Protein Signatures of Remodeled Airways in Transplanted Lungs with Bronchiolitis Obliterans Syndrome Obtained Using Laser-Capture Microdissection.

Bronchiolitis obliterans syndrome, a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histologic correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, which ultimately lead to organ failure. The molecular composition of these lesions is unknown. In this sutdy, the protein composition of the lesions in explanted lungs from four end-stage bronchiolitis obliterans syndrome patients was analyzed using laser-capture microdissection and optimized sample preparation protocols for mass spectrometry. Immunohistochemistry and immunofluorescence were used to determine the spatial distribution of commonly identified proteins on the tissue level, and protein signatures for 14 obliterative bronchiolitis lesions were established. A set of 39 proteins, identified in >75% of lesions, included distinct structural proteins (collagen types IV and VI) and cellular components (actins, vimentin, and tryptase). Each respective lesion exhibited a unique composition of proteins (on average, n = 66 proteins), thereby mirroring the morphologic variation of the lesions. Antibody-based staining confirmed these mass spectrometry-based findings. The 14 analyzed obliterative bronchiolitis lesions showed variations in their protein content, but also common features. This study provides molecular and morphologic insights into the development of chronic rejection after lung transplantation. The protein patterns in the lesions were correlated to pathways of extracellular matrix organization, tissue development, and wound healing processes.

The utility of transbronchial lung biopsies to guide the treatment decision in patients with rheumatic inflammatory diseases: a retrospective cross-sectional study.

The role of transbronchial lung biopsies (TBB) in the diagnostic workup of systemic inflammatory rheumatic disease-associated interstitial lung disease (SIRD-ILD) is unclear and TBB is not generally recommended. The study objective was to examine the utility of TBB to guide treatment in a population of patients with SIRD-ILD. All patients from the Department of Rheumatology, Rigshospitalet, Denmark, who had TBB performed, from 2002 to 2016 were identified. Patient demographics as well as smoking status, previous lung disease, pulmonary function test, SIRD-diagnosis, imaging results and immunomodulatory therapy pre- and post-bronchoscopy were obtained. Histology findings were used to dichotomize patients into a high-inflammatory group or a low-inflammatory group. The high-inflammation group primarily consisted of non-specific interstitial pneumonia, organizing pneumonia, lymphocytic infiltrating pneumonia and granulomatous inflammation whereas the low inflammation group primarily consisted of histological findings of usual interstitial pneumonitis and biopsies describing fibrosis and/or sparse unspecific inflammation. Therapeutic consequence was defined as intensification of therapy. Differences in treatment intensification were calculated using a binominal logistic regression model. Ninety-six patients had TBB performed. Biopsies from 55 patients were categorized as high inflammatory and 41 as low inflammatory, respectively. In the high-inflammatory group, 38 (69%) had their therapy intensified compared to 6 (14%) in the low-inflammatory group (Odds ratio 8.0, 95% confidence limits 3.2-20.0, P < 0.001). No procedure-related complications were registered. TBB findings can guide treatment strategy in SIRD-ILD patients with suspected activity in the pulmonary disease. TBB appears safe and could be considered as part of the diagnostic workup.

A Truncated Galectin-3 Isolated from Skin Mucus of Atlantic Salmon Salmo salar Binds to and Modulates the Proteome of the Gram-Negative Bacteria Moritella viscosa.

