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Background: USO1 vesicle transport factor (USO1) is a vesicular transport factor crucial for endoplasmic reticulum (ER) to Golgi transport and is required for transcytotic fusion and subsequent binding of the vesicles to the target membrane. USO1 has been studied in multiple cancers revealing high levels of expression and exerting its oncogenic role by increasing cell proliferation and evasion of apoptosis. Furthermore, multiple studies have implicated dysregulation of the Erk signalling pathway in the involvement of USO1 in multiple cancers. Overall survival (OS) in non-small cell lung cancer (NSCLC) remains low despite recent advances in treatments which are mainly due to the late stage of diagnosis and a significant cohort of patients lacking an available targeted therapy. The aim of this study was to investigate USO1 expression in NSCLC., Methods: An in-house NSCLC tissue microarray (TMA) comprising (n=204 patients) was stained for USO1. Scoring intensity (H score) was used to interrogate for correlations between USO1 expression and established prognostic factors, and OS. Further evaluation of the expression of USO1 in NSCLC was done using multiple online datasets including Lung Cancer Explorer (LCE), UALCAN, GEPIA, KM plotter, TIMER2 and MuTarget., Results: USO1, when highly expressed in lung adenocarcinomas (LUADs) leads to a significantly increased OS (P=0.028). There was no significant correlation between age, smoking status, lymph node status, tumour subgroup and stage. USO1 was significantly higher in patients with tumour size <5 cm compared to those ≥5 cm (P=0.016). Overexpression in LUAD occurred at an early stage being significantly upregulated in Stage 1 and N0 tumours. USO1's first neighbours, also involved in ER-Golgi transport have altered expression in LUAD and significantly impact overall survival. Overexpression occurred independently of commonly mutated genes in NSCLC and had no correlation with changes in the TME., Conclusions: This study highlights the importance of USO1 and ER-Golgi vesicular transport system in LUAD. USO1 overexpression occurs as an early event in LUAD and independently of commonly mutated genes in NSCLC and therefore may represent an attractive diagnostic biomarker as well as a potential target for treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-230/coif). AMB reports an unremunerated leadership role as the current President of Lung Cancer Europe (LuCE), and an honorarium from Roche (Ireland) for presentation at educational events. SC declares that costs for registration/travel to educational conference have been covered by funding from Merck Sharp & Dohme, Bristol Myers Squibb and Pfizer. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Mediastinal paragangliomas are rare tumors that have only been reported in individual cases or limited case series. Surgical resection of these tumors can be challenging, as they are highly vascular and intimately related to the great vessels. Surgery is usually performed via median sternotomy with or without cardiopulmonary bypass. We present the case of a mediastinal paraganglioma that was resected via a left-sided posterolateral thoracotomy. Histopathology revealed a completely resected 38-mm paraganglioma with a positive station 5 lymph node, indicative of locally aggressive disease. Hereditary paragangliomas are associated with malignant transformation; therefore, genetic testing is important. These tumors do not respond well to chemoradiotherapy, and consequently lifelong surveillance for early detection of recurrence is recommended.

Reproduction is linked to a plethora of costs in gravid females, not least of which is a reduction in locomotor performance. Locomotor constraints due to gravidity are apparent across aquatic, terrestrial, and arboreal habitats. Decrements to speed and maneuverability are the most often cited performance consequences of gravidity, regardless of habitat. Arboreal habitats present additional challenges, as they often are composed of unstable and varying substrates that affect locomotor performance. Many arboreal taxa exhibit morphological adaptations, such as grasping extremities and tails, that function to aid in stability during locomotion. Tail length has been found to correlate with lifestyle: arboreal mammals tend to have relatively longer tails compared with terrestrial counterparts. Balancing on a limb is hard on its own, but when combined with increased mass and shifts in center of mass due to pregnancy, it becomes even more challenging. However, few studies have explored the constraints that govern the intersection of arboreal locomotion, reproductive cost, and morphology. In this review, we identify fruitful areas for expansion of research and knowledge (i.e., the role of the tail) when it comes to arboreal balance during gestation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Thoracic surgical oncology is a time-sensitive, high-resource, complex surgical speciality to which coronavirus has posed a unique challenge. In response to the evolving situation in mainland Europe, our department rapidly established a coronavirus disease 2019-free site to maintain elective cancer surgery. This necessitated a strict admission pathway and perioperative patient management. It resulted in the maintenance of a high-volume, high-quality thoracic surgical oncology program with no coronavirus disease 2019-positive cases to date. Maintaining satisfactory training levels among surgical and anesthetic trainees has also been achieved. We suggest that this model could be adapted to local resource capabilities., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Specialization for a new habitat often entails a cost to performance in the ancestral habitat. Although aquatic lifestyles are ancestral among extant cryptodiran turtles, multiple lineages, including tortoises (Testudinidae) and emydid box turtles (genus Terrapene), independently specialized for terrestrial habitats. To what extent is swimming function retained in such lineages despite terrestrial specialization? Because tortoises diverged from other turtles over 50 Ma, but box turtles did so only 5 Ma, we hypothesized that swimming kinematics for box turtles would more closely resemble those of aquatic relatives than those of tortoises. To test this prediction, we compared high-speed video of swimming Russian tortoises (Testudo horsfieldii), box turtles (Terrapene carolina) and two semi-aquatic emydid species: sliders (Trachemys scripta) and painted turtles (Chrysemys picta). We identified different kinematic patterns between limbs. In the forelimb, box turtle strokes most resemble those of tortoises; for the hindlimb, box turtles are more similar to semi-aquatic species. Such patterns indicate functional convergence of the forelimb of terrestrial species, whereas the box turtle hindlimb exhibits greater retention of ancestral swimming motions., (© 2017 The Author(s).)

