Plasmapheresis as therapeutic option in a 16-year-old with EVALI: A case report.

Since 2019 when a cluster of cases with acute respiratory distress syndrome (ARDS) associated with e-cigarettes in the United States was reported, there have been increasing numbers of reports. Electronic-cigarette or Vaping Use-associated Lung Injury (EVALI) represents a recent entity of respiratory clinical syndromes, primarily in young adults. We report a previously healthy 16-year-old boy who developed severe ARDS following a brief nonspecific prodromal phase after excessive consumption of e-cigarettes. Despite maximum intensive care therapy, including several weeks of venovenous extracorporeal membrane oxygenation, plasmapheresis and repeated administration of immunoglobulins seemed the only way to achieve therapeutic success. Although many case reports have been published, to our knowledge, there are none to date on the therapeutic use of plasmaphoresis in severe EVALI. This case highlights the clinical features of EVALI and the diagnostic dilemma that can arise with EVALI occurring against the background of an expired SARS-CoV-2 infection, with a paediatric inflammatory syndrome (PIMS) as differential diagnosis. EVALI is a diagnosis of exclusion, and the medical history of vaping and e-cigarette use can provide valuable clues. Ethical approval for this case report (protocol number 23-145 RS) was provided by the Ethical Committee of the Department of Medicine, Philipps-Universität Marburg, Germany on 13th of June 2023. Written informed consent to publish this case and the associated images was obtained from the patient and his mother.

Mantle cell lymphomas with concomitant MYC and CCND1 breakpoints are recurrently TdT positive and frequently show high-grade pathological and genetic features.

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia.

[Drug-induced interstitial lung diseases]. / Medikamentös induzierte interstitielle Lungenerkrankungen.

Pulmonary drug reactions are a relatively common factor causing interstitial pulmonary disease. Histological findings of pulmonary drug reactions can mimic other conditions such as various forms of idiopathic interstitial pneumonia such as nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, or usual interstitial pneumonia. The correct diagnosis is important since a causal therapy is possible by stopping the administration. A stringent correlation between dose/time of administration and the type of reaction exists for only a few drugs. An increased risk of drug side effects can arise from known reactions to that specific drug, the patient's history, the type of underlying disease, genetic polymorphisms, occupational factors, and interactions with other drugs. The identification of a pulmonary drug reaction is a difficult task that can often only be solved in an interdisciplinary manner, for which in rare cases a lung biopsy is necessary. Pathology then has to identify histomorphological reaction patterns to exclude other causes and correlate findings with clinical data. In most cases, however, the diagnosis of a drug reaction will be by exclusion.

Fatal course of clofazimine-induced pulmonary crystal deposition in a patient with Melkersson-Rosenthal syndrome.

A wide variety of drugs and substances have the potential to damage the respiratory system by different mechanisms. Clofazimine is an anti-leprosy drug that is normally only prescribed for a few years. It has a very long half-life, and crystalline deposition of the drug in various tissues has been documented. But up to now, no fatalities due to pulmonary damage have been described. We report the case of a patient who took clofazimine for almost 27 years as off-label treatment for Melkersson-Rosenthal syndrome. He suffered from progressive dyspnea, productive cough, and occasional hemoptysis. X-ray and CT of the thoracic organs revealed extensive multilocular, compact, tumor-like infiltrates with central necrosis in both lungs. Pulmonary function tests showed restrictive impairment and manifest hypoxemia. Histology of lung biopsies revealed intense interstitial accumulation of histiocytes and marked deposition of crystalline foreign material. The patient died from progressive respiratory failure. Autopsy revealed crystalline deposition and a histiocytic reaction in many other parenchymal organs. Conclusion: Pulmonary parenchymal deposition of drug crystals is a rare mechanism of drug-induced pulmonary diseases. Long-standing, off-label use of clofazimine may cause severe destruction of the lungs and can be fatal.

DICER1 mutation-positive giant botryoid fibroepithelial polyp of the urinary bladder mimicking embryonal rhabdomyosarcoma.

Fibroepithelial polyps of the urinary tract are rare lesions. They occur mainly in the upper urinary tract of children. A high disease prevalence has been reported in families with pleuropulmonary blastoma. Here we present a case of a 46-year-old woman who presented with a giant botryoid fibroepithelial polyp of the urinary bladder. Histologically, the lesion showed prominent botryoid features with an embryonal rhabdomyosarcoma-like cambium layer lacking nuclear or cellular atypia. Immunohistochemical analysis ruled out rhabdomyoblastic differentiation. Next-generation sequencing was performed on the polyp tissue and revealed two pathogenic mutations in the DICER1 ribonuclease III (DICER1) gene (c.[5439G>T]; p.[Glu1813Asp] and c.[1525C>T]; p.[Arg509*]). Truncating DICER1 mutations, accompanied by characteristic "hotspot" mutations affecting the RNase IIIB domain of DICER1 are typically seen in DICER1-related lesions. Our findings indicate a role of DICER1 mutations in the pathogenesis of fibroepithelial polyps of the urinary tract.

Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies.

BACKGROUND: Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. OBJECTIVE: To investigate the presence of HP in the lung tissue of IPF patients. METHODS: Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. RESULTS: A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. CONCLUSION: The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF.

Expression of porcine endogenous retroviruses (PERV) in different organs of a pig.

Porcine endogenous retroviruses (PERVs) represent a particular risk for xenotransplantation using pig cells, tissues or organs. PERVs are integrated in the genome of all pig strains and can be released as particles that infect human cells. We performed for the first time a systematic analysis of PERV expression in different organs of a miniature pig using in parallel quantitative real-time RT-PCR, Western blot analysis, and immunohistochemistry. All three types of PERV, PERV-A, PERV-B and PERV-C were present in the germ line of the animal. In addition, recombinant PERV-A/C were detected in some tissues, but not in the germ line. Expression of the viral full-length and spliced mRNA and proteins was found in many organs, but at different levels. A high expression was found in lymphoid organs.

Rescue therapy with a pumpless extracorporeal lung assist device in a patient with acute interstitial lung disease and severe refractory hypercapnia.

Idiopathic interstitial pneumonia frequently causes severe pulmonary restriction that in turn makes mechanical ventilation difficult. We report the case of a 44-year-old woman who developed a refractory severe hypercapnic respiratory failure (P(aCO(2)) 281 mm Hg, pH 6.77) despite mechanical ventilation with high inspiratory pressure and PEEP. A pumpless extracorporeal lung assist device, Novalung, was used as rescue therapy for carbon dioxide removal, enabling lung-protective ventilation and normalization of life-threatening acidosis. Open lung biopsy revealed an idiopathic interstitial pneumonia with histological features of a nonspecific interstitial pneumonia. Corticosteroid therapy led to progressive improvement of pulmonary function, soon permitting cessation of mechanical ventilation and extracorporeal therapy. The patient was discharged from the intensive care unit after 20 days. This case demonstrates the successful use of pumpless extracorporeal lung assist as an alternative device to pump-driven extracorporeal membrane oxygenation in severe hypercapnic respiratory failure secondary to nonspecific interstitial pneumonia.

Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death.

BACKGROUND: Donor organ shortage represents a major problem in lung transplantation. Donation after cardiac death could help to expand the pool of organs, but the additional period of warm ischemia after cardiac arrest aggravates primary graft dysfunction. The pulmonary endothelium of the graft constitutes an important source and target of reactive oxygen species generated during ischemia and reperfusion. Targeted protection of graft pulmonary endothelial cells by the antioxidant enzyme catalase, conjugated with a platelet/endothelial cell adhesion molecule-1 (PECAM-1) antibody to nanosized particles (anti-PECAM/catalase conjugates), might improve outcome in lung transplantation using donors after cardiac death and prolonged hypothermic preservation. METHODS: Left lung transplantation was performed in 18 pigs. Before cardiac arrest, donors received anti-PECAM/catalase, unconjugated component mixture or vehicle solution. After 90-min warm and 18-hr hypothermic ischemia, lungs were transplanted, and function was assessed during 6 hr after reperfusion. Samples of bronchoalveolar lavage fluid and lung tissue were taken thereafter. Six sham-operated animals served as controls. RESULTS: During 6-hr reperfusion, anti-PECAM/catalase significantly ameliorated graft function, evidenced by major improvements of gas exchange and reduced intrapulmonary shunt fraction. Furthermore, lipid peroxidation, alveolar leakage, and edema formation were reduced in protected grafts. Similarly moderate lung pathology was seen after transplantation. CONCLUSIONS: Augmentation of the antioxidant capacity of graft pulmonary endothelial cells with anti-PECAM/catalase nanoparticles represents a straightforward approach to enable a safe transplantation of prolonged preserved donation after cardiac death lungs. Anti-PECAM/catalase protection alleviated oxidative stress and allowed immediate reconstitution of normal gas exchange and pulmonary microcirculation, a prerequisite for improved graft and patient outcome.

Effect of inpatient rehabilitation on quality of life and exercise capacity in long-term lung transplant survivors: a prospective, randomized study.

