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Can we push the boundaries of ABO-incompatible pediatric heart transplantation?

Tue, 08/01/2017 - 21:53
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Can we push the boundaries of ABO-incompatible pediatric heart transplantation?

J Heart Lung Transplant. 2017 Jul 17;:

Authors: Simpson KE, Canter C

PMID: 28756122 [PubMed - as supplied by publisher]

Distal airway microbiome is associated with immunoregulatory myeloid cell responses in lung transplant recipients.

Tue, 08/01/2017 - 21:53
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Distal airway microbiome is associated with immunoregulatory myeloid cell responses in lung transplant recipients.

J Heart Lung Transplant. 2017 Jul 15;:

Authors: Sharma NS, Wille KM, Athira S, Zhi D, Hough KP, Diaz-Guzman E, Zhang K, Kumar R, Rangarajan S, Eipers P, Wang Y, Srivastava RK, Rodriguez Dager JV, Athar M, Morrow C, Hoopes CW, Chaplin DD, Thannickal VJ, Deshane JS

Abstract
BACKGROUND: Long-term survival of lung transplant recipients (LTRs) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). Recent evidence suggests a role for microbiome alterations in the occurrence of BOS, although the precise mechanisms are unclear. In this study we evaluated the relationship between the airway microbiome and distinct subsets of immunoregulatory myeloid-derived suppressor cells (MDSCs) in LTRs.
METHODS: Bronchoalveolar lavage (BAL) and simultaneous oral wash and nasal swab samples were collected from adult LTRs. Microbial genomic DNA was isolated, 16S rRNA genes amplified using V4 primers, and polymerase chain reaction (PCR) products sequenced and analyzed. BAL MDSC subsets were enumerated using flow cytometry.
RESULTS: The oral microbiome signature differs from that of the nasal, proximal and distal airway microbiomes, whereas the nasal microbiome is closer to the airway microbiome. Proximal and distal airway microbiome signatures of individual subjects are distinct. We identified phenotypic subsets of MDSCs in BAL, with a higher proportion of immunosuppressive MDSCs in the proximal airways, in contrast to a preponderance of pro-inflammatory MDSCs in distal airways. Relative abundance of distinct bacterial phyla in proximal and distal airways correlated with particular airway MDSCs. Expression of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP), an endoplasmic (ER) stress sensor, was increased in immunosuppressive MDSCs when compared with pro-inflammatory MDSCs.
CONCLUSIONS: The nasal microbiome closely resembles the microbiome of the proximal and distal airways in LTRs. The association of distinct microbial communities with airway MDSCs suggests a functional relationship between the local microbiome and MDSC phenotype, which may contribute to the pathogenesis of BOS.

PMID: 28756121 [PubMed - as supplied by publisher]

Comparison of two strategies for ex vivo lung perfusion.

Tue, 08/01/2017 - 21:53
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Comparison of two strategies for ex vivo lung perfusion.

J Heart Lung Transplant. 2017 Jul 08;:

Authors: Nilsson T, Gielis JF, Slama A, Hansson C, Wallinder A, Ricksten SE, Dellgren G

Abstract
BACKGROUND: Two clinically used strategies for ex vivo lung perfusion (EVLP) were compared in a porcine model with respect to lung function, metabolism, inflammatory response, oxidative stress, and cell viability.
METHODS: Porcine lungs (n = 20) were preserved, harvested, and kept cooled for 2 hours. After randomization, EVLP was performed using a cellular perfusate and open left atrium (COA group) or an acellular perfusate and a closed left atrium (ACA group). Oxygenation (partial pressure of arterial oxygen/fraction of inspired oxygen), compliance, dead space, weight, and perfusate oncotic pressure were registered before and after a 4-hour period of reconditioning. Lung tissue samples were collected before and after EVLP for quantitative polymerase chain reaction analysis of gene expression for inflammatory markers, measurement of tissue hypoxia (hypoxia inducible factor-1α) and oxidative stress (ascorbyl radical), and viability (trypan blue staining) and lung histopathology.
RESULTS: In 3 of 10 lungs undergoing EVLP in the ACA group, EVLP was terminated prematurely because of severe lung edema and inability to perfuse the lungs. There were no significant differences in changes of lung oxygenation or pulmonary vascular resistance between groups. Compliance decreased and lung weights increased in both groups, but more in the ACA group (p = 0.083 and p = 0.065, respectively). There was no obvious difference in gene expression for hypoxia inducible factor-1α, inflammatory markers, free radicals, or lung injury between groups.
CONCLUSIONS: Lung edema formation and decreased lung compliance occurs with both EVLP techniques but were more pronounced in the ACA group. Otherwise, there were no differences in lung function, inflammatory response, ischemia/reperfusion injury, or histopathologic changes between the EVLP techniques.

