De landbouw en het landelijk gebied in Nederland in beeld : Een houtskoolschets van de SWOT voor het GLB

Voor de periode 2021-2027 moeten lidstaten in een Nationaal Strategisch Plan (NSP) uiteenzetten hoe zij met hun beleidsinzet gaan bijdragen aan door de Europese Commissie geformuleerde doelstellingen voor het Gemeenschappelijk Landbouwbeleid. Deze beleidsinzet is mede gebaseerd op een zogenaamde SWOT-analyse (Strengths Weaknesses Opportunities Threats). Met oog op het voorbereiden van het NSP, heeft het ministerie van LNV ervoor gekozen om een SWOT-analyse te maken in twee fasen. In de eerste fase wordt een SWOT-analyse op hoofdlijnen ('Houtskool-SWOT') opgesteld. In een tweede fase komt de definitieve SWOT-analyse tot stand. Dit rapport bevat de Houtskool-SWOT

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of &gt;50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.</p

Fluorescence studies on the mechanism of action of the cholesteryl ester transfer protein (CETP) in human plasma

Paper from the SmithKline & French Research Symposium, Cambridge, 1988Non peer reviewe

Preferential lipid association and mode of penetration of apocytochrome c in mixed model membranes as monitored by tryptophanyl fluorescence quenching using brominated phospholipids

The fluorescence of the single tryptophan residue at position 59 in apocytochrome c, the biosynthetic precursor of the inner mitochondrial membrane protein cytochrome c, was studied in small unilamellar vesicles composed of phosphatidylserine (PS) and phosphatidylcholine (PC) with or without specifically Br-labelled acyl chains at the sn-2 position. The protein has a very high affinity for PS-containing vesicles (dissociation constant Kd less than 1 microM). From the relative quenching efficiency by the brominated phospholipids, it could be concluded that the protein specifically associates with the PS component in mixed vesicles and that maximal quenching occurred with phospholipids in which the bromine was present at the 6,7-position of the 2-acyl chain suggesting that (part of) the bound protein penetrates 7-8 A deep into the hydrophobic core of the bilayer.Peer reviewe

Regulation of the activity of phosphatidylcholine transfer protein by vesicle phosphatidic-acid and membrane curvature : a fluorescence study using 2-parinaroylphosphatidylcholine

Peer reviewe

Fractalkine is expressed by smooth muscle cells in response to IFN-gamma and TNF-alpha and is modulated by metalloproteinase activity

Fractalkine/CX3C-chemokine ligand 1 is expressed as a membrane-spanning adhesion molecule that can be cleaved from the cell surface to produce a soluble chemoattractant. Within the vasculature, fractalkine is known to be generated by endothelial cells, but to date there are no reports describing its expression by smooth muscle cells (SMC). In this study we demonstrate that IFN-gamma and TNF-alpha, but not IL-1beta, cooperate synergistically to induce fractalkine mRNA and protein expression In cultured aortic SMC. We also report the release of functional, soluble fractalkine from the membranes of stimulated SMC. This release is inhibited by the zinc metalloproteinase inhibitor batimastat, resulting in the accumulation of membrane-associated fractalkine on the SMC surface. Therefore, an SMC-derived metalloproteinase activity is involved in fractalkine shedding. While soluble fractalkine present in SMC-conditioned medium is capable of inducing calcium transients in cells expressing the fractalkine receptor (CX3CR1), blocking experiments using neutralizing Abs reveal that it can be inactivated without affecting the chemotactic activity of SMC-conditioned media on monocytes. However, membrane-bound fractalkine plays a major role in promoting adhesion of monocytic cells to activated SMC. This fractalkine-mediated adhesion is further enhanced in the presence of batimastat, indicating that shedding of fractalkine from the cell surface down-regulates the adhesive properties of SMC. Hence, during vascular inflammation, the synergistic induction of fractalkine by IFN-gamma and TNF-alpha together with its metalloproteinase-mediated cleavage may finely control the recruitment of monocytes to SMC within the blood vessel wall.Peer reviewe

The effect of (-)-hydroxycitrate and mevinolin on the activity of the low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the human hepatoma Hep G2

Peer reviewe

Effects of a novel lanosterol 14α-demethylase inhibitor on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in Hep G2 cells

A 32-carboxylic acid derivative of lanosterol (SKF 104976) was found to be a potent inhibitor of lanosterol 14α-demethylase (14αDM). 14αDM activity in a Hep G2 cell extract was inhibited 50% by 2 nM SKF 104976. Exposure of intact cells to similar concentrations of the compound resulted in the inhibition of incorporation of [ 14C]acetate into cholesterol with concomitant accumulation of lanosterol as well as a 40-70% decrease in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity. SKF 104976 did not effect low density lipoprotein uptake and degradation in Hep G2 cells, suggesting that HMGR and low density lipoprotein receptor activity were not coordinately regulated under these conditions. Reduction of the flux of carbon units in the sterol synthetic pathway by as much as 80% did not alter the suppressing effect of SKF 104976 on HMGR activity. However, under conditions where sterol synthesis was almost completely blocked by lovastatin, HMGR activity was not suppressed by SKF 104976. Mevalonate, at concentrations that did not decrease HMGR activity, was able to restore the inhibiting effect of SKF 104976 on HMGR activity. The rapid inhibition (2-3 h) of HMGR activity by SKF 104976 to 30-60% of the level in controls was not dependent on the initial amount of HMGR enzyme present. These findings suggest that upon inhibition of 14αDM by SKF 104976, a mevalonate-derived precursor regulates HMGR activity, even when the sterol synthetic rate is considerably reduced and when HMGR protein levels are very high. In Hep G2 cells, formation of oxylanostenols from [ 3H]mevalonate reached a maximum between 1 and 10 nM SKF 104976 and was negligible at higher concentrations. This result suggests that oxylanostenols are not the key mediators of the modulation of HMGR in Hep G2 cells upon 14αDM inhibition.Peer reviewe

SKF 99085 a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, suppresses HMG-CoA reductase and induces LDL receptor activity by a novel mechanism

Poster abstractPeer reviewe