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Consecutive Sessions of Rescue Balloon Atrial Septostomy for an Idiopathic Pulmonary Arterial Hypertension Patient with Refractory Right Heart Failure - Usefulness of Intracardiac Echocardiography Guidance.

Thu, 06/01/2017 - 12:45
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Consecutive Sessions of Rescue Balloon Atrial Septostomy for an Idiopathic Pulmonary Arterial Hypertension Patient with Refractory Right Heart Failure - Usefulness of Intracardiac Echocardiography Guidance.

Acta Cardiol Sin. 2017 May;33(3):310-314

Authors: Chen YW, Pan HC, Wang KY, Liang KW

Abstract
For idiopathic pulmonary artery hypertension (PAH) patients with end-stage right heart failure who received maximal medical therapy, balloon atrial septostomy (BAS) is recommended by most guidelines as a palliative therapy or a bridging treatment before lung transplantation. In this report, we described a 32-year-old woman with idiopathic PAH, who received maximal PAH-specific medical treatment, including intravenous prostacyclin, but still suffered from refractory right heart failure. The markedly enlarged right atrium (RA), high mean RA pressure of 23 mmHg, low systemic arterial oxygen saturation of 86% and concomitant pancytopenia all increased the patient's risk for BAS. We used intracardiac echocardiography (ICE) guidance to facilitate trans-septal puncture, and performed graded BAS four times within 7 months to stabilize the patient. Our case showed that with dedicated PAH treatment, an experienced structural heart interventionist and ICE guidance, BAS could be done safely even in a patient in unfavorable clinical and hemodynamic condition.

PMID: 28559663 [PubMed - in process]

Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence.

Thu, 06/01/2017 - 12:45
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Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence.

Respir Res. 2017 May 30;18(1):105

Authors: Rahaghi FF, Miravitlles M

Abstract
Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes.

PMID: 28558837 [PubMed - in process]

PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.

Thu, 06/01/2017 - 12:45
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PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.

PLoS One. 2016;11(10):e0164660

Authors: Rehman M, Gurrapu S, Cagnoni G, Capparuccia L, Tamagnone L

Abstract
The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays. We found that Notch ligands and constitutively activated intracellular forms of Notch receptors upregulated PlexinD1 expression; conversely RNAi-based knock-down, or pharmacological inhibition of Notch signaling by gamma-secretase inhibitors, downregulated PlexinD1 levels. Notably, both Notch1 and Notch3 expression positively correlates with PlexinD1 levels in prostate cancer, as well as in other tumor types. In prostate cancer cells, Sema3E-PlexinD1 axis was previously reported to regulate migration; however, implicated mechanisms were not elucidated. Here we show that in these cells PlexinD1 activity induces the expression of the transcription factor Slug, downregulates E-cadherin levels and enhances cell migration. Moreover, our mechanistic data identify PlexinD1 as a pivotal mediator of this signaling axis downstream of Notch in prostate cancer cells. In fact, on one hand, PlexinD1 is required to mediate cell migration and E-cadherin regulation elicited by Notch. On the other hand, PlexinD1 upregulation is sufficient to induce prostate cancer cell migration and metastatic potential in mice, leading to functional rescue in the absence of Notch. In sum, our work identifies PlexinD1 as a novel transcriptional target induced by Notch signaling, and reveals its role promoting prostate cancer cell migration and downregulating E-cadherin levels in Slug-dependent manner. Collectively, these findings suggest that Notch-PlexinD1 signaling axis may be targeted to impair prostate cancer cell invasiveness and metastasis.

PMID: 27749937 [PubMed - indexed for MEDLINE]

A retrospective database analysis to evaluate the potential of EVLP to recruit declined lung donors.

Wed, 05/31/2017 - 12:45
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A retrospective database analysis to evaluate the potential of EVLP to recruit declined lung donors.

