Financiële draagkracht pluimveesector en het diergezondheidsfonds

De kosten voor de bestrijding van besmettelijke dierziekten, zoals de vogelpest, kunnen hoog oplopen. Het bedrijfsleven zelf heeft slechts beperkte mogelijkheden om de financiering van deze kosten te dragen. Alleen onder optimistische veronderstellingen blijft de draagkracht van de sector op hetzelfde niveau als de afgelopen jaren

Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-κB activation and sensitizes toward TNFα-induced cytotoxicity

Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-κB, respectively. Here, we systematically investigated Nrf2 and NF-κB signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-κB activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-κB, GFP-tagged p65, upon TNFR signaling induced by TNFα using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-κB nuclear translocation, yet reversely, activation of NF-κB by TNFα did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNFα-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNFα, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-κB signaling may be pivotal in the regulation of DILI. We propose that the NF-κB-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines

Standard Gross Margins in the Netherlands

This report contains information on the Standard Gross Margins (SGM), as they are used to classify farms and to fix the economic size of farms. Information is provided on the cal-culation, with details on the input costs and the data sources. Besides that a comparison is made between the results of the aggregation of SGM and the values in the Economic Ac-count on Agriculture (EAA) for the Netherlands. The report is made on request of Eurostat

Appendicular intussusception with lymphoid hyperplasia

A 4-year-old boy is sent to paediatric consultation for nightrecurring abdominal pain of 3 weeks duration

Calcium-induced cytotoxicity in hepatocytes after exposure to extracellular ATP is dependent on inorganic phosphate. Effects on mitochondrial calcium

In isolated mitochondria extensive uptake of Ca2+ in the presence of an "inducing agent," e.g. inorganic phosphate (Pi), causes permeabilization of the mitochondrial inner membrane and a collapse of the mitochondrial membrane potential. In this study we tested whether the effect of phosphate occurs in intact hepatocytes. Rat hepatocytes were incubated with ATP to induce a sustained increase in intracellular Ca2+ ([Ca2+]i), dissipation of the mitochondrial membrane potential, and cell death (Zoeteweij, J. P., van de Water, B., de Bont, H. J. G. M., Mulder, G. J., and Nagelkerke, J. F. (1992) Biochem. J. 288, 207-213). Omission of Pi from the incubation medium delayed the loss of viability. The nonhydrolyzable ATP analog adenosine 5'-O-(thiotriphosphate) (ATP gamma S) had similar effects on [Ca2+]i and viability, but now omission of extracellular Pi completely protected against cytotoxicity. Exposure to ATP or ATP gamma S induced a large cellular uptake of Pi. With the use of video-microscopy a significant increase in mitochondrial free calcium was observed before the onset of cell death. Accumulation of mitochondrial calcium was reduced when extracellular Pi was omitted. These results suggest that, after induction of high [Ca2+]i by ATP in hepatocytes, 1) mitochondria accumulate calcium which is associated with cell toxicity and 2) intracellular Pi increases which stimulates mitochondrial calcium uptake. These observations support a calcium-dependent mitochondrial dysfunction, induced by phosphate, as a valid model for ATP-induced cytotoxicity in hepatocytes.Toxicolog

Role of mitochondrial Ca2+ in the oxidative stress-induced dissipation of the mitochondrial membrane potential. Studies in isolated proximal tubular cells using the nephrotoxin 1,2-dichlorovinyl-L-cysteine