The mucus of fish skin plays a vital role in innate immune defense. Some mucus proteins have the potential to incapacitate pathogens and/or inhibit their passage through the skin. In this study the aim was to isolate and characterize galectin(s), ß-galactosides binding proteins, present in skin mucus. A novel short form of galectin-3 was isolated from Atlantic salmon skin mucus by α-lactose agarose based affinity chromatography followed by Sephadex G-15 gel filtration. Mass spectrometric analysis showed that the isolated protein was the C-terminal half of galectin-3 (galectin-3C). Galectin-3C showed calcium independent and lactose inhabitable hemagglutination, and agglutinated the Gram-negative pathogenic bacteria Moritella viscosa. Galectin-3 mRNA was highly expressed in skin and gill, followed by muscle, hindgut, spleen, stomach, foregut, head kidney, and liver. Moritella viscosa incubated with galectin-3C had a modified proteome. Proteins with changed abundance included multidrug transporter and three ribosomal proteins L7/12, S2, and S13. Overall, this study shows the isolation and characterization of a novel galectin-3 short form involved in pathogen recognition and modulation, and hence in immune defense of Atlantic salmon.

Lung Ultrasound in the Assessment of Pulmonary Complications After Lung Transplantation.

INTRODUCTION: Lung ultrasound (LUS) has a high diagnostic accuracy for identifying frequent conditions in the post-operative phase after lung transplantation (LTx). This study aimed to investigate the feasibility and clinical ability of LUS to identify pulmonary complications such as pleural effusions and pneumonias in the early postoperative phase after LTx. METHODS: A prospective cohort study of lung transplant recipients who consecutively underwent single LTx (SLTx) or double LTx (DLTx) at the National Lung Transplantation Center in Denmark from May 1 to October 31, 2015 was conducted. LUS was performed at four time points corresponding to post-transplant day 3, and weeks 2, 6, and 12 (LUS #1-4) to detect and monitor variation in pathological LUS findings over time. Concurrent with LUS #4, a high-resolution computed tomography examination of the thorax (HRCT) was also performed. RESULTS: 14 patients (1 SLTx/13 DLTx, 7 (50 %) women, mean age: 50.4 years) who had undergone the four prespecified LUS examinations were included. Pleural effusion was the most common condition and most pronounced at post-LTx week 2. Findings consistent with pneumonia increased during week 2 and subsequently decreased. Corresponding to LUS #1, 2, 3, and 4, pleural effusion occurred in 85.7 %, 92.9 %, 85.7 %, and 78.6 %, and pneumonia in 21.4 %, 28.6 %, 14.3 %, and 14.3 %, respectively. HRCT findings at post-LTx week 12 were predominantly presented by unspecific ground glass opacities. CONCLUSION: In a post-LTx setting, LUS represents a clinical novelty as a feasible diagnostic and monitoring tool to identify pathological pulmonary complications in the early post-operative phase.

Lobar Quantification by Ventilation/Perfusion SPECT/CT in Patients with Severe Emphysema Undergoing Lung Volume Reduction with Endobronchial Valves.

BACKGROUND: Endoscopic lung volume reduction (ELVR) therapy using one-way valves is used to treat chronic obstructive pulmonary disease patients with severe heterogeneous emphysema. A successful treatment results in atelectasis of the treated pulmonary lobe with subsequent reduction of ventilation (V) and perfusion (Q). OBJECTIVE: We evaluated the effects of ELVR on the targeted lobe using a new 3-dimensional ventilation and perfusion (V/Q) single-photon emission computed tomography (SPECT)/computed tomography (CT) analysis, which allows for simultaneous semi-automatic lobar pulmonary quantification of volume, ventilation and perfusion, on the first consecutive patients treated with ELVR at Rigshospitalet, Denmark. V/Q planar scintigraphy and V/Q SPECT/CT and lung function measurements were performed before and 6 months after intervention. RESULTS: We included 24 subjects (60 years, range 46-74 years; 37.5% men) with a baseline FEV1 of 25% predicted and RV of 257% predicted. V/Q SPECT/CT-assessed volume of the targeted lobe decreased by a mean of -395 mL and a relative mean of -26.8%, whilst ventilation and perfusion decreased by a relative mean of -37.1 and -25.7%. There was a significant increase in the same parameters of the non-targeted lobe(s) on the ipsilateral side. None of these changes were found in the analysis of planar V/Q imaging. The total lung volume decreased on average by -420 mL. Six months after ELVR, FEV1 had increased by 22%. Significant correlations were found between changes in FEV1 and changes in the volume of the treated lobe (SPECT/CT). CONCLUSION: Semi-automatic SPECT/CT analysis can quantify volume, ventilation and perfusion changes in pulmonary lobes and may be used in the assessment of patient eligibility for ELVR, identifying target lobes, and evaluation of the regional effects of treatment.