Transpl Int. 2017 May 27;:

Authors: Martens A, Van Raemdonck DE, Smits J, Verleden SE, Vos R, Vanaudenaerde BM, Verleden GM, Degezelle K, Desschans B, Neyrinck AP

Abstract
BACKGROUND: Ex-vivo lung perfusion (EVLP) is currently used for both standard and extended-criteria donor (ECD) lungs. To enlarge the donor pool, we might have to extend the threshold for ECD donation. The purpose of this study was to estimate how many additional ECD lungs could be recruited by EVLP.
METHODS: We reviewed all multi-organ donors (MODs) from our collaborative donor hospitals (January 2010 - June 2015). All unused lung donors, were categorized using registered donor data and evaluated by two independent investigators to identify which lungs could be transplanted after EVLP.
RESULTS: 584 MODs were registered at our transplant center. 268 (45.9%) were declined as lung donor at the moment of registration and 316 (54.1%) were considered as a donor for lung transplantation. In the latter, lungs from 220 (37.7%) donors were transplanted and 96 donors (16.4%) were not. We identified 78 out of 364 declined donors (21.4%) whose lungs could potentially become transplantable after EVLP.
CONCLUSIONS: With this retrospective database analysis of unused lung donors, we identified a large potential for EVLP to further increase the donor pool in transplant centers where the majority of donor lungs are already extended. This article is protected by copyright. All rights reserved.

PMID: 28556538 [PubMed - as supplied by publisher]

Risk Factors for Neurocognitive Functioning in Children with Autosomal Recessive Polycystic Kidney Disease.

Wed, 05/31/2017 - 12:45
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Risk Factors for Neurocognitive Functioning in Children with Autosomal Recessive Polycystic Kidney Disease.

Front Pediatr. 2017;5:107

Authors: Hooper SR

Abstract
This mini review provides an overview of the issues and challenges inherent in autosomal recessive polycystic kidney disease (ARPKD), with a particular focus on the neurological factors and neurocognitive functioning of this population. ARPKD typically is discovered at the end of pregnancy or during the neonatal developmental period and occurs in approximately 1 in 20,000 live births. During the neonatal period, there is a relatively high risk of death, with many infants dying from respiratory failure. As the child ages, they experience progressive kidney disease and become increasingly vulnerable to liver disease, with many individuals eventually requiring dual organ transplants. This mini review provides a brief description of ARPKD and describes the various factors that place children with ARPKD at risk for neurological and neuropsychological impairment (e.g., a genetic condition leading to chronic kidney disease and eventual transplant; difficult-to-treat hypertension; eventual liver disease; possible dual transplantation of the kidneys and liver; chronic lung disease), including that these factors are present during a critical period of brain development. Further, the mini review discusses the available studies that have addressed the neurocognitive functioning in children with ARPKD. This paper concludes by providing the key clinical and research challenges that face the field of pediatric nephrology with respect to the clinical and scientific study of the neurocognitive functioning of children with ARPKD. Selected directions are offered in both the clinical and research arenas for this multiorgan chronic condition.

PMID: 28555180 [PubMed - in process]

EGFR and KRAS molecular genotyping for pulmonary carcinomas: Feasibility of a simple and rapid technique implementable in any department of pathology.

Wed, 05/31/2017 - 12:45
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EGFR and KRAS molecular genotyping for pulmonary carcinomas: Feasibility of a simple and rapid technique implementable in any department of pathology.

Pathol Res Pract. 2017 Mar 30;:

Authors: Thomas De Montpréville V, Ghigna MR, Lacroix L, Lemoine A, Besse B, Mercier O, Fadel É, Dorfmuller P, Le Chevalier T, Institut d’Oncologie Thoracique

Abstract
OBJECTIVES: EGFR and KRAS genes are routinely tested in lung carcinomas with therapeutic implications. However the current testing methods require complex infrastructures and the delay for diagnosis remains often rather long, especially for initiating an appropriate treatment in patients with advanced stage tumor and short life expectancy.
MATERIAL AND METHODS: We evaluated the Idylla™ fully automated molecular diagnostic system in routine conditions in 79 lung adenocarcinomas and 14 other non-small cell lung carcinomas, mostly in advanced stages (III or IV: 85%). Tests were performed on formalin-fixed paraffin-embedded (n=83) or fresh (n=10) material, including cytological (n=24) and small biopsy (n=20) samples. In prospective cases (n=82), the most likely mutated gene (EGFR in non or occasional smokers and KRAS in smokers) was tested first; the second gene being only tested in case of negativity.
RESULTS: The system did not require complex training. Mutational status was obtained in few hours after making the histological diagnosis and on the day of the patient's sampling by analyzing fresh material. The sequential testing strategy avoided 15 EGFR and 15 KRAS tests that would have been negative. Compared with reference methods, global specificity and sensitivity were both 100% for EGFR mutations, and 89.1% and 91.7% for KRAS mutations, respectively.
CONCLUSIONS: We demonstrated that such easy-to-use systems can permit pathologists to integrate a reliable EGFR/KRAS status in their initial pathologic report, and could be useful complementary tools to the current molecular diagnostic methods, with regard to prompt therapeutic management of lung cancer patients.

PMID: 28554746 [PubMed - as supplied by publisher]

A novel method for ABO-incompatible heart transplantation.

Wed, 05/31/2017 - 12:45
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A novel method for ABO-incompatible heart transplantation.

J Heart Lung Transplant. 2017 May 05;:

Authors: Robertson A, Issitt R, Crook R, Gustafsson K, Eddaoudi A, Tsang V, Burch M

Abstract
BACKGROUND: Since 1996, ABO-incompatible heart transplantation has been undertaken by performing whole-body plasma exchange to remove isohemagglutinins using the cardiopulmonary bypass (CPB) circuit at the time of transplantation. This requires large volumes of donated blood and blood products, causes hemodynamic instability during the exchange transfusion, and limits practical use to small children. We sought to determine the efficacy of anti-A/B immunoadsorption within the CPB circuit on removal of isohemagglutinins in an ex vivo setting before its use clinically.
METHODS: An anti-A/B immunoadsorption column was placed into a CPB circuit mimicking a typical ABO-incompatible transplant patient, which had been primed with type O whole human blood. Samples were taken for determination of isohemagglutinin titers following each plasma volume pass through the anti-A/B immunoadsorption column.
RESULTS: There was a linear decrease of at least 1 dilution seen in both anti-A and anti-B IgG and IgM antibodies with each plasma volume pass through the column. This predictable removal allowed the formulation of selection criteria for ABO-incompatible heart transplantation given the reciprocal of titer and patient weight. This degree of predictability allowed us to use it successfully in the clinical setting, reducing antibodies to an undetectable level during ABO-incompatible heart transplantation.
CONCLUSIONS: The incorporation of an anti-A/B immunoadsorption column into the extracorporeal circuit reduces allogeneic blood product requirement for ABO-incompatible heart transplantation, while providing efficacious removal of anti-A and anti-B isohemagglutinins. This can be undertaken within the time period of CPB before graft reperfusion and expands the potential recipient pool to larger patients with higher isohemagglutinin titers.

PMID: 28554587 [PubMed - as supplied by publisher]

Overexpression of ZIC5 promotes proliferation in non-small cell lung cancer.

Wed, 05/31/2017 - 12:45
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Overexpression of ZIC5 promotes proliferation in non-small cell lung cancer.

Biochem Biophys Res Commun. 2016 Oct 21;479(3):502-509

Authors: Sun Q, Shi R, Wang X, Li D, Wu H, Ren B

Abstract
BACKGROUND: Non-small cell lung cancer (NSCLC) has become the leading cause of cancer-related deaths. It is therefore urgent that we identify new molecular targets to help cure NSCLC patients. Here, we identified ZIC5 as a potential novel oncogene.
METHODS: We detected the expression of ZIC5 in tumor and normal tissues of NSCLC patients using quantitative real-time PCR and explored its clinical appearance. We then knocked down ZIC5 to observe changes in NSCLC cell proliferation and metastasis. Nude mouse xenograft models were established to measure ZIC5's function in vivo.
RESULTS: Our results revealed that ZIC5 was expressed at dramatically higher levels in NSCLC tumor tissues than in normal tissues. High levels of ZIC5 expression were associated with a higher primary tumor grade. ZIC5 expression was significantly inhibited by small interfering RNA. After silencing ZIC5, the metastatic capacity of NSCLC cells was clearly lower. Knocking down ZIC5 significantly inhibited the proliferation of NSCLC cells, causing the cell cycle to be arrested in G2 phase. Xenograft tumor models showed that knocking down ZIC5 also inhibited tumor growth in vivo. Q-PCR and western blot analysis revealed that ZIC5 expression was closely associated with CCNB1 and CDK1 complex expression, while other cell cycle-related genes showed no significant correlation with ZIC5.
CONCLUSIONS: Our experiment show that ZIC5 is highly upregulated in NSCLC tumor tissues and suggest that ZIC5 may act as an oncogene by influencing CCNB1 and CDK1 complex expression. ZIC5 may therefore be a potential biomarker and therapeutic target for NSCLC patients.