Though ultimately descended from terrestrial amniotes, turtles have deep roots as an aquatic lineage and are quite diverse in the extent of their aquatic specializations. Many taxa can be viewed as "on the fence" between aquatic and terrestrial realms, whereas others have independently hyperspecialized and moved "all in" to aquatic habitats. Such differences in specialization are reflected strongly in the locomotor system. We have conducted several studies to evaluate the performance consequences of such variation in design, as well as the mechanisms through which specialization for aquatic locomotion is facilitated in turtles. One path to aquatic hyperspecialization has involved the evolutionary transformation of the forelimbs from rowing, tubular limbs with distal paddles into flapping, flattened flippers, as in sea turtles. Prior to the advent of any hydrodynamic advantages, the evolution of such flippers may have been enabled by a reduction in twisting loads on proximal limb bones that accompanied swimming in rowing ancestors, facilitating a shift from tubular to flattened limbs. Moreover, the control of flapping movements appears related primarily to shifts in the activity of a single forelimb muscle, the deltoid. Despite some performance advantages, flapping may entail a locomotor cost in terms of decreased locomotor stability. However, other morphological specializations among rowing species may enhance swimming stability. For example, among highly aquatic pleurodiran turtles, fusion of the pelvis to the shell appears to dramatically reduce motions of the pelvis compared to freshwater cryptodiran species. This could contribute to advantageous increases in aquatic stability among predominantly aquatic pleurodires. Thus, even within the potential constraints of a body plan in which the body is encased by a shell, turtles exhibit diverse locomotor capacities that have enabled diversification into a wide range of aquatic habitats., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Members of several terrestrial vertebrate lineages have returned to nearly exclusive use of aquatic habitats. These transitions were often accompanied by changes in skeletal morphology, such as flattening of limb bone shafts. Such morphological changes might be correlated with the exposure of limb bones to altered loading. Though the environmental forces acting on the skeleton differ substantially between water and land, no empirical data exist to quantify the impact of such differences on the skeleton, either in terms of load magnitude or regime. To test how locomotor loads change between water and land, we compared in vivo strains from femora of turtles (Trachemys scripta) during swimming and terrestrial walking. As expected, strain magnitudes were much lower (by 67.9%) during swimming than during walking. However, the loading regime of the femur also changed between environments: torsional strains are high during walking, but torsion is largely eliminated during swimming. Changes in loading regime between environments may have enabled evolutionary shifts to hydrodynamically advantageous flattened limb bones in highly aquatic species. Although circular cross sections are optimal for resisting torsional loads, the removal of torsion would reduce the advantage of tubular shapes, facilitating the evolution of flattened limbs., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Background: The prognostic significance of vascular and lymphatic invasion in non-small-cell lung cancer is under continuous debate. We analyzed the effect of tumor aggressiveness (lymphatic and/or vessel invasion) on survival and relapse in stage I and II non-small-cell lung cancer., Methods: We retrospectively analyzed prospectively collected data of 457 patients with stage I and II non-small-cell lung cancer from 1998 to 2008. Specimens were analyzed for intratumoral vascular invasion and lymphovascular space invasion. Overall survival and disease-free survival were estimated using the Kaplan-Meier method, and differences were determined by the logrank test. Cox regression analysis was performed to identify independent risk factors., Results: The incidence of intratumoral vascular invasion was 23.4%, and this correlated significantly with grade of differentiation, visceral pleural involvement, lymphovascular space invasion, and N status. The incidence of lymphovascular space invasion was 5.5%, and this correlated significantly with grade of differentiation, lymph nodes involved, and intratumoral vascular invasion. On multivariate analyses, intratumoral vascular invasion proved to be an significant independent risk factor for overall survival but not for disease-free survival. Lymphovascular space invasion was associated significantly with early tumor recurrence but not with overall survival., Conclusions: Vascular and lymphatic invasion can serve as independent prognostic factors in completely resected non-small-cell lung cancer. Intratumoral vascular invasion and lymphovascular space invasion in early stage non-small-cell lung cancer are important factors in overall survival and early tumor recurrence. Further large scale studies with more recent patient cohorts and refined histological techniques are warranted.