BACKGROUND: The purpose of this study was to examine the effect of an inpatient rehabilitation program on health-related quality of life (HRQOL) and exercise capacity (EC) in long-term (>1 year after lung transplantation) survivors (LTSs) in comparison to a control group (CG). METHODS: Sixty LTSs, 4.5 ± 3.2 years after lung transplantation (LTx), were randomly assigned to two equally sized groups that were stratified for gender and underlying disease. Thirty LTSs (age 49 ± 13 years, 13 male and 17 females, 19 double LTxs, 7 BOS Stage ≥ 1) attended an inpatient rehabilitation program (intervention group, IG) for 23 ± 5 days. The CG (age 50 ± 12 years, 13 males and 17 females, 20 double LTxs, 2 BOS Stage ≥ 1) received medical standard therapy (physiotherapy). Patients were evaluated by cardiopulmonary exercise testing, 6-minute walk test (6MWT), SF-36, SGRQ and the Quality of Life Profile for Chronic Diseases questionnaire before and after (18 ± 3 days) the program. RESULTS: The groups were statistically indistinguishable in terms of clinical data. Each treatment group significantly improved their sub-maximal EC (6MWT: IG, 493 ± 90 m vs 538 ± 90 m, p < 0.001; CG, 490 ± 88 m vs 514 ± 89 m, p < 0.001) and maximal EC (VO(2peak): IG, 17.0 vs 18.5 ml/min/kg, p = 0.039; CG, 18.0 vs 19.5 ml/min/kg, p = 0.005), without reaching statistical significance between the groups. In both study groups, patients HRQOL tended to improve. Significant correlations were found between EC parameters and HRQOL scales. CONCLUSIONS: Our data suggest that structured physical training may improve exercise tolerance in LTS. Our study results did not demonstrate a significant benefit of an inpatient over an outpatient exercise program.

Expression of therapeutic proteins after delivery of chemically modified mRNA in mice.

Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days.

Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a frequent indication for lung transplantation (LTX) with pulmonary hypertension (PH) negatively affecting outcome. The optimal procedure type remains a debated topic. The aim of this study was to evaluate the impact of pretransplant PH in IPF patients. Single LTX (SLTX, n = 46) was the standard procedure type. Double LTX (DLTX, n = 30) was only performed in cases of relevant PH or additional suppurative lung disease. There was no significant difference for pretransplant clinical parameters. Preoperative mean pulmonary arterial pressure was significantly higher in DLTX recipients (22.7 +/- 0.8 mmHg vs. 35.9 +/- 1.8 mmHg, P < 0.001). After transplantation, 6-min-walk distance and BEST-FEV(1) were significantly higher for DLTX patients (6-MWD: 410 +/- 25 m vs. 498 +/- 23 m, P = 0.02; BEST-FEV(1): 71.2 +/- 3.0 (% pred) vs. 86.2 +/- 4.2 (% pred), P = 0.004). Double LTX recipients demonstrated a significantly better 1-year-, overall- and Bronchiolitis obliterans Syndrome (BOS)-free survival (P < 0.05). Cox regression analysis confirmed SLTX to be a significant predictor for death and BOS. Single LTX offers acceptable survival rates for IPF patients. Double LTX provides a significant benefit in selected recipients. Our data warrant further trials of SLTX versus DLTX stratifying for potential confounders including PH.

CpG-free plasmid DNA prevents deterioration of pulmonary function in mice.

Nonviral gene vectors have been shown to be therapeutically effective in various animal models of inherited and acquired lung diseases. Although an acute unmethylated CG dinucleotide (CpG)-mediated inflammatory response has been previously observed for first-generation plasmids, its effect on pulmonary function has not been investigated to date. Here, we present data on lung functional parameters together with histopathology, cellular and inflammatory events in response to pulmonary administration of DNA-containing particles. We show that aerosol delivery of polyethylenimine gene vectors containing a first-generation CpG-rich plasmid induced an inflammatory response which was associated with a decrease in lung compliance. In contrast to these observations, aerosol application of CpG-free plasmid DNA prevented immune response and impairment of pulmonary function. These results demonstrate that aerosol delivery of CpG-free plasmid DNA is critical to avoid alteration of pulmonary function. Therefore, we suggest to use CpG-free pDNA for gene delivery to the lungs in future.

Recipient treatment with L-arginine attenuates donor lung injury associated with hemorrhagic shock.

