for controls). Although alphaGal and lung adsorption yielded more consistent lung protection (survival beyond 2 hours) than did PPE, no approach proved significantly superior. Complement C3a elaboration at 10 minutes was attenuated > 80% by each adsorption strategy, an effect that was most pronounced in the lung adsorption group (95%, p < 0.01). Histamine elaboration was blunted significantly by PPE adsorption but not in other groups (p < 0.05). Platelet but not leukocyte sequestration was decreased with antibody depletion compared with the nondepleted group (44% to 50% vs 82%, p < 0.01). CONCLUSIONS: Each antibody depletion strategy tested significantly prolongs lung xenograft survival and function compared with unmodified human blood, but none was sufficient to reliably prevent HALR. Depletion of antibodies against both alphaGal and additional cell membrane antigens, or control of antibody-independent pathogenic pathways, may be necessary to consistently prevent HALR.

Acute Disease↗
PubMed2001

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection.

The role of thromboxane (Tx) in hyperacute rejection of pig lung by human blood was studied in an ex vivo model, wherein lungs from juvenile piglets were perfused with fresh heparinized human blood. In this model, hyperacute lung rejection was characterized by an abrupt rise in pulmonary vascular resistance (PVR; >1 cmH2O x ml(-1) x min) and prolific Tx elaboration (>15 ng/ml) within 5 min and loss of function within 10 min. Although papaverine significantly blunted the rise in PVR (<0.2 cmH2O x ml(-1) x min), Tx production was not inhibited (>20 ng/ml), and florid tracheal edema was usually evident within 20 min. In contrast, both inhibition of Tx synthesis (Tx < 3 ng/ml) with OKY-046 and blockade of the Tx receptor with SQ-30741 (Tx > 20 ng/ml) were not only associated with significantly lower peak PVRs (<0.2 cmH2O x ml(-1) x min) but also with attenuated increase in lung wet-to-dry ratio and airway edema. In concert, elaboration of histamine and tumor necrosis factor was blunted, and median survival increased >10-fold to 2 h (SQ-30741) and >4 h (OKY-046). Depletion of the pig lung macrophages with dichloromethyl bisphosphonate in liposomes, but not Pall filtration of the human blood or liposomes alone, significantly inhibited Tx elaboration (<0.2 vs. >8 ng/ml for Pall filtration or liposomes) and blunted PVR elevation (<0.3 cmH(2)O x ml(-1) x min) during initial perfusion. C3a and histamine elaboration were inhibited, and median survival was significantly prolonged (>4 h). These findings implicate Tx in the inflammation associated with hyperacute lung rejection and demonstrate that pulmonary intravascular macrophages are critical to its elaboration.

Acute Disease↗
PubMed2001

Association of reactive nitrogen species metabolites, myeloperoxidase, and airway inflammation in lung transplants.

BACKGROUND: We have previously reported that patients who had single or double lung transplants had higher concentrations than controls of nitrite and nitrate, which are metabolites of reactive nitrogen species (RNS), in bronchoalveolar lavage fluid (BALF) and serum. METHODS: This study investigates implications of RNS metabolites as markers of airway inflammation in a distinct group of lung transplant patients (n = 40). All patients underwent spirometry, routine surveillance transbronchial lung biopsies, and bronchoalveolar lavage as required by clinical protocol. Four normal controls also had bronchoscopy for measurement of BALF nitrite (NO2-) and nitrate (NO3-). BALF NO2- and NO3-, myeloperoxidase (MPO), protein, and urea were assayed. Total nitrite (NO2- plus enzymatically reduced NO3-) and urea were measured in serum. RESULTS: BALF RNS metabolites were mainly NO3-. Forced expiratory volume in 1 s (FEV1) obtained near bronchoscopy was compared with best postoperative FEV1. Total nitrite in transplant patients' BALF and serum were 3.8 +/- 0.2 and 49 +/- 5 microM, respectively. Total nitrite in controls' BALF and serum were 2.2 +/- 0.7 and 19 +/- 2 microM, respectively (P < 0.05 compared with transplant values). Serum total nitrite correlated (Pearson product moment) with percentage of neutrophils in BALF (R = 0.650, P < 0.0001), MPO (R = 0.431, P = 0.0055), change in FEV1 from baseline (deltaFEV1) (R = -0348, P = 0.0298), and days after transplantation (R = 0.345, P = 0.0294). None of the associated variables, airway inflanmmation (quantified as a score, "B"), deltaFEV1, serum, or BALF total nitrite, were explained by infection. Univariate analysis of airway inflammation in patients showed that it was associated with BALF neutrophils, deltaFEV1, and serum total nitrite. CONCLUSIONS: Serum nitrite appears to reflect the degree of airway inflammation in this lung-transplant study group.