Background: Few patients diagnosed with lung cancer are still alive 5 years after diagnosis. The aim of the current study was to conduct a 10-year review of a consecutive series of patients undergoing curative-intent surgical resection at the largest tertiary referral centre to identify prognostic factors., Methods: Case records of all patients operated on for lung cancer between 1998 and 2008 were reviewed. The clinical features and outcomes of all patients with non-small cell lung cancer (NSCLC) stage I-IV were recorded., Results: A total of 654 patients underwent surgical resection with curative intent during the study period. Median overall survival for the entire cohort was 37 months. The median age at operation was 66 years, with males accounting for 62.7 %. Squamous cell type was the most common histological subtype, and lobectomies were performed in 76.5 % of surgical resections. Pneumonectomy rates decreased significantly in the latter half of the study (25 vs. 16.3 %), while sub-anatomical resection more than doubled (2 vs. 5 %) (p < 0.005). Clinico-pathological characteristics associated with improved survival by univariate analysis include younger age, female sex, smaller tumour size, smoking status, lobectomy, lower T and N status and less advanced pathological stage. Age, gender, smoking status and tumour size, as well as T and N descriptors have emerged as independent prognostic factors by multivariate analysis., Conclusion: We identified several factors that predicted outcome for NSCLC patients undergoing curative-intent surgical resection. Survival rates in our series are comparable to those reported from other thoracic surgery centres.

Habitats vary in temperature both spatially and temporally. Variation in thermal habitat introduces challenges to organisms and may reduce fitness unless organisms can physiologically adjust to such changes. Theory predicts that thermal variability should influence the capacity for acclimation such that increased variation should favor a reduction in the thermal sensitivity of physiological traits. In this study, we investigated acclimation to constant and variable conditions in populations of the salamander Desmognathus brimleyorum from the Ouachita Mountains of Arkansas, USA. We exposed salamanders to constant and variable temperature regimes for 8 weeks in the laboratory. We then tested salamanders for acclimation of thermal tolerance, and the thermal sensitivities of swimming performance and standard metabolic rate. Our results indicate limited capacity for thermal acclimation to constant and variable conditions in D. brimleyorum. Instead, variation in physiological traits is dominated by differences among populations. Population differences do not appear to be correlated with observed variation in the thermal conditions of the streams, but are likely a consequence of structural and ecological differences. Due to the mixed support for theoretical predictions for acclimation to alternative environments, further consideration should be given to revising and expanding current theoretical models.

Although melanoma of the right atrium is a rare cardiac tumor, melanoma in general has a high propensity to involve the heart. Unfortunately, however, when the tumor is involving the heart, widespread metastasis ensues and hence surgery becomes a questionable option. We report a case of a young female who presented with an advanced skin primary melanoma and regional lymph node involvement and a metastasis into the right atrium. Postoperatively tumor dissemination was controlled with adjuvant chemotherapy. A vigorous attempt aiming at tumor clearance followed by adjuvant multimodality therapy along with a tumor surveillance program may improve survival even in advanced cases.

Introduction: The female gender has been shown as high-risk factor for mortality and morbidity. We sought to assess the influence of female gender on coronary artery bypass graft (CABG) surgery from our own experience., Methods: This is a retrospective analysis of prospectively collected database from a single centre. Patients were grouped according to gender and potential differences in pre-operative, intra-operative and post-operative factors were explored. Significant high-risk factors were then fitted in a multivariate model to account for differences in predicting gender influence on surgical outcomes., Results: Two thousand eight hundred and four consecutive patients underwent isolated first-time CABG between February 2000 and December 2008; 562 (20%) patients were females. Pre-operatively, females were more likely to have significant comorbidities (age, congestive cardiac failure, hypercholesterolemia, hypertension, ischemic heart disease, peripheral vascular disease, pre-op arrhythmias, small body surface area and poor ejection fraction (p < 0.001)) consistent with higher Euroscore (p > 0.0001) and more urgent surgery (p < 0.002). Intra-operatively, they showed less extent pattern of disease requiring less bypass and cross-clamp time (p < 0.001). Observed surgical mortality was significantly higher in females (3.6 vs. 2.1%, p < 0.042); however, after adjusting for propensity score and significant factors identified in multivariate models, females only independently predicted a higher wound infection, lower neurological complications, lower rate of re-sternotomy, longer hospital stay and post-surgery stay (p < 0.01)., Conclusions: Despite higher risk profile and higher observed surgical mortality, early outcomes in females were similar to their matched males' counterpart in isolated CABG surgery. Females were associated with higher incidence of wound infections but lower rate of neurological complications.

Purpose: We looked at the complications and hospital resources of an elderly population undergoing first-time isolated coronary artery bypass graft surgery (CABG) in comparison to a younger counterpart for a propensity matched cohort., Methods: A retrospective analysis of prospectively collected data was conducted on 2804 CABG patients. Two age groups, >75 years and ≤75 years, were generated. Potential differences in demographic, baseline, preoperative, and intraoperative characteristics were investigated. A propensity score based on these differences was calculated and used to create a matched set of patients. Major postoperative complications were recorded, and data on indicators of resource utilization were collected., Results: In all, 311 (11.1%) patients were identified as >75 years of age. The observed complication rate was significantly higher in overall, pulmonary, cardiac, renal, gastrointestinal (GI), neurological, infective, and mortality categories (P < 0.0001). Observed hospital resource utilization was significant in the elderly group in terms of initial stay in the intensive care unit (ICU) and ICU readmission (P < 0.05) and in all preoperative, postoperative, cardiac surgery, and total hospital stays (P < 0.001). However, after propensity matching to 311 patients ≤75 years, the overall postoperative complication rate maintained its significance (P < 0.0001), in addition to atrial fibrillation and neurological, renal, and GI complications (P < 0.05). Elderly patients required longer duration of ventilation postoperatively and longer postoperative stay, cardiac surgery stay, and total hospital stay; and they maintained a higher surgical mortality rate (6.1% vs. 2.6%) (P < 0.05)., Conclusion: Elderly patients undergoing CABG had significantly higher rates of postoperative complications. Their prolonged hospital stay and consequently higher resources utilization need to be adequately highlighted to heath care officials and appropriately addressed.

Background: This study investigated the hypothesis that storage age of transfused red blood cells (RBCs) is associated with adverse outcome after cardiac surgery, and examined association between volume of RBC transfusions and outcome after cardiac surgery., Methods: Adult patients undergoing first time elective/urgent cardiac surgery who had received RBC transfusion perioperatively were included. Three prospective institutional databases were linked. Patients were grouped according to the oldest storage age of any RBCs transfused: those who received only RBCs stored for ≤14 days, only RBCs stored for >14 days, and a mixture of both ages of blood. The effect of RBC age on early mortality, postoperative ventilation ≥72 h, renal failure, pulmonary and infectious complications, length of intensive care stay, and postoperative ventilation time was examined using regression analyses with adjustment for confounding factors, including number of units transfused., Results: Data were analysed on 1153 patients who received a total of 5962 RBC units. There was no difference in adjusted odds of any outcome between the ≤14 days group and the group who received RBCs aged >14 days. Multivariate logistic regression analyses disclosed number of RBC units transfused as the most consistent factor associated with major postoperative complications, P<0.0001 in all cases. A trend of increasing complication rate was observed with more units transfused., Conclusions: Storage age of RBC transfusion up to 35 days was not associated with increased postoperative adverse outcome after cardiac surgery. The number of RBC units transfused is consistently associated with adverse outcome.

Objectives: Preoperative methicillin-resistant Staphylococcus aureus (MRSA) carriage is associated with higher rates of postoperative MRSA infection. Carriage can be eradicated but this requires delaying surgery, which presents a dilemma when the surgery is urgent. We analysed the incidence of preoperative MRSA carriage and the impact on postoperative outcomes in a cardiac surgery population., Patients and Methods: Patient data were collected prospectively from 2000 to 2007 (n=3789). MRSA screening is performed at a preadmission clinic for elective patients and on admission to the hospital for all patients. Three groups of MRSA carriers were identified: patients who were identified as carriers at a preadmission clinic (n=22, group 1), patients whose admission screening was positive but where the result was received postoperatively (n=103, group 2) and patients who acquired an MRSA infection or colonisation more than 48 h after admission (n=60, group 3)., Results: MRSA eradication measures prior to admission were successful in 21 of 22 in group 1 (95.4%). There were no MRSA infections in group 1. However, in group 2 there were 11 patients with an MRSA infection (10%) even though eradication measures were started on confirmation of carriage. In group 3, 19 of the 60 patients had an MRSA infection. The intensive care stay and mortality were significantly greater in groups 2 and 3 than in group 1 or compared with the overall patient population. However, groups 2 and 3 also had a significantly higher risk profile (European System for Cardiac Operative Risk Evaluation (EuroSCORE)). When matched with similar risk patients, patients in groups 2 and 3 had mortality outcomes that were consistent with matched risk patients., Conclusion: Patients who were MRSA carriers were older, more likely to have been on haemodialysis and to have been admitted from another hospital and underwent more complex surgical procedures. Carriage of MRSA was associated with a very high rate of MRSA infection, particularly among patients with diabetes. This suggests that delaying surgery may be warranted in patients expected to require implantation of prosthetic material such as valves, especially with diabetes. However, the survival outcomes for MRSA carriers are determined by their EuroSCORE rather than their MRSA status. This suggests that urgent cardiac surgery should not be delayed in patients with MRSA carriage., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

We describe the case of a 58 year old woman who presented with bronchial atypical carcinoid found at surgery to invade the left atrium along the pulmonary veins. A right pneumonectomy and removal of a portion of the left atrium was performed. The patient made an excellent post operative recovery. Three years later she presented in acute respiratory failure secondary to local recurrence. This is first case described in which recurrence after resection of bronchial carcinoid metastatic to the heart is described.

Background and Objectives: Patient anger because of a long wait is a common occurrence, but few studies have looked at how the anger should be addressed. This study determined patient levels of satisfaction, rating of importance, and preference for a variety of approaches for addressing anger being directed toward a physician., Methods: A video trigger tape of an angry patient and 12 physician responses to the angry patient were shown to 130 participants who then rated the physician responses based on four approaches, alone or in combination (apology, explanation, self disclosure, and acknowledgment) for satisfaction and importance of the response. Participants also evaluated four physician follow-up questions., Results: An apology combined with an explanation was rated highest in satisfaction and importance and individually ranked as the best approaches for physicians to use. "I apologize for your long wait" was rated significantly higher than "I am sorry you have been kept waiting." Although gender and prior high anger with clinicians affected the ratings of some responses, participants consistently preferred an apology and/or an apology combined with explanation as the best response. Participants also preferred physician follow-up questions that facilitated segue to the medical interview rather than questions that explored patient feelings., Conclusions: Participants clearly indicated that they would like a physician to apologize, explain the reason for the delay, and then quickly move along with the interview.

Acute traumatic transection of the thoracic aorta is most commonly seen in vehicular trauma and is generally accepted to be due to differential deceleration. A second mechanism is proposed for this injury and that is the osseous pinch mechanism. We report a case where aortic transection occurred due to a crush injury and supports the latter mechanism.

Isolated pig hearts, subsequently perfused with pig or human blood, were prepared for the cytochemical demonstration of sites of hydrogen peroxide generation and increased vascular permeability. Oxidant stress was associated with ultrastructural changes commonly seen following myocardial reperfusion. In addition, the precipitation of cerium perhydroxide following perfusion with physiological saline containing cerium chloride suggested the vascular endothelium and leukocytes as sources of oxidants. This was associated with rapid penetration of horseradish peroxidase through the intercellular clefts of the vascular endothelium into the interstitial space, suggesting increased vascular leakiness at these sites. The rapid penetration of horseradish peroxidase was observed at all monitored periods of reperfusion with pig or human blood. This indicates that the increased permeability occurred during the ischaemic period and continued during reperfusion. Morphological damage was greatest in pig hearts reperfused with whole human blood and this was attenuated if the blood was preabsorbed to remove antibodies prior to reperfusion. We conclude that oxidant stress was initiated during ischaemia and continued during reperfusion in this model.

