Internal report cluster 1: Urban freight innovations and solutions for sustainable deliveries (4/4)

Technical report about sustainable urban freight solutions, part 4 of

Spontaneous rescue from cystic fibrosis in a mouse model

BACKGROUND: From the original Cftr(TgH(neoim)Hgu )mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred Cftr(TgH(neoim)Hgu )mutant strains named CF/1-Cftr(TgH(neoim)Hgu )and CF/3-Cftr(TgH(neoim)Hgu), which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains. RESULTS: Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred Cftr(TgH(neoim)Hgu )strains, with higher residual amount observed for CF/1-Cftr(TgH(neoim)Hgu )than CF/3-Cftr(TgH(neoim)Hgu )for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-Cftr(TgH(neoim)Hgu )and 4% for CF/3-Cftr(TgH(neoim)Hgu). Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues. CONCLUSION: Unlike the outbred Cftr(TgH(neoim)Hgu )insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred Cftr(TgH(neoim)Hgu )strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-Cftr(TgH(neoim)Hgu )and CF/3-Cftr(TgH(neoim)Hgu )offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome

Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions

Nitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0–64% and 0–63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting. © 2000 Cancer Research Campaig

Mouse models of cystic fibrosis: Phenotypic analysis and research applications

AbstractGenetically modified mice have been studied for more than fifteen years as models of cystic fibrosis (CF). The large amount of experimental data generated illuminates the complex multi-organ pathology of CF and raises new questions relevant to human disease. CF mice have also been used to test experimental therapies prior to clinical trials. This review recapitulates the major phenotypic traits of CF mice and highlights important new findings including aberrant alveolar macrophages, bone and cartilage abnormalities and abnormal bioactive lipid metabolism. Novel data are presented on the intestinal and nasal physiology of F508del-CFTR CF mice backcrossed onto different genetic backgrounds. Caveats, and sources of variability including age, gender and animal husbandry, are discussed. Interspecies differences limit comparison of lung pathology in CF mice to the human disease. The recent development of genetically modified pigs and ferrets heralds the application of more advanced animal models to CF research and drug development

What is the potential benefit of pre-hospital extracorporeal cardiopulmonary resuscitation for patients with an out-of-hospital cardiac arrest?:A predictive modelling study

AIM: In this predictive modelling study we aimed to investigate how many patients with an out-of-hospital cardiac arrest (OHCA) would benefit from pre-hospital as opposed to in-hospital initiation of extracorporeal cardiopulmonary resuscitation (ECPR).METHODS: A temporal spatial analysis of Utstein data was performed for all adult patients with a non-traumatic OHCA attended by three emergency medical services (EMS) covering the north of the Netherlands during a one-year period. Patients were considered potentially eligible for ECPR if they had a witnessed arrest with immediate bystander CPR, an initial shockable rhythm (or signs of life during resuscitation) and could be presented in an ECPR-centre within 45 minutes of the arrest. Endpoint of interest was defined as the hypothetical number of ECPR eligible patients after 10, 15 and 20 minutes of conventional CPR and upon (hypothetical) arrival in an ECPR-centre as a fraction of the total number of OHCA patients attended by EMS.RESULTS: During the study period 622 OHCA patients were attended, of which 200 (32%) met ECPR eligibility criteria upon EMS arrival. The optimal transition point between conventional CPR and ECPR was found to be after 15 minutes. Hypothetical intra-arrest transport of all patients in whom no return of spontaneous circulation (ROSC) was obtained after that point (n = 84) would have yielded 16/622 (2.5%) patients being potentially ECPR eligible upon hospital arrival (average low-flow time 52 minutes), whereas on-scene initiation of ECPR would have resulted in 84/622 (13.5%) potential candidates (average estimated low-flow time 24 minutes before cannulation).CONCLUSION: Even in healthcare systems with relatively short transport distances to hospital, consideration should be given to pre-hospital initiation of ECPR for OHCA as it shortens low-flow time and increases the number of potentially eligible patients.</p

BESTFACT Best Practice Handbook 3

The Best Practice Handbook (BPH) gives an overview about current concepts, strategies and actions in freight transport all over Europe. It is disseminating information on successful projects and practices to increase awareness and share experiences. It is enabling knowledge transfer and supporting transferability for best practices. The third and last Best Practice Handbook focuses on the work done over the entire project, with 157 inventory cases and 60 in-depth analyses. After four years of case collection a wide field of solutions is available. The main findings of the BESTFACT cases are cross-checked and summarised for each of the cluster topics. The consistent form of collection and information provision broadens the structural understanding of best practice cases. The synthesis of cases per topic shows that under consideration of barriers and framework conditions replicable impacts are achievable. Main editors are Martin Ruesch & Simon Bohne (Rapptrans) and Jacques Leonardi (UoW). Project leader is Marcel Huschebeck (PTV)