Adult↗
PubMed2000

Surgical management of early stage lung cancer.

For patients with lung cancer, the greatest hope for cure rests with patients with early stage disease. Surgery has been the standard of care for this group with the best 5-year survival of only 65% being achieved in patients with earliest pathologic Stage IA disease. Using strategies gained from the management of patients with advanced disease, clinicians are investigating the use of perioperative chemotherapy and radiotherapy to improve survival. In addition, biologic and molecular markers are being evaluated to assist in predicting prognosis and to identify those patients at increased risk for recurrent disease. Postoperative surveillance of patients using helical computed tomography (CT) scanning is being investigated to detect early recurrences and second primary lesions. With such treatment and management plans on the horizon, the prognosis of patients with early stage non-small cell lung cancer (NSCLC) may be improved.

Algorithms↗
PubMed2000

The utility of open lung biopsy following lung transplantation.

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.

Biopsy↗
PubMed2000

Protein nitration, metabolites of reactive nitrogen species, and inflammation in lung allografts.

This study investigated nitration and chlorination of epithelial lining fluid (ELF) proteins in patients (n = 29) who had undergone lung allotransplantation. We assayed lung lavage nitrotyrosine (NT) and chlorotyrosine (CT) by HPLC. We measured NT, nitrate (NO(3)(-)), and nitrate (NO(2)(-)) in bronchoalveolar lavage fluid (BALF) and total nitrite (NO(2)(-) + NO(3)(-)) in serum of another group of lung transplant patients (n = 82). In the first group (n = 29), percent nitration of tyrosines (Tyr) (NT/total Tyr x 100) in BALF proteins was: patients, 0.01 (0.00-0.12)%; median (25th-75th% confidence interval), and control subjects 0.01 (0.00-0.02)%. CT (CT/ total Tyr x 100) occurred only in the patients' BALF: 0.01 (0. 00- 0.02)%. In the second group (n = 82), nitrotyrosine (NT) was detected by ELISA in the BALF of patients: 9 (0-41) pmol/mg pro and control subjects: 28 (26-33). Total nitrite (NO(2)(-) + NO(3)(-)) in BALF of the patients: 3.3 (1.9-5.1) microM significantly exceeded that in control subjects: 1.3 (0.8-1.3) microM; p = 0.0133. Serum nitrite also was significantly higher in patients: 37 (26-55) microM than control subjects: 19 (17-20) microM; p = 0.0037. Airway inflammation in transbronchial biopsies (B score) correlated with NT in BALF (p = 0.0369). Lung transplants have increased airway concentrations of reactive nitrogen species (RNS) metabolites. NT, a marker of peroxynitrite (ONOO(-)), is related to the degree of airway inflammation in lung transplants.

Adult↗
PubMed1999

Recurrence of bronchioloalveolar carcinoma in transplanted lungs.

BACKGROUND: Bronchioloalveolar carcinoma is a distinctive subtype of typical adenocarcinoma of the lung that tends to metastasize widely throughout the lungs but less commonly elsewhere. Because conventional therapies for intrapulmonary metastatic bronchioloalveolar carcinoma are generally ineffective, we treated seven patients who had intrapulmonary metastatic bronchioloalveolar carcinoma with lung transplantation. METHODS: Seven patients with biopsy-proved bronchioloalveolar carcinoma and no evidence of extrapulmonary disease received transplants of either one or two cadaveric lungs. At transplantation, all native lung tissue was removed and replaced with a donor lung or lungs. The patients received the usual post-transplantation care given at the institution. RESULTS: Four of the seven patients had recurrent bronchioloalveolar carcinoma within the donor lungs; the recurrences appeared from 10 to 48 months after transplantation. All recurrences were limited to the donor lungs. Histologic and molecular analyses showed that the recurrent tumors in three patients originated from the recipients of the transplants. CONCLUSIONS: Lung transplantation for bronchioloalveolar carcinoma is technically feasible, but recurrence of the original tumor within the donor lungs up to four years after transplantation was common.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1999

Antiperistaltic Roux-en-Y biliary-enteric bypass after bile duct injury: a technical error in reconstruction.