PMID: 27663664 [PubMed - indexed for MEDLINE]

Atomized Human Amniotic Mesenchymal Stromal Cells for Direct Delivery to the Airway for Treatment of Lung Injury.

Wed, 05/31/2017 - 12:45
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Atomized Human Amniotic Mesenchymal Stromal Cells for Direct Delivery to the Airway for Treatment of Lung Injury.

J Aerosol Med Pulm Drug Deliv. 2016 12;29(6):514-524

Authors: Kim SY, Burgess JK, Wang Y, Kable EP, Weiss DJ, Chan HK, Chrzanowski W

Abstract
BACKGROUND: Current treatment regimens for inhalation injury are mainly supportive and rely on self-regeneration processes for recovery. Cell therapy with mesenchymal stromal cells (MSCs) is increasingly being investigated for the treatment of inhalation injury. Human amniotic MSCs (hAMSCs) were used in this study due to their potential use in inflammatory and fibrotic conditions of the lung. This study aimed at demonstrating that hAMSCs can be atomized with high viability, for the purpose of achieving a more uniform distribution of cells throughout the lung. Another aim of this study was to set ground for future application to healthy and diseased lungs by demonstrating that hAMSCs were able to survive after being sprayed onto substrates with different stiffness.
METHODS: Two methods of atomization were evaluated, and the LMA MAD780 device was selected for atomizing hAMSCs for optimized delivery. To mimic the stiffness of healthy and diseased lungs, gelatin gel (10% w/v) and tissue culture plastic were used as preliminary models. Poly-l-lysine (PLL) and collagen I coatings were used as substrates on which the hAMSCs were cultured after being sprayed.
RESULTS: The feasibility of atomizing hAMSCs was demonstrated with high cell viability (81 ± 3.1% and 79 ± 11.6% for cells sprayed onto plastic and gelatin, respectively, compared with 85 ± 4.8% for control/nonsprayed cells) that was unaffected by the different stiffness of substrates. The presence of the collagen I coating on which the sprayed cells were cultured yielded higher cell proliferation compared with both PLL and no coating. The morphology of sprayed cells was minimally compromised in the presence of the collagen I coating.
CONCLUSIONS: This study demonstrated that hAMSCs are able to survive after being sprayed onto substrates with different stiffness, especially in the presence of collagen I. Further studies may advance the effectiveness of cell therapy for lung regeneration.

PMID: 27186789 [PubMed - indexed for MEDLINE]

Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

Wed, 05/31/2017 - 12:45
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Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

Crit Care Med. 2016 Aug;44(8):e594-603

Authors: Standage SW, Waworuntu RL, Delaney MA, Maskal SM, Bennion BG, Duffield JS, Parks WC, Liles WC, McGuire JK

Abstract
OBJECTIVES: Peroxisome proliferator-activated receptor-α is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-α null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-α in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-α confers a survival advantage.
DESIGN: Prospective randomized preclinical study.
SETTING: Laboratory investigation.
SUBJECTS: Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.
INTERVENTIONS: Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.
MEASUREMENTS AND MAIN RESULTS: Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-α status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.
CONCLUSIONS: Peroxisome proliferator-activated receptor-α expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-α expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-α-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.

PMID: 26757163 [PubMed - indexed for MEDLINE]

A retrospective analysis of delays in the diagnosis of lung cancer and associated costs.

Tue, 05/30/2017 - 12:45
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A retrospective analysis of delays in the diagnosis of lung cancer and associated costs.

Clinicoecon Outcomes Res. 2017;9:261-269

Authors: Gildea TR, DaCosta Byfield S, Hogarth DK, Wilson DS, Quinn CC

Abstract
PURPOSE: Diagnosis of lung cancer at advanced stages can result in missed treatment opportunities, worse outcomes, and higher health care costs. This study evaluated the wait time to diagnose non-small-cell lung cancer (NSCLC) and the cost of diagnosis and treatment based on the stage at diagnosis.
PATIENTS AND METHODS: Adult patients diagnosed with NSCLC between January 2007 and September 2011 were identified from a proprietary oncology registry and linked to health insurance claims from a large US health insurance company. Continuous enrollment in the health plan was required for at least 12 months prediagnosis (baseline) and at least 3 months postdiagnosis (follow-up). Use of diagnostic tests and time to diagnosis were examined. The rates of health care utilization and per-patient per-month (PPPM) health care costs were calculated.
RESULTS: A total of 1,210 patients with NSCLC were included in the analysis. Most patients (93.6%) had evidence of diagnostic tests beginning 5 to 6 months prior to diagnosis, and most were diagnosed at an advanced stage (23% Stage IIIb and 46% Stage IV). The PPPM total health care costs in USD pre- and postdiagnosis were $2,407±$3,364 (mean±standard deviation) and $16,577±$33,550, respectively. PPPM total health care costs and utilization after lung cancer diagnosis were significantly higher among patients diagnosed at Stage IV disease and lowest among patients diagnosed at Stage I disease ($7,239 Stage I, $9,484 Stage II, $11,193 Stage IIIa, $17,415 Stage IIIb, and $21,441 Stage IV).
CONCLUSION: This study showed that most patients experienced long periods of delay between their first diagnostic test for lung cancer and a definitive diagnosis, and the majority were diagnosed at advanced stages of disease. Costs associated with the management of lung cancer increased substantially with higher stages at diagnosis. Procedures that diagnose lung cancer at earlier stages may allow for less resource use and costs among patients with lung cancer.

PMID: 28553128 [PubMed - in process]

Unusual Case of Acute Lung Injury in a Renal Allograft Recipient.

Tue, 05/30/2017 - 12:45
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Unusual Case of Acute Lung Injury in a Renal Allograft Recipient.

Indian J Nephrol. 2017 May-Jun;27(3):215-217

Authors: Anandh U, Marda S

Abstract
A renal allograft recipient developed cough with hemoptysis on the 1(st) postoperative day. A chest X-ray was performed which was suggestive of fluid overload. His fluid was restricted and diuretics were added. On the same day, his pulmonary infiltrates worsened and a computed tomography (CT) of the chest was carried out, which was suggestive of the right lower lobe consolidation and left pleural effusion. He underwent a bronchoscopy and the lavage was sent for cultures, which did not grow any infective organism. Besides routine antibiotics, treatment for possible cytomegalovirus, fungal infections, and pneumocystis infection was instituted. Noninvasive ventilation was started on day 8. A repeat CT of the chest on the postoperative day 8 showed further worsening of the pulmonary infiltrates. As all the initial cultures and serology were negative, a possibility of interstitial pneumonitis was considered. Mycophenolate sodium was considered as a possible cause of the lung infiltrates and was withdrawn. The patient showed progressive improvement. His antibiotics were withdrawn. He was discharged on day 14. A repeat CT 4 weeks post transplant showed significant improvement in his pulmonary pathology. The acute lung injury was considered to be a drug reaction secondary to mycophenolate sodium. In a renal allograft recipient with persistent pulmonary infiltrates, interstitial involvement secondary to drugs should be considered if the patient does not improve with the standard treatment measures.

PMID: 28553043 [PubMed - in process]

Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation.

Tue, 05/30/2017 - 12:45
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Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation.

