45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 µCi45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2±1.7 and 19.3±0.5 hours respectively (mean±SEM). Plasma ammonia levels were 425±46 and 883±21 µmol/l, respectively (p<0.05). Control rabbits maintained normal plasma ammonia levels (13±5 µmol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours.45Ca2+-autoradiograms of 40 µm brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits

Natuurkwaliteit van het agrarisch gebied

Dit werkdocument geeft een beschrijving van de methode en de eerste resultaten van de natuurkwaliteit van het agrarisch gebied. Hiermee is een eerste kaart en graadmeter van de natuurkwaliteit van het agrarisch gebied op nationaal schaalniveau gereedgekomen. Het beeld vormt een aanvulling op de kaart van de actuele natuurkwaliteit van natuurreservaten, die al eerder beschikbaar is gekomen. De nu beschikbare indicator en kaart van de natuurkwaliteit van het agrarisch gebied voorziet in een belangrijke kennisleemte. Het belang van het agrarisch gebied in het behoud van biodiversiteit kan nu worden geduid. De ruimtelijke variatie in de natuurkwaliteit is ook inzichtelijk gemaakt. Het beleid kan bij het leggen van prioriteiten voor het behoud en bescherming van agrarische biodiversiteit nu rekening houden met het voorkomen van huidige natuurwaarden. Een van de belangrijkste conclusies is dat de natuurkwaliteit van het agrarisch gebied veel lager is dan in de natuurgebieden. Laagveengebieden hebben binnen het agrarische gebied de hoogste natuurkwaliteit, terwijl de centrale en noordelijke zeekleigebieden de laagste natuurkwaliteit bevatten. De aanwezige natuurkwaliteit in het agrarisch gebied, wordt voornamelijk bepaald door de aanwezigheid van broedvogels en veel minder door vaatplanten en dagvlinders. Het ruimtelijke patroon van aanwezige kwaliteit komt overeen binnen de verschillende soortgroepen broedvogels, vaatplanten en dagvlinders. De resterende natuurkwaliteit in het agrarisch gebied bevindt zich vooral in natuurlijke elementen zoals heggen, bosjes, sloten, dijken en perceelranden. Voor weidevogels is juist de mate van openheid van belang. Beschikbare landelijk dekkende verspreidingskaarten van doelsoorten dagvlinders, broedvogels en vaatplanten zijn gebruikt om de natuurkwaliteit te bepalen. Om dekkende landelijke verspreidingskaarten te maken zijn interpolatiemodellen gebruikt. De natuurkwaliteit is afgemeten aan een natuurlijke referentie, conform de systematiek van het Handboek Natuudoeltypen en daarmee ook coform de methode gebruikt voor de bepaling van de natuurkwaliteit van natuurreservaten. Elke 10-15 jaar zijn de verspreidingskaarten van dagvlinders, broedvogels en vaatplanten voldoende gedekt om een update van het landelijke beeld en de graadmeter mogelijk te maken. Tussentijdse veranderingen in de natuurkwaliteit kunnen worden gevolgd met het Netwerk Eologische Monitoring. De methode en resultaten hebben een voorlopig karakter. Er zijn nog een aantal methodische verbeteringen noodzakelijk om tot een definitief resultaat te komen. Tevens is het wenselijk om de natuurkwaliteit ook af te meten aan de hand van een meer cultuurlijke referentie

Current Tolerance-Associated Peripheral Blood Gene Expression Profiles After Liver Transplantation Are Influenced by Immunosuppressive Drugs and Prior Cytomegalovirus Infection