PMID: 28756120 [PubMed - as supplied by publisher]

What to do (or not to do) when randomization is not possible.

Tue, 08/01/2017 - 21:53
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What to do (or not to do) when randomization is not possible.

J Heart Lung Transplant. 2017 Jul 17;:

Authors: Naci H

PMID: 28756119 [PubMed - as supplied by publisher]

von Willebrand factor disruption and continuous-flow circulatory devices.

Tue, 08/01/2017 - 21:53
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von Willebrand factor disruption and continuous-flow circulatory devices.

J Heart Lung Transplant. 2017 Jun 12;:

Authors: Proudfoot AG, Davidson SJ, Strueber M

Abstract
Bleeding events remain a significant and frequent complication of continuous-flow left ventricular assist devices (VADs). von Willebrand factor (VWF) is critical to hemostasis by acting as a bridging molecule at sites of vascular injury for normal platelet adhesion as well as promoting platelet aggregation under conditions of high shear. Clinical and experimental data support a role for acquired von Willebrand disease in VAD bleeding episodes caused by shear-induced qualitative defects in VWF. Pathologic shear induces VWF unfolding and proteolysis of large multimers into smaller less hemostatic multimers via ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). This review outlines the pathobiology of VWF disruption in the context of VADs as well as current diagnostic and management strategies of the associated acquired von Willebrand disease.

PMID: 28756118 [PubMed - as supplied by publisher]

Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity.

Tue, 08/01/2017 - 21:53
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Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity.

Blood Rev. 2017 Jul 24;:

Authors: Boshuizen M, van der Ploeg K, von Bonsdorff L, Biemond BJ, Zeerleder SS, van Bruggen R, Juffermans NP

Abstract
As the main iron transporter, transferrin delivers iron to target tissues like the bone marrow for erythropoiesis. Also, by binding free iron, transferrin prevents formation of reactive oxygen species. Transferrin deficiency due to congenital hypotransferrinemia is characterized by anemia as well as oxidative stress related to toxic free iron. Transferrin supplementation may be beneficial in two ways. First, transferrin can correct anemia by modulating the amount of iron that is available for erythropoiesis. This is obvious for patients that suffer from hypotransferrinemia, but may also have beneficial effects for β-thalassemia patients. Second, under conditions of iron overload, transferrin reduces oxidative stress by binding free iron in the circulation and in tissues. Hereby, transferrin protects the host against the reactive oxygen species that can be formed as a consequence of free iron. This beneficial effect is shown in hematological patients undergoing chemotherapy and stem cell transplantation. Transferrin may also be beneficial in lung injury, ischemia-reperfusion injury and hypomyelination. This review summarizes the preclinical and clinical data on the efficacy of exogenous transferrin administration to modulate certain forms of anemia and to prevent the toxic effects of free iron. Thereby, we show that transferrin has promising therapeutic potential in a wide variety of conditions.

PMID: 28755795 [PubMed - as supplied by publisher]

Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model.

Tue, 08/01/2017 - 21:53
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Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model.