Evaluation of the i-STAT (portable clinical analyser) for measuring haematological parameters in Atlantic cod (Gadus morhua) at different CO2 and temperature conditions.

Portable clinical analysers are gradually being involved in on-site assessment of haematic parameters in fish. The purpose of this study was to evaluate the i-STAT portable clinical analyser (i-STAT PCA) for accuracy and reliability of measuring blood pH, partial pressure of oxygen (pO2), haematocrit, haemoglobin, sodium, potassium and calcium in Atlantic cod (Gadus morhua). Haematological parameters detected with the i-STAT PCA were compared with conventional laboratory techniques (CLTs). Two types of disposable cartridges were used (CHEM8+ and CG4+) with the i-STAT PCA, and experiments were performed at two different temperature regimes (5 °C and 15 °C) and four different carbon dioxide (CO2) levels (0%, 0.1%, 0.5% and 1%). All blood parameters measured with the i-STAT PCA showed heterogeneous inaccuracy under the tested conditions, but the highest discrepancies were registered in blood pO2. The i-STAT PCA systematically overestimated the pO2 measurements. Our research suggests that i-STAT PCA is not an appropriate tool for pO2 measurements especially in coldwater fish species. The i-STAT PCA consistently underestimated the pH and haematocrit values especially at a lower temperature, although those parameters indicate significant high correlation at 15 °C. Furthermore, the analysed ions showed overestimation of sodium and underestimation of potassium and calcium.

Lung transplantation after allogeneic stem cell transplantation: a pan-European experience.

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p<0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation <2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3-23.8; p=0.001).Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

The Role of Galectins as Modulators of Metabolism and Inflammation.

Galectins are ß-galcotosid-binding lectins. The function of galectins varies with their tissue-specific and subcellular location, and their binding to carbohydrates makes them key players in several intra- and extracellular processes where they bind to glycosylated proteins and lipids. In humans, there are 12 identified galectins, some with tissue-specific distribution. Galectins are found inside cells and in the nucleus, cytosol, and organelles, as well as extracellularly. Galectin-1, -2, -3, -4, -7, -8, -9, and -12 can all induce T-cell apoptosis and modulate inflammation. In the context of metabolic control and loss of the same in, for example, diabetes, galectin-1, -2, -3, -9, and -12 are especially interesting. This review presents information on galectins relevant to the control of inflammation and metabolism and the potential to target galectins for therapeutic purposes.

Functional Aspects of Fish Mucosal Lectins-Interaction with Non-Self.

Mucosal surfaces are of key importance in protecting animals against external threats including pathogens. In the mucosal surfaces, host molecules interact with non-self to prevent infection and disease. Interestingly, both inhibition and stimulation of uptake hinder infection. In this review, the current knowledgebase on teleost mucosal lectins' ability to interact with non-self is summarised with a focus on agglutination, growth inhibition, opsonisation, cell adhesion, and direct killing activities. Further research on lectins is essential, both to understand the immune system of fishes, since they rely more on the innate immune system than mammals, and also to explore these molecules' antibiotic and antiparasitic activities against veterinary and human pathogens.

Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study.

Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40-80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus 1.13 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.In patients with COPD, erdosteine can reduce both the rate and duration of exacerbations. The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.

An association of particulate air pollution and traffic exposure with mortality after lung transplantation in Europe.

Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500 m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.

Long-term persistence of human donor alveolar macrophages in lung transplant recipients.