J Heart Lung Transplant. 2017 May 06;:

Authors: Raphael J, Collins SR, Wang XQ, Scalzo DC, Singla P, Lau CL, Kozower BD, Durieux ME, Blank RS

Abstract
BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation. Statins reduce the risk of chronic rejection after lung transplantation, but their effects on PGD are unknown. We hypothesized that perioperative statin therapy decreases the risk for PGD after lung transplantation.
METHODS: We retrospectively reviewed records of all patients undergoing lung transplantation between January 1999 and December 2014 at the University of Virginia Health System. The primary outcome was PGD (grades 1-3). Secondary outcomes included grade 3 PGD, length of intensive care unit and hospital stay, and mortality.
RESULTS: Of 266 patients who met final inclusion criteria, 138 (52%) were diagnosed with PGD. In-hospital mortality among patients with PGD was 6.5%. There were no deaths in patients without PGD (p < 0.001). PGD was diagnosed in 24 patients taking statins (34.8%) and in 114 patients (57.9%) who did not take statins (p = 0.001). After propensity score adjustments, perioperative statin use was independently associated with a reduced risk for PGD (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.84, p = 0.015) and reduced risk to develop grade 3 PGD (OR 0.42, 95% CI 0.18-0.94, p = 0.036). Other risk factors associated with PGD included intraoperative use of cardiopulmonary bypass (OR 3.74, 95% CI 1.75-8.02, p = 0.001) and positive donor smoking status (OR 2.27, 95% CI 1.18-4.35, p = 0.014).
CONCLUSIONS: The results demonstrate that perioperative use of statins is independently associated with reduced risk for PGD after lung transplantation.

PMID: 28552627 [PubMed - as supplied by publisher]

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Tue, 05/30/2017 - 12:45
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Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Am J Hum Genet. 2017 May 23;:

Authors: Tachmazidou I, Süveges D, Min JL, Ritchie GRS, Steinberg J, Walter K, Iotchkova V, Schwartzentruber J, Huang J, Memari Y, McCarthy S, Crawford AA, Bombieri C, Cocca M, Farmaki AE, Gaunt TR, Jousilahti P, Kooijman MN, Lehne B, Malerba G, Männistö S, Matchan A, Medina-Gomez C, Metrustry SJ, Nag A, Ntalla I, Paternoster L, Rayner NW, Sala C, Scott WR, Shihab HA, Southam L, St Pourcain B, Traglia M, Trajanoska K, Zaza G, Zhang W, Artigas MS, Bansal N, Benn M, Chen Z, Danecek P, Lin WY, Locke A, Luan J, Manning AK, Mulas A, Sidore C, Tybjaerg-Hansen A, Varbo A, Zoledziewska M, Finan C, Hatzikotoulas K, Hendricks AE, Kemp JP, Moayyeri A, Panoutsopoulou K, Szpak M, Wilson SG, Boehnke M, Cucca F, Di Angelantonio E, Langenberg C, Lindgren C, McCarthy MI, Morris AP, Nordestgaard BG, Scott RA, Tobin MD, Wareham NJ, SpiroMeta Consortium, GoT2D Consortium, Burton P, Chambers JC, Smith GD, Dedoussis G, Felix JF, Franco OH, Gambaro G, Gasparini P, Hammond CJ, Hofman A, Jaddoe VWV, Kleber M, Kooner JS, Perola M, Relton C, Ring SM, Rivadeneira F, Salomaa V, Spector TD, Stegle O, Toniolo D, Uitterlinden AG, arcOGEN Consortium, Understanding Society Scientific Group, UK10K Consortium, Barroso I, Greenwood CMT, Perry JRB, Walker BR, Butterworth AS, Xue Y, Durbin R, Small KS, Soranzo N, Timpson NJ, Zeggini E

Abstract
Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

PMID: 28552196 [PubMed - as supplied by publisher]

Exploitation of Novel Molecular Targets to Treat Idiopathic Pulmonary Fibrosis: A Drug Discovery Perspective.

Tue, 05/30/2017 - 12:45
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Exploitation of Novel Molecular Targets to Treat Idiopathic Pulmonary Fibrosis: A Drug Discovery Perspective.