Background: Increasing interest has focused on xenotransplantation as a potential solution to the organ shortage. To overcome hyperacute rejection, pigs have been produced that are transgenic for human decay accelerating factor (DAF). For the evaluation of the effects of human DAF, an ex vivo working heart model was used., Methods: We compared hemodynamic performance of four transgenic pig hearts (group A) with that of four Landrace pig hearts (group B) and eight rhesus monkey hearts (group C). For perfusion fresh blood had been taken from healthy volunteers. From the coronary sinus effluent, samples were taken for the determination of 6-keto prostaglandin F1 alpha, prostaglandin E2, creatine phosphokinase, and lactate dehydrogenase, respectively. Hemodynamic parameters were measured continuously for 150 minutes after the start. After 15 minutes of reperfusion, the Langendorff-mode was switched to the working heart model. After hearts failed to pump against the afterload column, experiments were terminated, and tissue sections were taken for electron microscopy., Results: Groups A and C showed superior cardiac performance as measured by stroke work index (SWI) that exceeded group B by 2.5 to 3 times (p < 0.05). In all three groups the SWI slowly decreased during perfusion. In group B, SWI decreased to a minimum as early as 90 minutes after the start. In all groups, 6-keto prostaglandin F1 alpha and prostaglandin E2 as indicators of endothelial cell activation increased. In group B, however, the levels exceeded those of groups A and C by six and nine times, respectively (p < 0.05). As markers of myocardial damage, creatine phosphokinase and lactate dehydrogenase increased in all groups. But again levels in group B exceeded those of groups A and C by four to five times (p < 0.05). Electron microscopy revealed single cell necrosis in group B, whereas groups A and C showed interstitial edema only., Conclusions: Our experiments indicate a crucial role of DAF in preventing rejection in discordant species combinations. Transgenic human DAF seems to inhibit successfully complement-mediated damage to the endothelial cell, thus preventing endothelial activation and consequently myocardial damage. Transgenic human DAF makes a discordant species (pig) function as a concordant species, that is, hyperacute rejection does not occur.

Background: The physiology of hyperacute rejection of pig lung by human blood and the role of antispecies antibody and complement in this phenomenon have not previously been characterized., Methods: Human blood was perfused through an ex vivo pig heart-lung preparation. In the treatment groups, blood was either unmodified or modified to deplete alternative pathway complement (heat treatment), anti-pig antibody, or both. Control experiments were performed with unmodified and heat-treated pig blood. Physiologic parameters, organ survival, and immunohistology were the primary outcome measures assessed., Results: Pig lung was consistently damaged by human blood within 45 min (median 20 min), as evidenced by elevated pulmonary vascular resistance and parenchymal injury. Immunohistologic studies of perfused lungs showed prominent deposition of IgM and classical pathway component, C4, and weaker deposition of alternative pathway component, properdin. Heat treatment did not impede the rise in pulmonary vascular resistance or significantly prolong survival. Depletion of anti-pig antibody prolonged survival (median 90 min) and attenuated the rise in pulmonary vascular resistance. Antibody absorption, combined with heat treatment of plasma, prevented the elevation in pulmonary vascular resistance and yielded median graft survival (210 min) similar to pig blood perfusion (approximately 240 min)., Conclusions: These results show that elevated pulmonary vascular resistance and pulmonary parenchymal injury are mediated at least in part by antispecies antibody and heat-sensitive pathways. They are consistent with the hypothesis that complement activation contributes significantly to acute lung damage in the pig-to-human species combination.

Background: Hyperacute rejection currently prevents clinical application of discordant lung xenografts. Pigs transgenic for human regulators of complement activation offer one promising potential solution to this problem., Methods: Using fresh human blood in an ex vivo lung perfusion model, we studied eight different strains of pigs transgenic for human decay accelerating factor. Survival (by blood flow and gas transfer criteria) were correlated with immunohistologic evidence of pulmonary human decay accelerating factor expression and complement activation., Results: With human blood perfusion, blood flow through the unmodified pig lung rapidly falls and is not restored by continuous infusion or high-dose bolus of prostacyclin. Airway pressure also rises rapidly and is followed promptly by loss of gas transfer. Four of the transgenic pig strains showed no difference from this pattern. Immunohistochemistry for human decay accelerating factor revealed low or no pulmonary expression in these lungs. In contrast, two of five transgenic pig lungs that had significant decay accelerating factor expression demonstrated recovery of pulmonary blood flow within 1 hour, and rejection was delayed, from less than 20 minutes in controls to about 1 hour. Complement activation, particularly the alternative pathway, was inhibited in lungs with high levels of endothelial decay accelerating factor expression., Conclusions: Lungs from some strains of pig transgenic for human decay accelerating factor demonstrate incomplete physiologic and histologic protection from hyperacute rejection. Although complement-independent pathogenic mechanisms may present a formidable obstacle, pig lungs transgenic for human complement regulatory proteins may facilitate discordant lung transplantation in human beings.