Am J Physiol Lung Cell Mol Physiol. 2017 Jul 01;313(1):L92-L103

Authors: Huleihel L, Sellares J, Cardenes N, Álvarez D, Faner R, Sakamoto K, Yu G, Kapetanaki MG, Kaminski N, Rojas M

Abstract
Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice at day 7 after bleomycin instillation, and the mice were euthanized at day 14 Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis.

PMID: 28385811 [PubMed - indexed for MEDLINE]

Extracellular superoxide dismutase increased the therapeutic potential of human mesenchymal stromal cells in radiation pulmonary fibrosis.

Tue, 08/01/2017 - 21:53
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Extracellular superoxide dismutase increased the therapeutic potential of human mesenchymal stromal cells in radiation pulmonary fibrosis.

Cytotherapy. 2017 May;19(5):586-602

Authors: Wei L, Zhang J, Yang ZL, You H

Abstract
BACKGROUND AIMS: Pulmonary fibrosis induced by irradiation is a significant problem of radiotherapy in cancer patients. Extracellular superoxide dismutase (SOD3) is found to be predominantly and highly expressed in the extracellular matrix of lung and plays a pivotal role against oxidative damage. Early administration of mesenchymal stromal cells (MSCs) has been demonstrated to reduce fibrosis of damaged lung. However, injection of MSCs at a later stage would be involved in fibrosis development. The present study aimed to determine whether injection of human umbilical cord-derived MSCs (UC-MSCs) over-expressing SOD3 at the established fibrosis stage would have beneficial effects in a mice model of radiation pulmonary fibrosis.
METHODS: Herein, pulmonary fibrosis in mice was induced using Cobalt-60 ((60)Co) irradiator with 20 Gy, followed by intravenous injection of UC-MSCs, transduced or not to express SOD3 at 2 h (early delivery) and 60 day (late delivery) post-irradiation, respectively.
RESULTS: Our results demonstrated that the early administration of UC-MSCs could attenuate the microscopic damage, reduce collagen deposition, inhibit (myo)fibroblast proliferation, reduce inflammatory cell infiltration, protect alveolar type II (AE2) cell injury, prevent oxidative stress and increase antioxidant status, and reduce pro-fibrotic cytokine level in serum. Furthermore, the early treatment with SOD3-infected UC-MSCs resulted in better improvement. However, we failed to observe the therapeutic effects of UC-MSCs, transduced to express SOD3, during established fibrosis.
CONCLUSION: Altogether, our results demonstrated that the early treatment with UC-MSCs alone significantly reduced radiation pulmonary fibrosis in mice through paracrine effects, with further improvement by administration of SOD3-infected UC-MSCs, suggesting that SOD3-infected UC-MSCs may be a potential cell-based gene therapy to treat clinical radiation pulmonary fibrosis.

PMID: 28314668 [PubMed - indexed for MEDLINE]

An Investigation of Topics and Trends of Tracheal Replacement Studies Using Co-Occurrence Analysis.

Tue, 08/01/2017 - 21:53
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An Investigation of Topics and Trends of Tracheal Replacement Studies Using Co-Occurrence Analysis.

Tissue Eng Part B Rev. 2017 Apr;23(2):118-127

Authors: Ghorbani F, Feizabadi M, Farzanegan R, Vaziri E, Samani S, Lajevardi S, Moradi L, Shadmehr MB

Abstract
This study evaluated tracheal regeneration studies using scientometric and co-occurrence analysis to identify the most important topics and assess their trends over time. To provide the adequate search options, PubMed, Scopus, and Web of Science (WOS) were used to cover various categories such as keywords, countries, organizations, and authors. Search results were obtained by employing Bibexcel. Co-occurrence analysis was applied to evaluate the publications. Finally, scientific maps, author's network, and country contributions were depicted using VOSviewer and NetDraw. Furthermore, the first 25 countries and 130 of the most productive authors were determined. Regarding the trend analysis, 10 co-occurrence terms out of highly frequent words were examined at 5-year intervals. Our findings indicated that the field of trachea regeneration has tested different approaches over the time. In total, 65 countries have contributed to scientific progress both in experimental and clinical fields. Special keywords such as tissue engineering and different types of stem cells have been increasingly used since 1995. Studies have addressed topics such as angiogenesis, decellularization methods, extracellular matrix, and mechanical properties since 2011. These findings will offer evidence-based information about the current status and trends of tracheal replacement research topics over time, as well as countries' contributions.

PMID: 27758155 [PubMed - indexed for MEDLINE]

Genetically modified mesenchymal stromal cells in cancer therapy.

Tue, 08/01/2017 - 21:53
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Genetically modified mesenchymal stromal cells in cancer therapy.

Cytotherapy. 2016 Nov;18(11):1435-1445

Authors: Sage EK, Thakrar RM, Janes SM

Abstract
The cell therapy industry has grown rapidly over the past 3 decades, and multiple clinical trials have been performed to date covering a wide range of diseases. The most frequently used cell is mesenchymal stromal cells (MSCs), which have been used largely for their anti-inflammatory actions and in situations of tissue repair and although they have demonstrated a good safety profile, their therapeutic efficacy has been limited. In addition to these characteristics MSCs are being used for their homing and engraftment properties and have been genetically modified to enable targeted delivery of a variety of therapeutic agents in both malignant and nonmalignant conditions. This review discusses the science and technology behind genetically modified MSC therapy in malignant disease and how potential problems have been overcome to enable their use in two novel clinical trials in metastatic gastrointestinal and lung cancer.

PMID: 27745603 [PubMed - indexed for MEDLINE]

Preferentially Expressed Antigen of Melanoma Prevents Lung Cancer Metastasis.

Tue, 08/01/2017 - 21:53
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Preferentially Expressed Antigen of Melanoma Prevents Lung Cancer Metastasis.

PLoS One. 2016;11(7):e0149640

Authors: Huang Q, Wei H, Wu Z, Li L, Yao L, Sun Z, Li L, Lin Z, Xu W, Han S, Cao W, Xu Y, Song D, Yang X, Xiao J

Abstract
Lung cancer is the most common cause of cancer death worldwide. The poor survival rate is largely due to the extensive local invasion and metastasis. However, the mechanisms underlying the invasion and metastasis of lung cancer cells remain largely elusive. In this study, we examined the role of preferentially expressed antigen of melanoma (PRAME) in lung cancer metastasis. Our results show that PRAME is downregulated in lung adenocarcinoma and lung bone metastasis compared with normal human lung. Knockdown of PRAME decreases the expression of E-Cadherin and promotes the proliferation, invasion, and metastasis of lung cancer cells by regulating multiple critical genes, most of which are related to cell migration, including MMP1, CCL2, CTGF, and PLAU. Clinical data analysis reveals that the expression of MMP1 correlates with the clinical features and outcome of lung adenocarcinoma. Taken together, our data demonstrate that PRAME plays a role in preventing the invasion and metastasis of lung adenocarcinoma and novel diagnostic or therapeutic strategies can be developed by targeting PRAME.

PMID: 27391090 [PubMed - indexed for MEDLINE]

Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy.

Tue, 08/01/2017 - 21:53
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Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy.

Cytotherapy. 2016 Jul;18(7):860-9

Authors: Yuan Z, Lourenco Sda S, Sage EK, Kolluri KK, Lowdell MW, Janes SM

Abstract
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are being extensively researched for cell therapy and tissue engineering. We have engineered MSCs to express the pro-apoptotic protein tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and are currently preparing this genetically modified cell therapy for a phase 1/2a clinical trial in patients with metastatic lung cancer. To do this, we need to prepare a cryopreserved allogeneic MSCTRAIL cell bank for further expansion before patient delivery. The effects of cryopreservation on a genetically modified cell therapy product have not been clearly determined.
METHODS: We tested different concentrations of dimethyl sulfoxide (DMSO) added to the human serum albumin ZENALB 4.5 and measured post-thaw cell viability, proliferation ability and differentiation characteristics. In addition, we examined the homing ability, TRAIL expression and cancer cell-killing capacities of cryopreserved genetically modified MSCs compared with fresh, continually cultured cells.
RESULTS: We demonstrated that the post-thaw viability of MSCs in 5% DMSO (v/v) with 95% ZENALB 4.5 (v/v) is 85.7 ± 0.4%, which is comparable to that in conventional freezing media. We show that cryopreservation does not affect the long-term expression of TRAIL and that cryopreserved TRAIL-expressing MSCs exhibit similar levels of homing and, importantly, retain their potency in triggering cancer cell death.
CONCLUSIONS: This study shows that cryopreservation is unlikely to affect the therapeutic properties of MSCTRAIL and supports the generation of a cryopreserved master cell bank.

PMID: 27260207 [PubMed - indexed for MEDLINE]

Human HER2 overexpressing mouse breast cancer cell lines derived from MMTV.f.HuHER2 mice: characterization and use in a model of metastatic breast cancer.

Sun, 07/30/2017 - 12:45
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Human HER2 overexpressing mouse breast cancer cell lines derived from MMTV.f.HuHER2 mice: characterization and use in a model of metastatic breast cancer.

Oncotarget. 2017 Jul 10;:

Authors: Park S, Nedrow JR, Josefsson A, Sgouros G

Abstract
Preclinical evaluation of therapeutic agents against metastatic breast cancer require cell lines and animal models that recapitulate clinical metastatic breast cancer as much as possible. We have previously used cell lines derived from the neu-N transgenic model to investigate anti-neu targeting of metastatic breast cancer using an alpha-emitter labeled antibody reactive with the rat variant of HER2/neu expressed by the neu-N model. To investigate alpha-particle emitter targeting of metastatic breast cancer using clinically relevant, commercially available anti-HER2/neu antibodies, we have developed cell lines derived from primary tumors and lung metastases from HuHER2 transgenic mice. We extracted primary mammary gland tumors, isolated the epithelial breast cancer cells, and established seven different cell lines. We also established 2 different cell lines from spontaneous lung metastases and cell lines from a serial transplantation of tumor tissues in HuHER2 transgenic mice. HuHER2 protein was overexpressed in all of the established cell lines. The mRNA level of ER (estrogen receptor) and PR (progesterone receptor) was relatively low in the cell lines compared to normal mammary gland (MG). As EMT markers, the expression of E-Cadherin in the cell lines was downregulated while the expression of TWIST1 and Vimentin were upregulated, relative to MG. Furthermore, trastuzumab directly inhibited cellular viability. Biodistribution studies with 111In-DTPA-trastuzumab in HuHER2 cell tumor xenografts demonstrated specific targeting with a clinically relevant antibody. Collectively, these cell lines show all the hallmarks of highly aggressive, metastatic breast cancer and are being used to evaluate combination therapy with alpha-particle emitter labeled HER2/neu reactive antibodies.

PMID: 28754862 [PubMed - as supplied by publisher]

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis.

Sun, 07/30/2017 - 12:45
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Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis.

J Immunol. 2017 Jul 28;:

Authors: Li FJ, Surolia R, Li H, Wang Z, Kulkarni T, Liu G, de Andrade JA, Kass DJ, Thannickal VJ, Duncan SR, Antony VB

Abstract
Autoimmunity has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-β1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham (n = 102) and the University of Pittsburgh (U. Pitt., n = 70) than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function (i.e., forced expiratory volumes and diffusing capacities). Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels (University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006). These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.

PMID: 28754682 [PubMed - as supplied by publisher]

Consensus Report by PALISI and PBMTC Joint Working Committees, Supportive Care Guidelines for Management of VOD in Children and Adolescents Part 1: Focus on Investigations, Prophylaxis and Specific Treatment.

Sun, 07/30/2017 - 12:45
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Consensus Report by PALISI and PBMTC Joint Working Committees, Supportive Care Guidelines for Management of VOD in Children and Adolescents Part 1: Focus on Investigations, Prophylaxis and Specific Treatment.