BACKGROUND: Organ donors are frequently trauma victims, but the impact of donor hemorrhagic shock and resuscitation (HSR) on pulmonary graft function has not been assessed. L-arginine treatment during reperfusion increases the production of endothelial nitric oxide and thus ameliorates ischemia-reperfusion injury. Objective of the present porcine study was to investigate the effect of donor hemorrhage on pulmonary graft function and potential beneficial effects of L-arginine administration. METHODS: In the control-group (n=6), lungs were harvested from donors without hypotensive periods. In the HSR-group (n=6) and HSR-Arg-group (n=6), donors were subjected to hemorrhagic shock (40% blood shed) and resuscitation before harvest. Left lungs were transplanted after hypothermic preservation of 18 hr, and graft function was observed for 6 hr after reperfusion. Recipients in the HSR-Arg-group received a bolus of L-arginine (50 mg/kg BW) intravenously 5 min before reperfusion followed by a continuous intravenous administration of L-arginine 200 mg/kg BW for 2 hr. Tissue specimens and bronchoalveolar lavage fluid were obtained at the end of the observation period. RESULTS: Donor lung function did not differ between study groups. Compared with the control group, pulmonary graft gas exchange was significantly impaired in the HSR-group. Graft function in the HSR-Arg-group did not differ from control organs. Neutrophil fraction, protein content, and malondialdehyde levels in the bronchoalveolar lavage fluid in the HSR-group were higher compared with control and HSR-Arg-Group. CONCLUSION: Although fulfilling ideal donor criteria, pulmonary graft function of lungs harvested from donors subjected to HSR is impaired, but improves significantly when l-arginine is administered during reperfusion.

Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients.

BACKGROUND: Bronchoalveolar lavage (BAL) neutrophilia may identify patients prone to develop bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). This study assessed the predictive value of BAL neutrophilia in stable recipients. METHODS: Evaluated were 63 consecutive recipients 3 to 12 months after LTx demonstrating no acute rejection (AR) and lymphocytic bronchitis (LB; B < or = 1 without infection; BOS, 0). Recipients were subdivided into never-BOS (follow-up > or = 12 months) and ever-BOS groups (i.e., BOS development > or = 1 after bronchoscopy). RESULTS: The groups were statistically indistinguishable for demographic data and preceding AR and LB episodes. Onset of BOS was at a median of 232 days (range, 87-962) after bronchoscopy. The ever-BOS group (16 patients) demonstrated a significantly higher percentage of neutrophils compared with the never-BOS group (47 patients) at the time of bronchoscopy (33.6% +/- 2.1% vs 9.9% +/- 1.1%, p < 0.05). By Cox regression analysis, a BAL neutrophil percentage of > or = 20% remained a significant predictor for BOS > or = 1 (hazard ratio, 3.57; 95% confidence interval, 1.71-8.40, p < 0.05) distinct from known potential BOS predictor variables. The positive and negative predictive value of BAL neutrophilia of > or = 20% for future BOS was 0.72 and 0.93, respectively (p < 0.05). CONCLUSION: BAL neutrophilia in stable recipients is of predictive value to identify recipients at risk for BOS. These data warrant prospective confirmation and further studies to evaluate the benefit of preemptive therapy for potential BOS patients.

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation.

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS > or = 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.

Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases.

Various inflammatory diseases are characterized by tissue infiltration of neutrophils. Chemokines recruit and activate leukocytes, but neutrophils are traditionally known to be restricted in their chemokine receptor (CR) expression repertoire. Neutrophils undergo phenotypic and functional changes under inflammatory conditions, but the mechanisms regulating CR expression of infiltrated neutrophils at sites of chronic inflammation are poorly defined. Here we show that infiltrated neutrophils from patients with chronic inflammatory lung diseases and rheumatoid arthritis highly express CR on their surface that are absent or only marginally expressed on circulating neutrophils, i.e., CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4, as measured by flow cytometry, immunohistochemistry, and confocal microscopy. The induction of CR surface expression on infiltrated neutrophils was functionally relevant, because receptor activation by chemokine ligands ex vivo modulated neutrophil effector functions such as respiratory burst activity and bacterial killing. In vitro studies with isolated neutrophils demonstrated that the surface expression of CR was differentially induced in a cytokine-mediated, protein synthesis-dependent manner (CCR1, CCR3), through Toll-like (CXCR3) or NOD2 (CCR5) receptor engagement, through neutrophil apoptosis (CCR5, CXCR4), and/or via mobilization of intracellular CD63(+) granules (CXCR3). CR activation on infiltrated neutrophils may represent a key mechanism by which the local inflammatory microenvironment fine-tunes neutrophil effector functions in situ. Since the up-regulation of CR was exclusively found on infiltrated neutrophils at inflammatory sites in situ, the targeting of these G protein-coupled receptors may have the potential to site-specifically target neutrophilic inflammation.