As a potential source of organs for xenotransplantation, pigs that are transgenic for human decay accelerating factor (DAF) have been bred in order to overcome hyperacute rejection. We investigated the protective effect of human DAF in a porcine working heart model perfused by human blood. Hearts of normal landrace pits served as controls. The following parameters were measured: stroke work index, coronary flow and arteriovenous oxygen consumption, 6-keto prostaglandin F1alpha and prostaglandin E2 as markers of endothelial cell activation; creatine phosphokinase and lactate dehydrogenase for evaluation of the extent of myocardial damage; TNFalpha and IL-6 as markers of mononuclear cell activation. Histological and ultrastructural investigations from myocardial tissue sections were done at the end of perfusion. Human (h) DAF appeared to inhibit complement-mediated endothelial cell activation of transgenic pig hearts successfully. This was in contrast to landrace pig hearts, which had a sixfold increase of prostaglandin levels during perfusion with human blood. The cardiac weight increase during perfusion time due to interstitial edema tended to be less in the hDAF group. Myocardial damage was minimal in transgenic hearts, whereas normal pig hearts produced a threefold increase of creatine phosphokinase and lactate dehydrogenase levels. In these hearts, electron microscopy revealed single cell necrosis of myocytes and vacuolization of mitochondria with cristae rupture. According to the results obtained in the working heart model, the breeding of pigs that are transgenic for hDAF represents a promising step to making heart xenotransplantation a clinical reality in the future.

Prominent components of vascularized xenograft rejection such as platelet activation and microvascular thrombosis may be dependent upon thrombin generation in vivo. To study potential therapeutic benefits of a synthetic low-molecular-weight thrombin inhibitor, SDZ MTH 958, in hyperacute porcine heart rejection by human blood ex vivo, a working model of hyperacute rejection of porcine by fresh, heparinized (6 microM/ml) human blood with or without 1 microM SDZ MTH 958 was used. Thrombin-antithrombin complexes (TAT) and prothrombin fragment F1.2 levels as markers of thrombin activation were determined, and biopsies from rejected hearts were analyzed by immunohistopathology. Control porcine hearts (n=8) underwent a rapid and consistent decline in cardiac output, ceasing function by 60 min. Experimental cardiac output values of 14 ml/g (SEM 1.2) were significantly higher than seen in controls (5 ml/g SEM 0.6) after 5 min of cardiac work, and prolonged survival times up to 120 min were noted (P<0.05). Activity of SDZ MTH 958 was confirmed by functional assays throughout perfusion. Levels of TAT and F1.2 increased consistently in control samples when compared with plasma samples containing SDZ MTH 958. Immunohistopathological examination confirmed diminished fibrin deposition, reduced leukocyte adherence to endothelium, impaired diapedesis and less tissue necrosis in the hearts perfused with SDZ MTH 958. SDZ MTH 958, in this xenoperfusion model, prolonged survival, enhanced function of the explanted organ, and improved histological features at the time of rejection. Effective and specific antagonism of thrombin may be useful as an adjunct therapy to complement inhibition for xenograft rejection

Extracorporal pig liver perfusion could bridge the deadly problem of acute human liver failure. However, preformed natural antibodies and complement activation (CA) are the predominant mechanisms of hyperacute xenogeneic rejection. The blockade of both pathways of CA in the xenograft, using transgenic livers expressing human decay accelerating factor on the endothelial surface results in prolonged graft survival and lower release of mediators.

Ex vivo perfusions of human decay accelerating factor-expressing transgenic (n = 3), and nontransgenic (n = 6) porcine livers with human blood revealed a higher degree of organ damage in non-transgenic pig livers. Transgenic livers were protected from immunohistologically detectable complement deposition, despite corresponding IgM and IgG deposits in both groups. Complement activation and consumption of C3 and C4 turned out to be lower in transgenic pig livers. In contrast to livers of normal landrace pigs, livers from genetically manipulated pigs showed no morphological alterations after perfusion.