Biol Blood Marrow Transplant. 2017 Jul 25;:

Authors: Bajwa RP, Mahadeo KM, Taragin BH, Dvorak CC, McArthur J, Jeyapalan A, Duncan CN, Tamburro R, Gehred A, Lehman L, Richardson P, Auletta JJ, Woolfrey AE

Abstract
Veno occlusive disease (VOD) is a common and potentially fatal complication in children undergoing hematopoietic cell transplantation (HCT). It occurs in about a third of all patients undergoing transplant and is fatal in 50% of patients with severe disease. Early intervention and specific treatment with defibrotide is associated with improved outcomes. However, there is lack of supportive care guidelines for management of the multi-organ dysfunction seen in most cases. There is high variability in the management of VOD which may contribute to the increased morbidity and mortality. While there is ample research in the specific treatment of VOD, there is paucity of literature regarding the management of ascites, transfusions requirements, fluids and electrolyte dysfunction, delirium and investigations in children with VOD. The joint working committees of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and the Pediatric Blood and Marrow transplantation Consortium (PBMTC) collaborated to develop a series of evidence-based, supportive care guidelines for management of VOD. The quality of evidence was rated and recommendations made using the GRADE criteria. This manuscript is part 1 of the series and focuses on the need to develop these guidelines, methodology used to establish the guidelines, and investigations needed for diagnosis, prophylaxis, and treatment of VOD in children.

PMID: 28754544 [PubMed - as supplied by publisher]

Lung transplant outpatient clinic at Centro Hospitalar São João - 10 year review.

Sun, 07/30/2017 - 12:45
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Lung transplant outpatient clinic at Centro Hospitalar São João - 10 year review.

Rev Port Pneumol (2006). 2017 Jul 25;:

Authors: Araújo D, Damas C

PMID: 28754529 [PubMed - as supplied by publisher]

Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

Sun, 07/30/2017 - 12:45
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Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

J Heart Lung Transplant. 2017 Jul 04;:

Authors: Magnussen C, Bernhardt AM, Ojeda FM, Wagner FM, Gummert J, de By TMMH, Krabatsch T, Mohacsi P, Rybczynski M, Knappe D, Sill B, Deuse T, Blankenberg S, Schnabel RB, Reichenspurner H

Abstract
BACKGROUND: Despite the increasing use of ventricular assist devices (VADs), gender differences in indications, hemodynamics, and outcome are not well understood. We examined gender differences and gender-specific predictors for perioperative outcome in patients on ventricular support.
METHODS: Multicenter data of 966 patients (median age 55 years, 151 women) from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) were analyzed. Median follow-up was 1.26 years.
RESULTS: At the time of VAD implantation, women were more often in an unstable condition (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1 and 2) (51.7% vs 41.6% in men), experiencing significantly more often major bleeding (p = 0.0012), arrhythmias (p = 0.022), and right ventricular (RV) failure (p < 0.001) with need for additional RV support. The survival of women on isolated LVAD support was significantly worse (1-year survival 75.5% vs 83.2% in men). Age-adjusted Cox regression analyses showed significant associations with mortality for preoperative inotropic therapy, percutaneous mechanical support, INTERMACS profile 1 and 2, RV dysfunction, major bleeding, cerebral bleeding, ischemic stroke, and RV failure. In women, pump thrombosis was more strongly related with mortality compared to men, while the direction of the association of renal dysfunction with mortality was different for women and men (p-value interaction 0.028 and 0.023, respectively).
CONCLUSIONS: Women and men differ in perioperative hemodynamics, adverse events, and mortality after VAD implantation. A gender-dependent association of pump thrombosis with mortality was seen. The impact on treatment practice needs to be shown.

PMID: 28754423 [PubMed - as supplied by publisher]

Mechanical versus humoral determinants of brain death-induced lung injury.

Sat, 07/29/2017 - 12:45
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Mechanical versus humoral determinants of brain death-induced lung injury.