Bilioenteric reconstruction using a Roux limb of jejunum is a well-established surgical option for the reconstruction of the proximal bile duct. Previous studies discussing short- and long-term complications of biliary-enteric anastomosis have focused on technical aspects, such as the use of anastomotic stenting or the level of the biliary tree used. We report two cases of previously unreported complications after hepaticojejunostomy that resulted from a technical error in constructing the Roux limb. Within a 3-month period, two patients were referred to our institution with recurrent cholangitis after biliary reconstruction for injuries sustained during laparoscopic cholecystectomy. Reexploration disclosed major technical flaws in the construction of the Roux limb used for biliary drainage. Antiperistaltic limbs had been constructed in both patients: one from the distal ileum and one from the conventional location in the jejunum. In both cases, isoperistaltic reconstruction of the Roux limbs resolved the recurrent cholangitis. Cholangitis after biliary-enteric bypass can arise from a variety of etiologies and lead to anastomotic narrowing or ineffective drainage of the biliary tree. Review of the literature failed to disclose reports of technically flawed Roux limb construction as a cause of cholangitis. We present these cases to highlight the devastating consequences of antiperistaltic construction of the Roux limb. We hope that by publishing the role of this avoidable error in recurrent cholangitis after biliary-enteric bypass we may help prevent its future occurrence.

Adult↗
PubMed1998

A prospective algorithm for the management of air leaks after pulmonary resection.

BACKGROUND: Air leaks (ALs) are a common complication after pulmonary resection, yet there is no consensus on their management. METHODS: An algorithm for the management of chest tubes (CT) and ALs was applied prospectively to 101 consecutive patients who underwent elective pulmonary resection. Air leaks were graded daily as forced expiratory only, expiratory only, inspiratory only, or continuous. All CTs were kept on 20 cm of suction until postoperative day 2 and were then converted to water seal. On postoperative day 3, if both a pneumothorax and AL were present, the CT was placed to 10 cm H2O of suction. If a pneumothorax was present without an AL, the CT was returned to 20 cm H2O of suction. Air leaks that persisted after postoperative day 7 were treated with talc slurry. RESULTS: There were 101 patients (67 men); on postoperative day 1, 26 had ALs and all were expiratory only. Univariable analysis showed a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (p = 0.005), increased age (p = 0.007), increased ratio of residual volume to total lung capacity (RV/TLC) (p = 0.04), increased RV (p = 0.02), and an increased functional residual capacity (FRC) (p = 0.02) to predict the presence of an AL on postoperative day 1. By postoperative day 2, 22 patients had expiratory ALs. After 12 hours of water seal, 13 of the 22 patients' ALs had stopped, and 3 more sealed by the morning of postoperative day 3. However, 2 of the 6 patients whose ALs continued experienced a pneumothorax. Five of the 6 patients with ALs on postoperative day 4 still had ALs on postoperative day 7, and all were treated by talc slurry through the CT. All ALs resolved within 24 hours after talc slurry. CONCLUSIONS: Most ALs after pulmonary resection are expiratory only. A low FEV1/FVC ratio, increased age, increased RV/TLC ratio, increased RV, and an increased FRC were predictors of having an ALs on postoperative day 1. Conversion from suction to water seal is an effective way of sealing expiratory AL, and pneumothorax is rare. If an expiratory AL does not stop by postoperative day 4 it will probably persist until postoperative day 7, and talc slurry may be an effective treatment.

Adult↗
PubMed1997

Stiff-persons' syndrome associated with thymoma and subsequent myasthenia gravis.

We report the first case of stiff-persons' (-man) syndrome in the setting of a histologically proven thymoma. Muscular hyperactivity was abolished under general anesthesia and the symptoms of stiffness resolved after thymectomy and three courses of intravenous immunoglobulins. After thymectomy, the patient developed ocular myasthenia gravis which later resolved spontaneously. We suggest that thymoma be sought for in cases with neuromuscular hyperactivity syndromes. Myasthenia gravis may develop subsequently in these cases.

Electromyography↗
PubMed1996

Transmission of Mycobacterium tuberculosis to recipients of single lung transplants from the same donor.