Fifty-one patients in whom a clinical diagnosis of acute appendicitis had been made underwent peritoneal aspiration cytology (PAC). Thirty-six had a positive result, 11 had a negative result and aspiration failed in four cases. All patients had an appendicectomy and the histological findings were correlated with the PAC results. Thirty-five of the 36 patients with a positive PAC had histologically proven appendicitis. Seven of the 11 patients with a negative result had normal appendices. The sensitivity of PAC for acute appendicitis was 85% and the specificity was 70%. The positive predictive value was found to be 97% and the negative predictive value 60%. Peritoneal aspiration cytology is a useful aid in the diagnosis of acute appendicitis however, a negative result does not exclude this diagnosis.

A new method of detecting occult glove punctures was devised to determine its frequency during cardiac operations. Glove puncture is of relevance to the transmission of infectious diseases and the potential contamination of implanted cardiac prostheses. A study was therefore carried out in 48 adult patients undergoing open heart operations in which gloves worn by surgeons and nurses were collected and evaluated at the end of each procedure. In 22 of these cases, gloves were changed at three different stages of the cardiac operation for the principal operators: stage I, skin incision to commencement of cardiopulmonary bypass; stage II, cardiopulmonary bypass to sternotomy closure; and stage III, sternotomy closure to skin closure. One hundred sixty-two gloves (31.5%) had one or more punctures out of a total of 514 gloves tested. Only 20 glove punctures were recognized either at the time or at the end of the operation. There were 185 occult glove punctures. The majority (60%) of punctures were on the nondominant hand, with 30% of perforations located in the nondominant index finger. Using the chi 2 test with two degrees of freedom, there is no significant difference between the glove perforation rates for the principal operators in stages I, II, and III. The most important finding from this study was that 61% of gloves worn by scrub nurses had one or more punctures compared with 23.6% of surgeons.

Invasive pulmonary aspergillosis is a specific form of pulmonary Aspergillus infection that occurs almost exclusively in immunocompromised patients. It differs both histologically and in its clinical course from classic aspergillomas. During a 5-year period (1986-1990), 8 patients underwent resection for cavitating invasive pulmonary aspergillosis that developed as a consequence of neutropenia during chemotherapy for malignancy. There were no perioperative deaths and no complications. This contrasts with reports of operation for classic aspergillomas. Histologic examination of the resected specimens showed that cavitating invasive pulmonary aspergillosis differed from classic aspergillomas. They consisted of necrotic lung tissue invaded by fungus with separation from the surrounding lung so that the sequestrum had the appearance of a fungus ball. Pulmonary aspergillosis is a common complication of profound neutropenia. The first hemoptysis in this group of patients is often life-threatening. The excellent results of operation in our series of patients may be attributed to their young age, good pulmonary function, and limited operation. This has lead us to recommend early surgical intervention in invasive aspergillosis once cavitation develops.

1. The fluorescence spectra of the alga Porphyridium have been recorded as energy distribution curves for eleven different incident wave lengths of monochromatic incident light between wave lengths 405 and 546 mmicro. 2. In these spectra chlorophyll fluorescence predominates when the incident light is in the blue part of the spectrum which is strongly absorbed by chlorophyll. 3. For blue-green and green light the spectrum excited in Porphyridium contains in addition to chlorophyll fluorescence, the fluorescence bands characteristic of phycoerythrin and of phycocyanin. 4. From these spectra the approximate curves for the fluorescence of the individual pigments phycoerythrin, phycocyanin, and chlorophyll in the living material have been derived and the relative intensity of each of them has been obtained for each of the eleven incident wave lengths. 5. The effectiveness spectrum for the excitation of the fluorescence of these three pigments in vivo has been plotted. 6. From comparisons of the effectiveness spectrum for the excitation of each of these pigments it appears that both phycocyanin and chlorophyll receive energy from light which is absorbed by phycoerythrin. 7. It is suggested that phycocyanin may be an intermediate in the resonance transfer of energy from phycoerythrin to chlorophyll. 8. Since phycoerythrin and phycocyanin transfer energy to chlorophyll, it appears probable that chlorophyll plays a specific chemical role in photosynthesis in addition to acting as a light absorber.