PLoS One. 2017;12(7):e0181899

Authors: Belhaj A, Dewachter L, Rorive S, Remmelink M, Weynand B, Melot C, Hupkens E, Dewachter C, Creteur J, Mc Entee K, Naeije R, Rondelet B

Abstract
BACKGROUND: The mechanisms of brain death (BD)-induced lung injury remain incompletely understood, as uncertainties persist about time-course and relative importance of mechanical and humoral perturbations.
METHODS: Brain death was induced by slow intracranial blood infusion in anesthetized pigs after randomization to placebo (n = 11) or to methylprednisolone (n = 8) to inhibit the expression of pro-inflammatory mediators. Pulmonary artery pressure (PAP), wedged PAP (PAWP), pulmonary vascular resistance (PVR) and effective pulmonary capillary pressure (PCP) were measured 1 and 5 hours after Cushing reflex. Lung tissue was sampled to determine gene expressions of cytokines and oxidative stress molecules, and pathologically score lung injury.
RESULTS: Intracranial hypertension caused a transient increase in blood pressure followed, after brain death was diagnosed, by persistent increases in PAP, PCP and the venous component of PVR, while PAWP did not change. Arterial PO2/fraction of inspired O2 (PaO2/FiO2) decreased. Brain death was associated with an accumulation of neutrophils and an increased apoptotic rate in lung tissue together with increased pro-inflammatory interleukin (IL)-6/IL-10 ratio and increased heme oxygenase(HO)-1 and hypoxia inducible factor(HIF)-1 alpha expression. Blood expressions of IL-6 and IL-1β were also increased. Methylprednisolone pre-treatment was associated with a blunting of increased PCP and PVR venous component, which returned to baseline 5 hours after BD, and partially corrected lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score.
CONCLUSIONS: Brain death-induced lung injury may be best explained by an initial excessive increase in pulmonary capillary pressure with increased pulmonary venous resistance, and was associated with lung activation of inflammatory apoptotic processes which were partially prevented by methylprednisolone.

PMID: 28753621 [PubMed - in process]

A novel moonlight function of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for immunomodulation.

Sat, 07/29/2017 - 12:45
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A novel moonlight function of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for immunomodulation.

Biofactors. 2017 Jul 28;:

Authors: Nakano T, Goto S, Takaoka Y, Tseng HP, Fujimura T, Kawamoto S, Ono K, Chen CL

Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an energy metabolism-related enzyme, which generates NADH in glycolysis. Our previous study revealed a novel role of exogenous GAPDH in the amelioration of lipopolysaccharide (LPS)-induced sepsis-related, severe acute lung injury (ALI) in mice. Here, we show the effect of extracellular GAPDH on the physiological functions of macrophages, which play an important role in the onset of sepsis and ALI. GAPDH has no effect on cell viability, while it strongly suppressed cell adhesion, spreading, and phagocytic function of LPS-stimulated macrophages. GAPDH treatment significantly reduced tumor necrosis factor (TNF)-α, while it induced interleukin (IL)-10 production from LPS-stimulated macrophages in a dose-dependent manner. It is noteworthy that heat inactivation of GAPDH lost its immunomodulatory activity. Correspondingly, NADH significantly inhibited TNF-α and enhanced IL-10 production with elevation of both M1/M2 macrophage markers. These data suggest that extracellular GAPDH induces intermediate M1/M2 macrophages for termination of inflammation, partly through its enzyme activity for generation of NADH. © 2017 BioFactors, 2017.

PMID: 28753256 [PubMed - as supplied by publisher]

Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study.

Sat, 07/29/2017 - 12:45
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Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study.

Pharmacoepidemiol Drug Saf. 2017 Jul 28;:

Authors: Kitamura N, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Takada T, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Arai T, Sugimoto C, Hattori N, Watanabe K, Tamada T, Akazawa K, Tanaka T, Nakata K

Abstract
PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial.
METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses.
RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study.
CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

PMID: 28752672 [PubMed - as supplied by publisher]

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