Curr Med Chem. 2017 May 26;:

Authors: Vaidya B, Patel R, Muth A, Gupta V

Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing lung disease and is caused by excessive lung scarring. IPF-associated severe mortality can be attributed to late diagnosis due to its generic symptoms, and more importantly, due to the lack of effective therapies available. Despite extensive research in past decades, lung transplant still remains the most effective treatment for IPF. Though two drugs recently approved by FDA, Pirfenidone and Nintedanib, have shown an ability to reduce the progression of disease. However, they have shown minimal survival benefits to patients.
METHODS: IPF is a multifaceted disorder with poorly understood pathophysiology. We believe that there are better therapeutic targets veiled in IPF pathophysiology, exploitation of which may improve current therapeutic approaches to the disease. We have performed an extensive literature search using several bibliographic databases for peer reviewed articles discussing molecular targets/pathways involved in the pathogenesis of the disease. Furthermore, studies involving exploitation of these therapeutic targets and potential therapeutic agents were identified.
RESULTS: Recently, new and promising targets have been revealed from GWA studies and genetic microarrays of IPF patients. In this review, we discuss the efficacy and feasibility of several novel molecular targets including Semaphorin (SEMA) 7A, connective tissue growth factor, integrin αvβ6, caveolin-1, let 7-d, calcium activated potassium channel KCa3.1, matrix metalloproteinase-19, lysocardiolipin acetyltransferase, dimethylarginine dimethylaminohydrolase, and transglutaminase 2. These targets have all shown the potential to modulate IPF pathophysiology, thereby inhibiting disease progression.
CONCLUSION: Information gained from this review will be valuable to this field, enabling the design and development of novel therapeutics for IPF.

PMID: 28552057 [PubMed - as supplied by publisher]

Review of 1,000 consecutive extracorporeal membrane oxygenation runs as a quality initiative.

Tue, 05/30/2017 - 12:45
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Review of 1,000 consecutive extracorporeal membrane oxygenation runs as a quality initiative.

Surgery. 2017 May 24;:

Authors: Lovvorn HN, Hardison DC, Chen H, Westrick AC, Danko ME, Bridges BC, Walsh WF, Pietsch JB

Abstract
BACKGROUND: Extracorporeal membrane oxygenation is a resource-intensive mode of life-support potentially applicable when conventional therapies fail. Given the initial success of extracorporeal membrane oxygenation to support neonates and infants in the 1980s, indications have expanded to include adolescents, adults, and selected moribund patients during cardiopulmonary resuscitation. This single-institution analysis was conducted to evaluate programmatic growth, outcomes, and risk for death despite extracorporeal membrane oxygenation across all ages and diseases.
METHODS: Beginning in 1989, we registered prospectively all extracorporeal membrane oxygenation patient data with the Extracorporeal Life Support Organization. We queried this registry for our institution-specific data to compare the parameter of "discharge alive" between age groups (neonatal, pediatric, adult), disease groups (respiratory, cardiac, cardiopulmonary resuscitation), and modes of extracorporeal membrane oxygenation (veno-venous; veno-arterial). Extracorporeal membrane oxygenation-specific complications (mechanical, hemorrhagic, neurologic, renal, cardiovascular, pulmonary, infectious, metabolic) were analyzed similarly. Descriptive statistics, Kaplan-Meier, and linear regression analyses were conducted.
RESULTS: After 1,052 extracorporeal membrane oxygenation runs, indications have expanded to include adults, to supplement cardiopulmonary resuscitation, to support hemodialysis in neonates and plasmapheresis in children, and to bridge all age patients to heart and lung transplant. Overall survival to discharge was 52% and was better for respiratory diseases (P < .001). Probability of individual survival decreased to <50% if pre-extracorporeal membrane oxygenation mechanical ventilation exceeded respectively 123 hours for cardiac, 166 hours for cardiopulmonary resuscitation, and 183 hours for respiratory diseases (P = .013). Complications occurred most commonly among cardiac and cardiopulmonary resuscitation runs (P < .001), the veno-arterial mode (P < .001), and in adults (P = .044).
CONCLUSION: Our extracorporeal membrane oxygenation program, an Extracorporeal Life Support Organization-designated Center of Excellence, has experienced substantial growth in volume and indications, including increasing age and disease severity. Considering the entire cohort, pre-extracorporeal membrane oxygenation ventilation exceeding 7 days was associated with an increased probability of death.