The relationship between mitochondrial Ca2+, oxidative stress, and a dissipation of the mitochondrial membrane potential (delta psi) was investigated in proximal tubular kidney cells. Freshly isolated proximal tubular cells from rat kidney were exposed to the nephrotoxin 1,2-dichlorovinyl-L-cysteine (DCVC). DCVC stimulated the formation of hydroperoxides as determined by flow cytometry using the hydroperoxide-sensitive compound dichlorofluorescein. This was prevented by the antioxidant diphenylphenylenediamine (DPPD) and the iron chelator desferrioxamine. Studies in individual cells with video-intensified fluorescence microscopy showed that a DCVC-induced increase in the intracellular free calcium concentration ([Ca2+]i) was accompanied by an increase in the mitochondrial free calcium concentration ([Ca2+]m). The latter increase was selectively prevented by an inhibitor of the mitochondrial calcium uniporter, ruthenium red (RR). Chelation of cellular Ca2+ with EGTA acetoxymethyl ester (EGTA/AM) completely prevented the formation of hydroperoxides, whereas inhibition of the uptake of Ca2+ by the mitochondria with RR reduced it. This indicates that the increase in [Ca2+]m is important for the induction of oxidative stress by DCVC. DPPD and desferrioxamine did not protect against a DCVC-induced increase in [Ca2+]i and [Ca2+]m, indicating that oxidative stress is the consequence rather than the cause of the cellular calcium perturbations. DCVC decreased delta psi and caused cell death; both effects were clearly delayed by EGTA/AM and RR, although they could not prevent a decrease in delta psi. The latter decrease was completely prevented by inhibition of the beta-lyase-mediated metabolism of DCVC with aminooxyacetic acid. Like EGTA/AM, inhibition of oxidative stress with DPPD and desferrioxamine delayed the decrease in delta psi. This strongly suggests that the decrease in delta psi caused by metabolites of DCVC directly is potentiated by Ca(2+)-dependent DCVC-induced hydroperoxide formation. The importance of both hydroperoxide formation and mitochondrial damage in DCVC-induced cell killing is discussed.Toxicolog

Suikerbeleid: vergelijking oxfam en EU-voorstellen

Dit rapport vergelijkt de mogelijke gevolgen van voorstellen met betrekking tot de hervorming van de EU-suikermarktordening. Het betreft de voorstellen van de Europese Commissie, gepresenteerd in juli 2004, en van Oxfam. Ingegaan wordt op de gevolgen voor de werkgelegenheid en de economie in Nederland en op de effecten voor het inkomen van de akkerbouwers. Sugar policy: comparison between Oxfam and EU proposals This report compares the possible consequences of proposals in respect of the reform of the EU sugar market organisation. The proposals concerned are the European Commission proposals presented in July 2004 and the Oxfam proposals. The report looks at the consequences for employment and the economy in the Netherlands and the impact on the income of arable farmers

The residence time of focal adhesion kinase (FAK) and paxillin at focal adhesions in renal epithelial cells is determined by adhesion size, strength and life cycle status

Toxicolog

An illness-focused interactive booklet to optimise management and medication for childhood fever and infections in out-of-hours primary care: Study protocol for a cluster randomised trial

Background: Fever is the most common reason for a child to be taken to a general practitioner (GP), especially during out-of-hours care. It is mostly caused by self-limiting infections. However, antibiotic prescription rates remain high, especially during out-of-hours care. Anxiety and lack of knowledge among parents, and perceived pressure to prescribe antibiotics amongst GPs, are important determinants of excessive antibiotic prescriptions. An illness-focused interactive booklet has the potential to improve this by providing parents with information about fever self-management strategies. The aim of this study is to develop and determine the effectiveness of an interactive booklet on management of children presenting with fever at Dutch GP out-of-hours cooperatives. Methods/design: We are conducting a cluster randomised controlled trial (RCT) with 20 GP out-of-hours cooperatives randomised to 1 of 2 arms: GP access to the illness-focused interactive booklet or care as usual. GPs working at intervention sites will have access to the booklet, which was developed in a multistage process. It consists of a traffic light system for parents on how to respond to fever-related symptoms, as well as information on natural course of infections, benefits and harms of (antibiotic) medications, self-management strategies and 'safety net' instructions. Children < 12 years of age with parent-reported or physician-measured fever are eligible for inclusion. The primary outcome is antibiotic prescribing during the initial consultation. Secondary outcomes are (intention to) (re)consult, antibiotic prescriptions during re-consultations, referrals, parental satisfaction and reassurance. In 6 months, 20,000 children will be recruited to find a difference in antibiotic prescribing rates of 25% in the control group and 19% in the intervention group. Statistical analysis will be performed using descriptive statistics and by fitting two-level (GP out-of-hours cooperative and patient) random intercept logistic regression models. Discussion: This will be the first and largest cluster RCT evaluating the effectiveness of an illness-focused interactive booklet during GP out-of-hours consultations with febrile children receiving antibiotic prescriptions. It is hypothesised that use of the booklet will result in a reduced number of antibiotic prescriptions, improved parental satisfaction and reduced intention to re-consult. Trial registration: ClinicalTrials.gov identifier: NCT02594553. Registered on 26 Oct 2015, last updated 15 Sept 2016