Soluble Galalpha(1,3)Gal conjugate combined with hDAF preserves morphology and improves function of cardiac xenografts.

BACKGROUND: Cytotoxic anti-Galalpha(1,3)Gal antibodies play a key role in the rejection of pig organs transplanted into primates. Regimens reducing anti-Galalpha(1,3)Gal antibodies were associated with severe side effects unable to prevent antibody rebound until soluble synthetic oligosaccharides with terminal Galalpha(1,3)Gal inhibiting antigen binding became available. We displayed kinetics of anti-pig and anti-Galalpha(1,3)Gal IgM and IgG antibody levels using GAS914, a Galalpha(1,3)Gal trisaccharide conjugated to poly-l-lysine, and investigated corresponding changes of parameters of heart function. METHODS: Using a working heart model, hDAF pig hearts were perfused with human blood containing GAS914 (group 1). As controls hDAF pig hearts (group 2) and landrace pig hearts (group 3) were perfused with human blood only. Levels of anti-Galalpha(1,3)Gal (IgM, IgG) and anti-pig antibodies were assessed to prove the effectiveness of GAS914. As parameters of heart function, cardiac output (CO), stroke work index (SWI), coronary blood flow (CBF) and coronary resistance were measured. Creatine phosphokinases, lactate dehydrogenase and aspartate aminotransferase were evaluated as markers of myocardial damage. Histological and immunohistochemical investigations were performed at the end of perfusion. RESULTS: In group 1 an immediate and extensive reduction in both IgM and IgG anti-Galalpha(1,3)Gal was found. Anti-pig antibodies were eliminated accordingly. Antibody binding to GAS914 was complete before the start of organ perfusion. Corresponding to rapid antibody elimination in group 1 GAS914 not only was able to significantly prolong the beating time of the heart in hDAF pigs, but also to clearly improve functional parameters. When switching to the working heart mode hDAF pig hearts perfused with human blood containing GAS914 (group 1) revealed a CO starting at a significantly higher level than hDAF (group 2) and non-transgenic pig hearts (group 3) perfused with human blood only. Similarly, in group 1 SWI was significantly increased at the beginning of perfusion compared to that of group 2 and group 3. The increase in CBF during perfusion and the corresponding fall of coronary resistance occurred without significant differences between the groups revealing the independence of hDAF and GAS914. CONCLUSIONS: Due to an immediate and profound reduction in Galalpha(1,3)Gal-specific antibodies, soluble Galalpha(1,3)Gal conjugates not only prolong survival, but also improve the hemodynamic performance of the heart in DAF pigs.

Reduced fibrin deposition and intravascular thrombosis in hDAF transgenic pig hearts perfused with tirofiban.

BACKGROUND: Solid organ xenograft rejection is associated with vascular injury resulting at least in part in platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis and interstitial hemorrhage. Complement activation plays a prominent role in platelet-endothelial interaction. We tested the effects of platelet GPIIb/IIIa inhibitor tirofiban during perfusion of hDAF pig hearts. METHODS: Using a working-heart model, nontransgenic and hDAF pig hearts were perfused with tirofiban or human blood only. Myocardial damage was determined by hemodynamic parameters (cardiac output, stroke work index) and creatine phosphokinase. Further monitoring included the assessment of complement factors (C3, C4), platelets, fibrinogen, ATIII, and graft histology. RESULTS: Tirofiban increased cardiac output (CO) and stroke work index (SWI) of nontransgenic pig hearts and improved superior CO and SWI of hDAF pig hearts. Although perfusion time of nontransgenic pig hearts was prolonged by tirofiban (196+/-65 min vs. 162+/-122 min), a similar effect in hDAF pig hearts (218+/-116 min vs. 222+/-30 min) could not be demonstrated. Tirofiban reduced consumption of C3 and C4 independently from hDAF. Depletion of fibrinogen was equally diminished by tirofiban and hDAF; the combination of both agents obtained no further reduction. ATIII consumption was most effectively inhibited by this combination. Intravascular fibrin deposition was reduced by tirofiban and hDAF, but particularly by the combination of the two agents. CONCLUSIONS: Improvement of heart performance and reduction of myocardial damage and intravascular thrombosis confirm a role of the GPIIb/IIIa inhibitor tirofiban for the prevention of hDAF pig heart rejection and xenograft function.

Targeted delivery of magnetic aerosol droplets to the lung.

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory infection and, more recently, lung cancer. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles--so-called nanomagnetosols--in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.