PMID: 28551379 [PubMed - as supplied by publisher]

The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion.

Tue, 05/30/2017 - 12:45
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The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion.

J Heart Lung Transplant. 2017 May 12;:

Authors: Andreasson ASI, Borthwick LA, Gillespie C, Jiwa K, Scott J, Henderson P, Mayes J, Romano R, Roman M, Ali S, Fildes JE, Marczin N, Dark JH, Fisher AJ, DEVELOP-UK Investigators

Abstract
BACKGROUND: Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study.
METHODS: Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform.
RESULTS: The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R(2) = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R(2) = 0.30, p = 0.001) and E-selectin (R(2) = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R(2) = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002).
CONCLUSIONS: Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.

PMID: 28551353 [PubMed - as supplied by publisher]

Survival in pulmonary hypertension: Experiences from a referral center.

Tue, 05/30/2017 - 12:45
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Survival in pulmonary hypertension: Experiences from a referral center.

J Heart Lung Transplant. 2017 May 15;:

Authors: Kanwar MK

PMID: 28551352 [PubMed - as supplied by publisher]

Identifying children appropriate for bridge-to-transplantation with the Berlin Heart EXCOR.

Tue, 05/30/2017 - 12:45
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Identifying children appropriate for bridge-to-transplantation with the Berlin Heart EXCOR.

J Heart Lung Transplant. 2017 May 12;:

Authors: Davies RR

PMID: 28551351 [PubMed - as supplied by publisher]

Characterization of Liver Metastasis and Its Effect on Targeted Therapy in EGFR-mutant NSCLC: A Multicenter Study.

Sun, 05/28/2017 - 12:45
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Characterization of Liver Metastasis and Its Effect on Targeted Therapy in EGFR-mutant NSCLC: A Multicenter Study.

Clin Lung Cancer. 2017 May 05;:

Authors: Jiang T, Cheng R, Zhang G, Su C, Zhao C, Li X, Zhang J, Wu F, Chen X, Gao G, Li W, Cai W, Zhou F, Zhao J, Xiong A, Ren S, Zhang G, Zhou C, Zhang J

Abstract
BACKGROUND: The risk factors for liver metastasis (LM) in patients with non-small-cell lung cancer (NSCLC) remain unknown. Whether LM predicts for the effect of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC needs to be explored.
PATIENTS AND METHODS: A total of 598 NSCLC patients from 3 centers underwent EGFR testing, and 293 had EGFR-mutant NSCLC. Of the 598 NSCLC patients, 99 had LM; 56 patients with EGFR-mutant NSCLC received EGFR-TKIs as first-line therapy.
RESULTS: EGFR mutation was not associated with LM in NSCLC patients (relative ratio, 1.305, P = .261). In the EGFR-mutant group that received first-line EGFR-TKIs, patients with LM had shorter progression-free survival (PFS; 7.5 vs. 11.8 months; P = .0003) and overall survival (OS; 20.8 vs. 30.6 months; P = .0190) than patients without LM. The significant difference in PFS was observed in both patients with EGFR exon 19 deletion (19del) and Leu858Arg mutation (L858R). However, patients with EGFR 19del and LM showed marginally significantly shorter OS (P = .0531) and patients with EGFR L858R and LM had OS similar to that of patients without LM (P = .1883). Regardless of EGFR status, patients with LM who received first-line chemotherapy had PFS and OS similar to those of patients without LM. Univariate analyses identified only never smoking (hazard ratio, 0.536; P = .012) was significantly associated with better OS for patients with NSCLC and LM.
CONCLUSION: EGFR mutation is not an independent risk factor for LM in NSCLC patients. However, the presence of LM is a negative predictive factor for first-line EGFR-TKI therapy for patients with EGFR-mutant NSCLC.

PMID: 28549835 [PubMed - as supplied by publisher]

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