Interferentie door icodextrine bij POC-glucosemetingen

Een belangrijk deel van de dialysepatiënten verkiest peritoneaaldialyse boven hemo-dialyse. Bij een deel van de peritoneaaldialysepatiënten wordt icodextrine, een glucose-polymeer, als osmotisch agens aan de dialysevloeistof toegevoegd, omdat dit langer dan glucose een osmotische gradiënt over het peritoneum kan handhaven en derhalve een langere dialyseduur mogelijk maakt. Het blijkt echter dat een deel van het icodextrine via het lymfestelsel in de bloedbaan terechtkomt, waar het wordt gehydrolyseerd tot onder andere maltose en maltotriose. Deze glucose-oligomeren hopen zich op in het bloed en blijken in een aantal POC (point-of-care) glucosemeters aanleiding te geven tot significante overschattingen van de glucosewaarde met mogelijk dramatische gevolgen. Dit effect is voor een serie POC-glucosemeters bestudeerd, zowel door het bloed van peritoneaaldialysepatiënten te analyseren, als door in-vitro te kijken naar de kwantitatieve effecten van (commercieel) maltose en maltotriose: voornamelijk de POC-meters die gebruik maken van bacterieel geproduceerd glucosedehydrogenase lijken glucosespecificiteit te ontberen

Interferentie door icodextrine bij POC-glucosemetingen

Een belangrijk deel van de dialysepatiënten verkiest peritoneaaldialyse boven hemo-dialyse. Bij een deel van de peritoneaaldialysepatiënten wordt icodextrine, een glucose-polymeer, als osmotisch agens aan de dialysevloeistof toegevoegd, omdat dit langer dan glucose een osmotische gradiënt over het peritoneum kan handhaven en derhalve een langere dialyseduur mogelijk maakt. Het blijkt echter dat een deel van het icodextrine via het lymfestelsel in de bloedbaan terechtkomt, waar het wordt gehydrolyseerd tot onder andere maltose en maltotriose. Deze glucose-oligomeren hopen zich op in het bloed en blijken in een aantal POC (point-of-care) glucosemeters aanleiding te geven tot significante overschattingen van de glucosewaarde met mogelijk dramatische gevolgen. Dit effect is voor een serie POC-glucosemeters bestudeerd, zowel door het bloed van peritoneaaldialysepatiënten te analyseren, als door in-vitro te kijken naar de kwantitatieve effecten van (commercieel) maltose en maltotriose: voornamelijk de POC-meters die gebruik maken van bacterieel geproduceerd glucosedehydrogenase lijken glucosespecificiteit te ontberen

Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation

T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.</p

Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

The Cercospora nicotianae gene encoding dual O-methyltransferase and FAD-dependent monooxygenase domains mediates cercosporin toxin biosynthesis

Cercosporin, a photo-activated, non-host-selective phytotoxin produced by many species of the plant pathogenic fungus Cercospora, causes peroxidation of plant cell membranes by generating reactive oxygen species and is an important virulence determinant. Here we report a new gene, CTB3 that is involved in cercosporin biosynthesis in Cercospora nicotianae. CTB3 is adjacent to a previously identified CTB1 encoding a polyketide synthase which is also required for cercosporin production. CTB3 contains a putative O-methyltransferase domain in the N-terminus and a putative flavin adenine dinucleotide (FAD)-dependent monooxygenase domain in the C-terminus. The N-terminal amino acid sequence also is similar to that of the transcription enhancer AFLS (formerly AFLJ) involved in aflatoxin biosynthesis. Expression of CTB3 was differentially regulated by light, medium, nitrogen and carbon sources and pH. Disruption of the N-or C-terminus of CTB3 yielded mutants that failed to accumulate the CTB3 transcript and cercosporin. The Delta ctb3 disruptants produced a yellow pigment that is not toxic to tobacco suspension cells. Production of cercosporin in a Delta ctb3 null mutant was fully restored when transformed with a functional CTB3 clone or when paired with a Delta ctb1-null mutant (defective in polyketide synthase) by cross feeding of the biosynthetic intermediates. Pathogenicity assays using detached tobacco leaves revealed that the Delta ctb3 disruptants drastically reduced lesion formation. (c) 2006 Elsevier Inc. All rights reserved