BACKGROUND: Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce. METHODS: To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100 weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed. RESULTS: The number of donor-derived AMFs was unchanged during the 2 year post-transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period. CONCLUSIONS: The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-term persistence of donor AMFs may be important for the development of chronic graft rejection.

Pulmonary hypertension as a risk factor of mortality after lung transplantation.

PURPOSE: Pulmonary hypertension (PH) is recognized as a risk factor in lung transplantation as reflected in the lung allocation score (LAS). We examined the impact of PH on outcome after lung transplantation, with special emphasis on pre- and post-capillary PH. METHODS: Consecutive lung transplant recipients were evaluated according to ISHLT criteria including right heart catheterization in the period from 1992 to October 2014. Post-transplant survival was assessed according to hemodynamic characteristics: post-capillary PH (mean pulmonary arterial pressure [mPAP] ≥ 25 mmHg and pulmonary arterial wedge pressure [PAWP] > 15 mmHg), pre-capillary PH (mPAP ≥ 25 mmHg, PAWP ≤ 15 mmHg) and non-PH (mPAP < 25 mmHg). RESULTS: Of 518 transplant recipients, 58 (11%) had post-capillary PH. Pre-capillary PH was present in 211 (41%) and 249 (48%) non-PH. Post-capillary PH and pre-capillary PH were associated with worse 90-d outcomes after transplantation compared to non-PH (p = 0.043 and 0.003, respectively). The negative effect persisted 1 yr post-transplantation in pre-capillary PH (p = 0.037), but not in post-capillary PH (p = 0.447). Long-term survival was unaffected by hemodynamic classification. CONCLUSION: Post-capillary PH was present in 11% and pre-capillary PH in 41% of the transplant cohort. Post-capillary PH and pre-capillary PH were associated with inferior 90-d survival, but long-term survival was unaffected.

Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial.

The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)ml/min with everolimus versus -7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.

Salinity effects on plasma ion levels, cortisol, and osmolality in Chinook salmon following lethal sampling.

Studies on hydromineral balance in fishes frequently employ measurements of electrolytes following euthanasia. We tested the effects of fresh- or salt-water euthanasia baths of tricaine mesylate (MS-222) on plasma magnesium (Mg(2+)) and sodium (Na(+)) ions, cortisol and osmolality in fish exposed to saltwater challenges, and the ion and steroid hormone fluctuations over time following euthanasia in juvenile spring Chinook salmon (Oncorhynchus tshawytscha). Salinity of the euthanasia bath affected plasma Mg(2+) and Na(+) concentrations as well as osmolality, with higher concentrations in fish euthanized in saltwater. Time spent in the bath positively affected plasma Mg(2+) and osmolality, negatively affected cortisol, and had no effect on Na(+) concentrations. The difference of temporal trends in plasma Mg(2+) and Na(+) suggests that Mg(2+) may be more sensitive to physiological changes and responds more rapidly than Na(+). When electrolytes and cortisol are measured as endpoints after euthanasia, care needs to be taken relative to time after death and the salinity of the euthanasia bath.

The number of FoxP3+ cells in transbronchial lung allograft biopsies does not predict bronchiolitis obliterans syndrome within the first five years after transplantation.

BACKGROUND: An important limitation to the success of lung transplantation is the development of bronchiolitis obliterans syndrome (BOS). It has been hypothesized that regulatory T lymphocytes (Tregs) are related to the risk of BOS. We aim to evaluate whether the number of forkhead box P3 (FoxP3+) cells/mm(2) in lung allograft biopsies is a predictor of long-term outcome. MATERIALS AND METHODS: A total of 58 consecutive lung transplant patients were included in the study. For 233 routine surveillance biopsy samples, the numbers of FoxP3+ cells/mm(2) were assessed by immunohistochemical staining with antibodies against FoxP3. BOS scores were calculated for the first five yr after transplantation. RESULTS: We determined that acute rejection was related to the time elapsed from transplantation to BOS with hazard ratios of 3.18 (p = 0.02) and 3.73 (p = 0.04) when comparing the levels of acute rejection grade 1 and grade 2/3, respectively, to no rejection. According to a Cox regression analysis, the number of FoxP3+ cells/mm(2) was not predictive of time to BOS. DISCUSSION AND CONCLUSIONS: Our data indicate that the number of FoxP3+ cells in the lung allograft did not correlate with BOS-free survival time. Previous studies have been contradictory and included different time points. Our findings emphasize the importance of including a time factor.

