Search

It is imperative to ensure biological products are free of contaminating pyrogenic material prior to administration to patients. Historically the rabbit pyrogen test (RPT) was used to screen for such contamination in medicines for intravenous delivery. This test was adapted for use to screen vaccines. However, some, including meningococcal vaccines containing outer membrane vesicles, are intrinsically pyrogenic. Indeed, this is the case for Bexsero which contains relatively high levels of endotoxin and other potential pyrogens such as lipoproteins and porins. The RPT proved a difficult method for measuring the pyrogenic content of Bexsero and differences between laboratories in different countries made repeat testing at the control laboratories problematic resulting in batches being wrongly identified as unsafe. At NIBSC a monocyte activation test (MAT) was adapted and validated as an alternative. This required setting of a specification in-house and deciding on a decisional procedure using multiple donors, allowing batches equally pyrogenic or less, than those batches shown to be safe in a clinical trial, to be certified as safe. The resulting format was a reference comparison method with an upper limit of 1.8 relative pyrogen units (RPU). The batch passed if an initial four donors had a response equal to or less than 1.8 RPU, if one donor is above this limit the batch was tested in a further four donors and seven of the eight must be equal to or below 1.8 RPU. If two donors have a response greater than 1.8 the batch failed., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes an irreversible, cumulative and dose-dependent cardiomyopathy that ultimately leads to congestive heart failure. The mechanisms responsible for DOX cardiotoxicity remain poorly understood, but seem to involve mitochondrial dysfunction on several levels. Epigenetics may explain a portion of this effect. Since mitochondrial dysfunction may affect the epigenetic landscape, we hypothesize that this cardiac toxicity may result from epigenetic changes related to disruption of mitochondrial function. To test this hypothesis, eight-week-old male Wistar rats (n=6/group) were administered 7 weekly injections with DOX (2mgkg -1 ) or saline, and sacrificed two weeks after the last injection. We assessed gene expression patterns by qPCR, global DNA methylation by ELISA, and proteome lysine acetylation status by Western blot in cardiac tissue from saline and DOX-treated rats. We show for the first time that DOX treatment decreases global DNA methylation in heart but not in liver. These differences were accompanied by alterations in mRNA expression of multiple functional gene groups. DOX disrupted cardiac mitochondrial biogenesis, as demonstrated by decreased mtDNA levels and altered transcript levels for multiple mitochondrial genes encoded by both nuclear and mitochondrial genomes. Transcription of genes involved in lipid metabolism and epigenetic modulation were also affected. Western blotting analyses indicated a differential protein acetylation pattern in cardiac mitochondrial fractions of DOX-treated rats compared to controls. Additionally, DOX treatment increased the activity of histone deacetylases. These results suggest an interplay between mitochondrial dysfunction and epigenetic alterations, which may be a primary determinant of DOX-induced cardiotoxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) is currently used in cancer chemotherapy, however, its use often results in adverse effects highlighted by the development of cardiomyopathy and ultimately heart failure. Interestingly, DOX cardiotoxicity is decreased by resveratrol or by physical activity, suggesting that increased mitochondrial activity may be protective. Conversely, recent studies showed that troglitazone, a PPARγ agonist, increases the cytotoxicity of DOX against breast cancer cells by up-regulating mitochondrial biogenesis. The hypothesis for the current investigation was that DOX cytotoxicity in H9c2 cardiomyoblasts is decreased when mitochondrial capacity is increased. We focused on several end-points for DOX cytotoxicity, including loss of cell mass, apoptotic signaling and alterations of autophagic-related proteins. Our results show that a galactose-based, modified cell culture medium increased H9c2 basal mitochondrial respiration, protein content, and mtDNA copy number without increasing maximal or spare respiratory capacity. H9c2 cardiomyoblasts cultured in the galactose-modified media showed lower DOX-induced activation of the apoptotic pathway, measured by decreased caspase-3 and -9 activation, and lower p53 expression, although ultimately loss of cells was not prevented. Treatment with the PPARγ agonist troglitazone had no effect on DOX toxicity in this cardiac cell line, which agrees with the fact that troglitazone did not increase mitochondrial DNA content or capacity at the concentrations and duration of exposure used in this investigation. Our results show that mitochondrial remodeling caused by stimulating basal rates of oxidative phosphorylation decreased DOX-induced apoptotic signaling and increased DOX-induced autophagy in H9c2 cardiomyoblasts. The differential effect on cytotoxicity in cardiac versus breast cancer cell lines suggests a possible overall improvement in the clinical efficacy for doxorubicin in treating cancer., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Setting an appropriate positive end-expiratory pressure (PEEP) value is determined by respiratory mechanics, gas exchange and oxygen transport. As these variables may be optimal at different PEEP values, a unique PEEP value may not exist which satisfies both the demands of minimizing mechanical stress and optimizing oxygen transport. In 15 surfactant-deficient piglets, PEEP was increased progressively. Arterial oxygenation and functional residual capacity (FRC) increased, while specific compliance of the respiratory system decreased. Static compliance increased up to a threshold value of PEEP of 8 cm H2O, after which it decreased. This threshold PEEP did not coincide with the lower inflection point of the inspiratory limb of the pressure-volume (PV) loop. Oxygen transport did not correlate with respiratory mechanics or FRC. In the lavage model, the lower inflection point of the PV curve may reflect opening pressure rather than the pressure required to keep the recruited lung open. Recruitment takes place together with a change in the elastic properties of the already open parts of the lung. No single PEEP level is optimal for both oxygen transport and reduction of mechanical stress.

1. INTRODUCTION. A computer-based patient record (CPR) system, Swedestar, has been developed for use in primary health care. The principal aim of the system is to support continuous quality improvement through improved information handling, improved decision-making, and improved procedures for quality assurance. The Swedestar system has evolved during a ten-year period beginning in 1984. 2. SYSTEM DESIGN. The design philosophy is based on the following key factors: a shared, problem-oriented patient record; structured data entry based on an extensive controlled vocabulary; advanced search and query functions, where the query language has the most important role; integrated decision support for drug prescribing and care protocols and guidelines; integrated procedures for quality assurance. 3. A SHARED PROBLEM-ORIENTED PATIENT RECORD. The core of the CPR system is the problem-oriented patient record. All problems of one patient, recorded by different members of the care team, are displayed on the problem list. Starting from this list, a problem follow-up can be made, one problem at a time or for several problems simultaneously. Thus, it is possible to get an integrated view, across provider categories, of those problems of one patient that belong together. This shared problem-oriented patient record provides an important basis for the primary care team work. 4. INTEGRATED DECISION SUPPORT. The decision support of the system includes a drug prescribing module and a care protocol module. The drug prescribing module is integrated with the patient records and includes an on-line check of the patient's medication list for potential interactions and data-driven reminders concerning major drug problems. Care protocols have been developed for the most common chronic diseases, such as asthma, diabetes, and hypertension. The patient records can be automatically checked according to the care protocols. 5. PRACTICAL EXPERIENCE. The Swedestar system has been implemented in a primary care area with 30,000 inhabitants. It is being used by all the primary care team members: 15 general practitioners, 25 district nurses, and 10 physiotherapists. Several years of practical experience of the CPR system shows that it has a positive impact on quality of care on four levels: 1) improved clinical follow-up of individual patients; 2) facilitated follow-up of aggregated data such as practice activity analysis, annual reports, and clinical indicators; 3) automated medical audit; and 4) concurrent audit. Within that primary care area, quality of care has improved substantially in several aspects due to the use of the CPR system [1].