Recipients of organ transplants are at increased risk for infection both because of immunosuppression and because of the transfer of microbes through the donor organs. We report two cases of M. tuberculosis disease in recipients of single lung transplants who shared a common donor. Both recipients developed pulmonary tuberculosis, one having fever and pulmonary infiltrates and the other having subclinical disease with M. tuberculosis organisms being recovered from bronchoalveolar lavage. Restriction fragment length polymorphism analysis on both isolates of M. tuberculosis revealed a common source. The donor of both lungs had a normal chest radiograph and no known prior history of M. tuberculosis infection of disease. These cases are the first report of two single lung recipients developing pulmonary tuberculosis from a common donor.

Adult↗
PubMed1995

Acute repair of aorta-innominate vein fistulas.

Penetrating wounds of the central vasculature are highly lethal. Ten cases of aorta-left innominate vein fistulas have been reported in the past, but most have presented late after injury. We report three successfully managed cases that had a short interval between injury and repair, and where we used cardiopulmonary bypass with total circulatory arrest. Preoperative arteriography facilitated planning the operative approach. The ready availability of complete radiologic and surgical resources at a trauma center were responsible for the successful outcome of these highly lethal central vascular injuries.

Adult↗
PubMed1993

Use of expanded polytetrafluoroethylene pericardial substitute with ventricular assist devices.

Expanded polytetrafluoroethylene membrane was used to reconstruct the pericardium after ventricular assist device insertion in 7 consecutive patients. One patient remains on support with the membrane in place and 6 have had the membrane removed. The expanded polytetrafluoroethylene membrane protected the device cannulas during repeat sternotomy and expedited the dissection of the heart and great vessels at the time of device removal. Reconstruction of the pericardium with expanded polytetrafluoroethylene membrane is recommended at the time of ventricular assist device insertion.

Foreign-Body Reaction↗
PubMed1992

Rejection after cardiac transplantation. A time-related risk factor analysis.

BACKGROUND: The determinants of early and repeated episodes of acute rejection after cardiac transplantation remain elusive. METHODS AND RESULTS: To gain insight into this phenomenon, a multivariate analysis for repeated events was applied to 229 patients receiving 249 transplanted hearts between 1981 and July 1, 1991 (595 rejection episodes). The mean frequency of rejection per patient after initial cardiac transplantation was 1.2 at 3 months, 1.8 at 1 year, and 2.8 at 5 years. The pattern of rejection was characterized by an early period of higher risk (greatest during the first month) followed by a low constant risk that continued throughout the period of follow-up (maximum, 9.5 years). By multivariate analysis, risk factors were identified for the likelihood of subsequent rejection after a previous rejection episode (or time of transplantation). Triple-drug immunosuppression plus induction therapy yielded a higher risk of early subsequent rejection compared with other baseline immunotherapy protocols, but it also provided the greatest freedom (95%) from rejection-related death during the first year. Risk factors in the constant phase of hazard included younger age at transplant, female donor and/or recipient, longer donor ischemic time, greater HLA donor-recipient mismatch, and an increased number of previous rejection episodes. CONCLUSIONS: Immunologic and other patient-specific characteristics as well as rejection history predict the likelihood of future rejection events. The value of any antirejection protocol must be evaluated both in terms of rejection episodes and rejection-related deaths. Future analyses may identify specific high- and low-risk patient subsets for rejection, which may provide a more rational basis for altering the amount of chronic immunosuppressive therapy.

Adult↗
PubMed1992

Surgical management of chronic pulmonary thromboembolic disease.

Chronic obstruction of the proximal pulmonary arteries appears to be a rare complication of pulmonary thromboembolus. The syndrome, however, may prove to be more common than previously suspected as general awareness of the syndrome increases prompted by the availability of efficacious therapy. Medical management has been ineffective in providing symptomatic or consistent hemodynamic improvement in patients with this syndrome, but a growing body of literature now suggests that surgical relief of obstruction can be undertaken with acceptable surgical risk and with the expectation of dramatic clinical improvement in a selected group of patients. Although no true control groups exist, one might hypothesize that hemodynamic and clinical improvement may translate into improved survival in these patients as well. The most recent series reported by Daily et al7 is the first to include more than 100 patients, and their reported hospital mortality of less than 13% is very encouraging. Whether these results will be reproducible at other centers remains to be seen. It is hoped that future investigation will refine both patient selection and operative technique such that results continue to improve. Pulmonary physicians should be aware of the syndrome and have a high index of suspicion in patients with unexplained pulmonary hypertension or right-sided heart failure. V/Q scans have proved to be useful screening procedures in these patients and can help identify patients at risk who require further more invasive investigation.

Adult↗