T cell subsets in human airways prior to and following endobronchial administration of endotoxin.

BACKGROUND AND OBJECTIVES: Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to determine whether pro- and anti-inflammatory T cells are involved in the local immune response to lung inflammation. METHODS: Bronchoalveolar lavage (BAL) was performed in 15 healthy volunteers, after which Escherichia coli LPS (4 ng/kg) was administered. BAL was repeated at 2, 4, 6, 8 or 24 h after instillation of LPS. RESULTS: BALF CD4+ and CD8+ T cells were characterized by expression of activation markers (HLA-DR+CD38+), the proportion of cells expressing naïve markers (CD45RA+CD27+CCR7+) was lower, and that of cells expressing effector memory markers (CD45RA-CD27+CCR7-) was higher, compared with peripheral blood. Bronchial LPS induced a local inflammatory response with recruitment of CD4+ (P=0.014), CD8+ T cells (P=0.034), an increase in the proportion of CD4+CD25+CD127lowFoxp3+ regulatory T cells (Tregs) (P=0.045) and a tendency towards an increase in CD4+CD161+ cells (P=0.071) were observed. CONCLUSIONS: A unique distribution of T cells with little day-to-day variation was found in human airways. An increase in Tregs after endobronchial LPS suggests a role for Tregs during early stages of pulmonary inflammation.

Transcompartmental inflammatory responses in humans: IV versus endobronchial administration of endotoxin*.

OBJECTIVES: Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following lipopolysaccharide-induced pulmonary and systemic inflammation. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING ICU SUBJECTS: Healthy male volunteers. INTERVENTIONS: Fifteen volunteers (mean age, 23; SD, 2 yr) received Escherichia coli endotoxin (lipopolysaccharide, 4 ng/kg) IV or endobronchially on two different study days. Groups were evaluated by bronchoalveolar lavage at baseline (0 hr) and 2, 4, 6, 8, or 24 hours postchallenge. Cardiorespiratory variables were continuously recorded throughout the study day, and plasma and bronchoalveolar lavage fluid markers of inflammation were measured. MEASUREMENTS AND MAIN RESULTS: IV endotoxin elicited a systemic inflammatory response with a time-dependent increase and peak in tumor necrosis factor-α, interleukin-6, and leukocyte counts (all p < 0.001). Furthermore, a delayed (6-8 hr) increase in bronchoalveolar lavage fluid interleukin-6 concentration (p < 0.001) and alveolar leukocyte count (p = 0.03) and a minor increase in bronchoalveolar lavage fluid tumor necrosis factor-α were observed (p = 0.06). Endobronchial endotoxin was followed by progressive alveolar neutrocytosis and increased bronchoalveolar lavage fluid tumor necrosis factor-α, interleukin-6, and albumin (all p < 0.001); a systemic inflammatory response was observed after 2-4 hours, with no change in plasma tumor necrosis factor-α. CONCLUSIONS: Acute lung or systemic inflammation in humans is followed by a transcompartmental proinflammatory response, the degree and differential kinetics of which suggests that the propagation of inflammation may depend on the primary site of injury.

The effect of allostatic load on hypothalamic-pituitary-interrenal (HPI) axis before and after secondary vaccination in Atlantic salmon postsmolts (Salmo salar L.).

