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Effects of different fat sources, technological forms and characteristics of the basal diet on milk fatty acid profile in lactating dairy cows - a meta-analysis

A meta-analysis was conducted to study milk fatty acid (FA) profile in dairy cows in response to changes in dietary nutrient composition in relation to supplementation of fat sources, their technological form, addition of fish oil and main forage type in the basal diet. Data comprised 151 treatment means from 50 experiments, which were included in the database when diet composition, nutrient composition, FA composition, dry matter (DM) intake, milk yield, milk composition and milk FA profile were reported. Mixed model regression analysis including a random experiment effect and unequal variances among experiments was used. Least squares means were obtained for the different fat sources (unsupplemented, rapeseed, soybean+sunflower, linseed, or fish oil), technological form including addition of fish oil (oil, seed, protected and added fish oil), and main forage type (lucerne silage, barley silage, maize silage, grass silage, maize silage combined with haylage, or haylage) in the basal diet. Results showed that the technological form of supplemental rapeseed, soybean, sunflower, or linseed significantly influenced the effect of dietary nutrient composition on milk fat content and milk FA profile resulting in significant differences between technological forms within the different fat sources. Protected rapeseed and linseed increased C18:2n6 and C18:3n3 proportions in milk fat, respectively, whereas soybean and sunflower seed increased transfer efficiencies for C18:2n6 and C18:3n3 and their proportions in milk fat. Soybean, sunflower, or linseed supplied as oil increased trans-11-C18:1 proportions in milk fat, whereas the addition of fish oil to a diet containing soybean or sunflower decreased C18:0 and cis-9-C18:1 proportions in milk fat. The main forage type in the diet also significantly influenced the effect of dietary nutrient composition on milk fat content and milk FA profile, resulting in significant differences between main forage types in the diet within the different fat sources. Maize silage as the main forage type increased trans-11-C18:1 in unsupplemented diets or diets supplemented with a source of soybean or sunflower. For rapeseed supplemented diets, barley silage increased transfer efficiency and milk fat proportion of C18:2n6, whereas grass silage increased proportion of C18:3n3 in milk fat. For soybean or sunflower supplemented diets, haylage increased proportions of saturated FA, cis-9-C18:1 and C18:2n6, whereas the combination of maize silage and haylage increased transfer efficiency and milk fat proportion of C18:3n3. For linseed supplemented diets, grass silage as the main forage type resulted in the highest C18:3n3 proportion, whereas cis-9-C18:1 proportion was comparable for grass silage, lucerne silage and maize silage as the main forage type. This meta-analysis confirmed that the effect of dietary nutrient composition on several milk FA proportions depends on the type and form of fat supplementation, addition of fish oil, and main forage type in the basal diet

Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models

Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-drug was synthesized (CP-4126), with an elaidic fatty acid esterified at the 5'position. CP-4126 was tested in cell lines resistant to cytarabine, another dCyd analog or gemcitabine. Activity of gemcitabine and the derivative was comparable in the parent cell lines, while in dCK deficient cells all compounds were inactive. However, inhibition of nucleoside transport increased the IC(50) for gemcitabine up to 200-fold, but not for CP-4126, underlining the independence of a nucleoside transporter. For in vivo evaluation, nude mice bearing a human xenograft were treated intraperitoneally every third day for five doses at the maximal tolerated dose. In melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts, gemcitabine and CP-4126 were equally and highly effective; in four other xenografts moderately but equally active. In contrast to gemcitabine, CP-4126 could be administered orally, with a schedule and dose dependent toxicity and antitumor activity. In a colon cancer xenograft, antitumor activity of orally administered CP-4126 was equal to the intraperitoneally administered drug. In conclusion, CP-4126 is membrane transporter independent. Intraperitoneally administered CP-4126 was as effective as gemcitabine in several xenografts and CP-4126 is tolerated when orally administered. CP-4126 seems to be a promising new anticancer drug

DEVELOPMENT OF INACTIVATED POLIO VACCINE FROM ATTENUATED SABIN STRAINS FOR CLINICAL STUDIES AND TECHNOLOGY-TRANSFER PURPOSES

Recently, responding to WHO’s call for new polio vaccines, the development of Sabin-IPV (injectable, formalin-Inactivated Polio Vaccine, based on attenuated ‘Sabin’ polio virus strains) was initated at NVI. This activity plays an important role in the WHO polio eradication strategy. The use of Sabin instead of wild-type Salk polio strains will provide additional safety during vaccine production. Initially, the Sabin-IPV production process will be based on the scale-down model of the current, and well-established, Salk-IPV process. In parallel, process development, optimization and formulation research is being carried out to further modernize the process and reduce cost per dose. The lab-scale accelerated process development, product characterization, clinical lot production, and preparations for technology transfer will be discussed. Multivariate data analysis (MVDA) was applied on data from current IPV production (more than 60 Vero cell culture based runs) to extract relevant information, like operating ranges. Subsequently, based on the MVDA analysis, a 3-L scale-down model of the current twin 750-L bioreactors has been setup. Currently, in this lab-scale process, cell and virus culture approximate the large-scale and process improvement studies are in progress. This includes the application of increased cell densities, animal component free media, and DOE optimization in multiple parallel bioreactors. Also, results will be shown from large-scale (to prepare for future technology transfer) generation and testing of Master- and Working virus seedlots, and clinical lot (for phase I studies) production under cGMP conditions. The obtained product was used for immunogenicity studies in rats. It was shown that Sabin-IPV induces a good immune response, and a comparison will be made to regular Salk-IPV. Finally, technology transfer to vaccine manufacturers in low and middle–income countries will take place. For that, an international Sabin-IPV manufacturing course, including practical training at pilot-scale, is being setup

Measuring burden of disease in both asthma and COPD by merging the ACQ and CCQ:less is more?

Symptoms of asthma and COPD often overlap, and both diseases can co-exist in one patient. The asthma control questionnaire (ACQ) and clinical COPD questionnaire (CCQ) were developed to assess disease burden in respectively asthma or COPD. This study explores the possibility of creating a new questionnaire to assess disease burden in all obstructive lung diseases by integrating and reducing questions of the ACQ and CCQ. Data of patients with asthma, COPD and asthma-COPD overlap (ACO) were collected from a primary and secondary care center. Patients completed ACQ and CCQ on the same day. Linear regression tested correlations. Principal Component Analysis (PCA) was used for item reduction. The secondary cohort with asthma and COPD patients was used for initial question selection (development cohort). These results were reproduced in the primary care cohort and secondary cohort of patients with ACO. The development cohort comprised 252 patients with asthma and 96 with COPD. Correlation between ACQ and CCQ in asthma was R = 0.82, and in COPD R = 0.83. PCA determined a selection of 9 questions. Reproduction in primary care data (asthma n = 1110, COPD n = 1041, ACO = 355) and secondary care data of ACO patients (n = 53) resulted in similar correlations and PCA-derived selection of questions. In conclusion, PCA determined a selection of nine questions of the ACQ and CCQ: working title ‘the Obstructive Lung Disease Questionnaire’. These results suggest that this pragmatic set of questions might be sufficient to assess disease burden in obstructive lung disease in both primary as secondary care.</p

Limited effect of duration of CMV infection on adaptive immunity and frailty:insights from a 27-year-long longitudinal study

Objectives: Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation.Methods: We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint.Results: In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4+ T-cell numbers and frailty.Conclusion: Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.</p