The localized inflammatory response to bronchoscopic thermal vapor ablation.

Background: Bronchoscopic thermal vapor ablation (BTVA) reduces lung volumes in emphysema patients by inducing a localized inflammatory response (LIR) leading to a healing process of fibrosis, but may also increase symptoms.

Objectives: We sought to evaluate whether the clinical manifestation of LIR correlated with patient outcome.

Methods: Respiratory adverse events and inflammatory markers were analyzed from a multicenter trial of BTVA in patients with upper-lobe-predominant emphysema.

Sustained function of genetically modified porcine lungs in an ex vivo model of pulmonary xenotransplantation.

Background: Xenotransplantation could provide a solution to the donor shortage that is currently the major barrier to solid-organ transplantation. The ability to breed pigs with multiple genetic modifications provides a unique opportunity to explore the immunologic challenges of pulmonary xenotransplantation.

Methods: Explanted lungs from wild-type and 3 groups of genetically modified pigs were studied: (i) α1,3-galactosyltransferase gene knockout (GTKO); (ii) GTKO pigs expressing the human complementary regulatory proteins CD55 and CD59 (GTKO/CD55-59); and (iii) GTKO pigs expressing both CD55-59 and CD39 (GTKO/CD55-59/CD39).

Evolution to twice daily bolus intravenous tacrolimus: optimizing efficacy and safety of calcineurin inhibitor delivery early post lung transplant.

Background: Achieving therapeutic levels of cyclosporine (CSA) or Tacrolimus (TAC) early post lung transplantation (LTx) is challenging. Gut dysmotility, renal dysfunction and seizure risk are variably present and problematic. This study reports a single center.

The influence of clinical donor factors on acute rejection among lung and kidney recipients from the same multi-organ donor.

Background: Acute (AR) and Chronic (CR) rejection cause considerable morbidity and mortality following transplantation. This study explores the associations of biopsy proven AR in lung (LTx) and kidney (KTx) transplants recipients from the one donor.

Material And Methods: Between 2001 and 2006, 136 multiorgan donors contributed 144 LTx and 261 matching KTx.

Donor selection and management.

This article reviews recent developments in the selection, assessment, and management of the potential lung donor, which aim to increase donor organ use. The scarcity of suitable donor organs continues to limit lung transplantation, but the situation is changing. An expanded donor pool, including the now widespread use of donation after cardiac death (DCD) lungs; the use of extended donor lungs; and the ability of ex vivo lung perfusion (EVLP) to evaluate and improve donor lungs are key initiatives.

Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients.

Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.

Acute fibrinoid organizing pneumonia after lung transplantation.

Rationale: The barrier to long-term success after lung transplantation is the development of chronic lung allograft dysfunction. As the experience with lung transplantation accrues, it has become increasingly apparent that not all chronic allograft dysfunction is consistent with the traditionally recognized small-airway histological process of obliterative bronchiolitis (OB).

Objectives: To identify and describe chronic allograft dysfunction that is not consistent with the well-described bronchiolitis obliterans syndrome and to further characterize a novel histopathological process, acute fibrinoid organizing pneumonia (AFOP), that has led invariably to respiratory decline and death after lung transplantation.

Managing bronchiolitis obliterans syndrome (BOS) and chronic lung allograft dysfunction (CLAD) in children: what does the future hold?

The success of pediatric lung transplantation continues to be limited by long-term graft dysfunction. Historically this has been characterized as an obstructive spirometric defect in the form of the bronchiolitis obliterans syndrome (BOS). It is recognized, however, that this does not reflect many of the other acknowledged etiologies of chronic lung dysfunction-noting it is the sum of the parts that contribute to respiratory morbidity and mortality after transplant.

Impact of commonly used transplant immunosuppressive drugs on human NK cell function is dependent upon stimulation condition.

Lung transplantation is a recognised treatment for patients with end stage pulmonary disease. Transplant recipients receive life-long administration of immunosuppressive drugs that target T cell mediated graft rejection. However little is known of the impact on NK cells, which have the potential to be alloreactive in response to HLA-mismatched ligands on the lung allograft and in doing so, may impact negatively on allograft survival.

Preemptive treatment with voriconazole in lung transplant recipients.

Background: Invasive fungal infection (IFI) is associated with high mortality in lung transplant (LTx) recipients. Data for voriconazole use in preemptive treatment remain scant.

Method: A single-center, retrospective cohort study was conducted to investigate the efficacy and safety of voriconazole preemptive treatment for post-LTx colonization.

Lessons and insights from ABO-incompatible lung transplantation.

With ABO blood group incompatibility (ABOi) between donor and recipient becoming a part of mainstream living-donor renal transplantation, the applicability of ABOi to other areas of transplantation is being reconsidered. Here we present a case of inadvertent ABOi lung retransplantation managed successfully with initial plasmapheresis, antithymocyte globulin and intravenous immunoglobulin; and subsequently with oral cyclophosphamide and sirolimus in addition to tacrolimus and prednisolone. Interestingly, in the setting of solid levels of tacrolimus and sirolimus, the patient developed a fatal thrombotic microangiopathy of uncertain origin subsequent to the cessation of cyclophosphamide at 9 years posttransplant.

Quantification of voriconazole in human bronchoalveolar lavage fluid using high-performance liquid chromatography with fluorescence detection.

The quantification of voriconazole concentration in lung epithelial lining fluid to facilitate the management of pulmonary fungal colonisation or aspergillosis is of increasing interest. An accurate and reproducible high-performance liquid chromatography method to quantify voriconazole in human bronchoalveolar lavage (BAL) fluid was developed and validated. BAL samples were concentrated by freeze-drying and reconstituted with water prior to deproteinisation.

Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic.

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.

An unexpectedly high prevalence of undiagnosed diabetes in patients awaiting lung transplantation.

Background: Diabetes mellitus (DM) is a common complication after lung transplantation but its prevalence prior to transplantation has not been determined. We sought to determine the prevalence of and risk factors for DM in adults awaiting lung transplantation and to determine whether pre-transplant DM could be diagnosed by hemoglobin A1c (HbA1c) alone.

Methods: All patients wait-listed for lung transplantation over a 2-year period had HbA1c measured.

Preoperative echocardiographic-defined moderate-severe pulmonary hypertension predicts prolonged duration of mechanical ventilation following lung transplantation for patients with COPD.

Purpose: Recent studies have suggested that pretransplant secondary pulmonary hypertension (PHT) may be associated with worse outcomes following lung transplantation. We sought to determine whether COPD patients with secondary PHT have inferior intensive care outcomes following lung transplantation.

Methods: This is a single-center, retrospective analysis of all lung transplant recipients between 2000 and 2009 for a primary diagnosis of COPD.

Characterization of outcomes 1 year after endoscopic thermal vapor ablation for patients with heterogeneous emphysema.

Introduction: Endoscopic lung volume reduction has been developed as a therapeutic option for advanced emphysema. Six-month results following treatment with endoscopic thermal vapor ablation (InterVapor; Uptake Medical, Tustin, CA) were described previously, and here we report observations from the 12-month assessment.

Methods: Two multicenter, international, single-arm trials of InterVapor (unilateral upper lobe treatment) in patients with upper lobe predominant emphysema were conducted.

Donor clara cell secretory protein polymorphism is a risk factor for bronchiolitis obliterans syndrome after lung transplantation.

Background: We hypothesized that a reduced potential for bronchiolar stem-cell (Clara cell)-related repair in the setting of an ever-present risk of small airway injury would increase the risk of bronchiolitis obliterans syndrome (BOS).

Method: CCSP A38G gene polymorphism was assessed in both lung donors and recipients in a longitudinal study cohort of 63 consecutive lung transplant recipients (LTR) with a median follow-up of 493 days (range, 26-894). Clara cell secretory protein (CCSP) and interleukin 8 levels were assessed in the bronchoalveolar lavage and plasma at 1, 3, 6, and 12 months after transplantation.

Single-centre experience of donation after cardiac death.

Objectives: To describe the design, development and implementation of an organ and tissue donation after cardiac death (DCD) program, evaluate its success and assess its impact on tissue and organ availability and the number of donors after brain death.

Design, Participants And Setting: Prospective collection of patient characteristics and outcomes for actual and potential donors from 2000 to 2010, thus including the 5 years after the implementation of a DCD program at a major Australian tertiary hospital in 2006.

Main Outcome Measures: The number and type of donors before and after implementation of the DCD program, and subsequent numbers of solid organ and tissue donations.

Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.

Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes.

Cadaveric lobar lung transplantation: technical aspects.

Background: The use of lobar transplantation and other size reduction techniques has allowed larger donor lungs to be utilized for smaller recipients who tend to have longer waiting times for transplantation. However, despite these advantages, the techniques have not been widely adopted. We outline the surgical and sizing issues associated with this technique.

Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.

In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD).

Efficacy of bronchoscopic thermal vapor ablation and lobar fissure completeness in patients with heterogeneous emphysema.

Background: Bronchoscopic thermal vapor ablation (BTVA) ablates emphysematous tissue through a localized inflammatory response followed by contractive fibrosis and tissue shrinkage leading to lung volume reduction that should not be influenced by collateral ventilation.

Objectives: To determine the correlation of clinical data from a trial of BTVA with fissure integrity visually assessed by computed tomography (CT).

Methods: We conducted a single-arm study of patients with upper lobe-predominant emphysema (n = 44).

X-ray sources and high-throughput data collection methods.

X-ray diffraction experiments on protein crystals are at the core of the structure determination process. An overview of X-ray sources and data collection methods to support structure-based drug design (SBDD) efforts is presented in this chapter. First, methods of generating and manipulating X-rays for the purpose of protein crystallography, as well as the components of the diffraction experiment setup are discussed.