The experiment consisted of three experimental groups: (1) "vaccine and stress", (2) "stress and vaccine" and (3) control. All groups have previously been vaccinated 6 months prior to the start of the experiment. At the start of the experiment, the "vaccine and stress" group was vaccinated with Pentium Forte Plus for the second time (25.02.2008) and then given a daily stressor (confinement stressor 267 kg m-3 in 15 min) for a period of 4 weeks. The "stress and vaccine" group was given a similar daily stressor for 4 weeks and then vaccinated for the second time. The control group was neither stressed nor vaccinated a second time. The results indicates that fish in the "stress and vaccine" group may have entered an allostatic overload type 2 due to oversensitivity to ACTH, a reduced efficient negative feedback system with elevated baseline levels of plasma cortisol and reduced immune response with pronounced effects on the well-being of the animal. The "vaccine and stress" group may likewise have entered an allostatic overload type 1 response, with oversensitivity to ACTH and transient reduced efficient negative feedback system. This study shows that if plasma cortisol becomes elevated prior to vaccination, it could perhaps instigate an allostatic overload type 2 with dire consequences on animal welfare. To reduce the risk of compromising the animal welfare during commercial vaccination of salmon, one propose to grade the fish minimum a week prior to vaccination or grade simultaneously with vaccination. This could reduce the overall allostatic load during handling and vaccination and secure a healthy fish with intact immune response and improved animal welfare.

Antibody induction therapy for lung transplant recipients.

BACKGROUND: Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation. OBJECTIVES: We aimed to assess the benefits and harms of immunosuppressive T-cell antibody induction with ATG, ALG, IL-2RA, alemtuzumab, or muromonab-CD3 for lung transplant recipients. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 4 March 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared immunosuppressive monoclonal and polyclonal T-cell antibody induction for lung transplant recipients. An inclusion criterion was that all participants must have received the same maintenance immunosuppressive therapy within each study. DATA COLLECTION AND ANALYSIS: Three authors extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool and trial sequential analyses were undertaken to assess the risk of random errors (play of chance). MAIN RESULTS: Our review included six RCTs (representing a total of 278 adult lung transplant recipients) that assessed the use of T-cell antibody induction. Evaluation of the included studies found all to be at high risk of bias.We conducted comparisons of polyclonal or monoclonal T-cell antibody induction versus no induction (3 studies, 140 participants); polyclonal T-cell antibody versus no induction (3 studies, 125 participants); interleukin-2 receptor antagonists (IL-2RA) versus no induction (1 study, 25 participants); polyclonal T-cell antibody versus muromonab-CD3 (1 study, 64 participants); and polyclonal T-cell antibody versus IL-2RA (3 studies, 100 participants). Overall we found no significant differences among interventions in terms of mortality, acute rejection, adverse effects, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, post-transplantation lymphoproliferative disease, or cancer.We found a significant outcome difference in one study that compared antithymocyte globulin versus muromonab-CD3 relating to adverse events (25/34 (74%) versus 12/30 (40%); RR 1.84, 95% CI 1.13 to 2.98). This suggested that antithymocyte globulin increased occurrence of adverse events. However, trial sequential analysis found that the required information size had not been reached, and the cumulative Z-curve did not cross the trial sequential alpha-spending monitoring boundaries.None of the studies reported quality of life or kidney injury. Trial sequential analyses indicated that none of the meta-analyses achieved required information sizes and the cumulative Z-curves did not cross the trial sequential alpha-spending monitoring boundaries, nor reached the area of futility. AUTHORS' CONCLUSIONS: No clear benefits or harms associated with the use of T-cell antibody induction compared with no induction, or when different types of T-cell antibodies were compared were identified in this review. Few studies were identified that investigated use of antibodies against T-cells for induction after lung transplantation, and numbers of participants and outcomes were also limited. Assessment of the included studies found that all were at high risk of methodological bias.Further RCTs are needed to perform robust assessment of the benefits and harms of T-cell antibody induction for lung transplant recipients. Future studies should be designed and conducted according to methodologies to reduce risks of systematic error (bias) and random error (play of chance).