Surfactant alterations and treatment of lung transplant ischemia-reperfusion injury

This review addresses surfactant alterations and treatment in lung transplant ischemia-reperfusion injury. Lung ischemia-reperfusion injury damages the endogenous surfactant system as a result of the production of reactive oxygen species, proteolytic enzymes and (phospho)lipases. Surfactant is composed of phospholipids and proteins and its main function is to reduce the surface tension inside the alveolus. Impairment of surfactant will cause atelectasis, influx of serum proteins, pulmonary edema, decreased lung compliance and impaired gas exchange. Surfactant therapy restores the quantity and composition of surfactant and reduces the inhibitory effect of serum proteins; other effects are that it serves as an antioxidant and anti-inflammatory agent. Pretreatment may be more beneficial than treatment after the development of lung ischemia-reperfusion injury. However, the cost of surfactant must be weighed against the clinical outcome

Partial liquid ventilation improves lung function in ventilation-induced lung injury

Disturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish lung function after ventilation-induced lung injury. Adult rats were exposed to high PIP without PEEP for 20 min. Thereafter, the animals were randomly divided into five groups. The first group was killed immediately after randomization and used as an untreated control. The second group received only sham treatment and ventilation, and three groups received treatment with perfluorocarbon (10 mL x kg(-1), 20 mL x kg(-1), and 20 ml x kg(-1) plus an additional 5 mL x kg(-1) after 1 h). The four groups were maintained on mechanical ventilation for a further 2-h observation period. Blood gases, lung mechanics, total protein concentration, minimal surface tension, and small/large surfactant aggregates ratio were determined. The results show that in ventilation-induced lung injury, partial liquid ventilation with different amounts of perflubron improves gas exchange and pulmonary function, when compared to a group of animals treated with standard respiratory care. These effects have been observed despite the presence of a high intra-alveolar protein concentration, especially in those groups treated with 10 and 20 mL of perflubron. The data suggest that replacement of perfluorocarbon, lost over time, is crucial to maintain the constant effects of partial liquid ventilation

The delivery of personalised, precision medicines via synthetic proteins

Introduction: The design of advanced drug delivery systems based on synthetic and su-pramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements. The Problem: As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities. The Solution: The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein the use of synthetic proteins for drug delivery has been reviewed

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved

Diagnostic and Therapeutic Aspects of Acute Lung Injury: empirical studies

The thesis emphases research on prognostic markers as well as on different approaches for treating lung injury. Thereby, the prevention and treatment of pneumonia and possible ventilation induced bacterial translocation from the lung into the blood represents the main focus of thesis