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplant (LTx) recipients weaned off immunosuppressive drugs (IS). Several previous studies have investigated whether peripheral blood gene expression profiles could identify operational tolerance in LTx recipients. However, the reported gene expression profiles differed greatly amongst studies, which could be caused by inadequate matching of clinical parameters of study groups. Therefore, the purpose of this study was to validate differentially expressed immune system related genes described in previous studies that identified tolerant LTx recipients after IS weaning. Blood was collected of tolerant LTx recipients (TOL), a control group of LTx recipients with regular IS regimen (CTRL), a group of LTx recipients with minimal IS regimen (MIN) and healthy controls (HC), and groups were matched on age, sex, primary disease, time after LTx, and cytomegalovirus serostatus after LTx. Quantitative Polymerase Chain Reaction was used to determine expression of twenty selected genes and transcript variants in PBMCs. Several genes were differentially expressed between TOL and CTRL groups, but none of the selected genes were differentially expressed between HC and TOL. Principal component analysis revealed an IS drug dosage effect on the expression profile of these genes. These data suggest that use of IS profoundly affects gene expression in peripheral blood, and that these genes are not associated with operational tolerance. In addition, expression levels of SLAMF7 and NKG7 were affected by prior cytomegalovirus infection in LTx recipients. In conclusion, we found confounding effects of IS regimen and prior cytomegalovirus infection, on peripheral blood expression of several selected genes that were described as tolerance-associated genes by previous studies

Natuurverkenning 2010-2040 : visies op de ontwikkeling van natuur en landschap

De Natuurverkenning verschijnt in een turbulente tijd waarin natuur en landschap sterk gepolitiseerd zijn. Met de verkenning wil het PBL een bijdrage leveren aan het structureren van het debat over de vernieuwing van het langetermijnbeleid en een impuls geven aan de politieke afwegingen. Nieuw is het gebruik van normatieve toekomstscenario’s als hulpmiddel om de achterliggende drijfveren voor natuurbeleid te verhelderen

Genetic Analyses in Small for Gestational Age Newborns

Context: Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more CNVs and disturbed methylation and sequence variants may be present in genes known to be associated with fetal growth. Design: A prospective cohort study of subjects with a low birthweight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birthweight below the 1st centile and a control cohort of 24 appropriate for gestational age newborns were studied. Intervention: Array comparative genomic hybridization, genome-wide methylation studies and exome sequencing were performed. Main Outcome Measures The numbers of copy number variations, methylation disturbances and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern and one sequence variant explaining the SGA. Additional methylation disturbances and sequence variants were present 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We conclude that copy number variations, methylation disturbances and sequence variants all contribute to prenatal growth failure. Such genetic workup can be an effective diagnostic approach in SGA newborns

Can point shear wave elastography differentiate focal nodular hyperplasia from hepatocellular adenoma

Purpose: Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are liver tumors that require different management. We assessed the potential of point shear wave elastography (pSWE) to differentiate FNH from HCA and the interobserver and intraobserver reliability of pSWE in the examination of these lesions and of native liver tissue (NLT). Methods: The study included 88 patients (65 FNH, 23 HCA). pSWE was performed by two experienced liver sonographers (observers 1 [O1] and 2 [O2]) and acquired within the lesion of interest and NLT. Group differences, optimal cutoff for characterization and interobserver reliability was assessed with Mann-Whitney-U, area under the ROC curce (AUROC) and intraclass correlation coefficient (ICC). Intraobserver reliability in NLT was assessed in 20 healthy subjects using ICC. Results: Median stiffness was significantly higher in FNH than in HCA (7.01 kPa vs 4.98 kPa for O1 (P=0.017) and 7.68 kPa vs 6.00 kPa for O2 (P=0.031)). A cutoff point for differentiation between the two entities could not be determined with an AUROC of 0.67 (O1) and 0.69 (O2). Interobserver reliability was good for lesion- stiffness (ICC=0.86) and poor for NLT stiffness (ICC=0.09). In healthy subjects, intraobserver reliability for NLT-stiffness was poor for O1 (ICC=0.23) and moderate for O2 (ICC=0.62). Conclusion: This study shows that pSWE cannot reliably differentiate FNH from HCA. Interobserver and intraobserver reliability for pSWE in NLT were insufficient. Interpretation of results gained with this method should be done with great caution

Population screening for liver fibrosis: towards early diagnosis and intervention for chronic liver diseases

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy non-invasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using non-invasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18 to 27%- in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression