Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS

Abnormal IgD and IgA1 O-glycosylation in hyperimmunoglobulinaemia D and periodic fever syndrome

In order to determine the glycosylation pattern for IgD, and to examine whether there are changes in the pattern of IgD and IgA1 O-glycosylation in patients with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) during acute febrile attacks and during periods of quiescence, serum was obtained from 20 patients with HIDS and 20 control subjects. In the HIDS group, serum was obtained either during an acute febrile episode (n = 9) or during a period of quiescence (n = 11). The O-glycosylation profiles of native and desialylated IgA1 and IgD were measured in an ELISA-type system using the lectins Helix aspersa and peanut agglutinin, which bind to alternative forms of O-glycan moieties. IgD is more heavily O-galactosylated and less O-sialylated than IgA1 in healthy subjects. HIDS is associated with more extensive O-galactosylation of IgD and a reduction in O-sialylation of both IgD and IgA1. These changes are present both during acute febrile attacks and periods of quiescence. The T cell IgD receptor is a lectin with binding affinity for the O-glycans of both IgD and IgA1. The observed changes in IgD and IgA1 O-glycosylation are likely to have a significant effect on IgD/IgA1–T cell IgD receptor interactions including basal immunoglobulin synthesis, and possibly myeloid IgD receptor-mediated cytokine release

Nanozymes: Gold-nanoparticles-based Transphosphorylation Catalysts

Particularly effective: The self-assembly of triazacyclonane-functionalized thiols on the surface of nanosize gold particles provides a facile entry to functional gold nanoparticles that, upon complexation with ZnII, turn into powerful catalysts for the cleavage of phosphate esters (see scheme). Because of their RNase-like behavior they are dubbed nanozymes

Development of advanced control strategies for a dynamic triaxial soil testing machine

As civil engineering projects become increasingly ambitious, the earthworks that form a significant part of these projects become increasingly critical. Geotechnical engineering is concerned with the measurement , modelling and simulation of soil under various conditions for the application within civil engineering. In triaxial testing, an actuator applies a force or displacement to a soil sample. Dynamic triaxial testing is concerned with applying forces conforming to a rapidly changing pattern. The simplest case is concerned with applying a force in a sinusoidal pattern. The accuracy of models produced during triaxial testing depends largely on the accuracy of the equipment used for testing. As such, the control of the applied force is of great importance. The response of the soil sample directly influences the closed loop behaviour of the system. The soil sample response is unknown at the start of the test , can vary throughout a test and depends on various parameters, many of which are unobservable. This research investigates the issues faced in developing accurate control of dynamic triaxial testing equipment. Models of the load frame and various nonlinear soil sample responses are built for the purpose of simulation and controller design. Various control strategies are developed, implemented and tested, including the use of PID control, adaptive repetitive control and sliding mode control techniques. The recursive least squares algorithm is investigated and used for online identification in order to compensate for unknown and time varying plant parameters. Simulation and testing methods are investigated and several control methods are tested in simulation, on the target triaxial load frame using and finally using embedded processing hardware. Development and implementation techniques are also used including rapid prototyping and hardware-in-the-loop testing.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Evaluation of EU Risk Assessments Existing Chemicals (EC Regulation 793/93).

Abstract not availableJRC.I-Institute for Health and Consumer Protection (Ispra

Evaluatie van EU Risicobeoordelingen Bestaande Stoffen (EG Verordening 793/93)

An evaluation was performed on the first group (41) of completed risk assessments for chemicals of the EU priority lists (Existing Chemicals; EC Regulation 793/93). The evaluation focussed on the conclusions of the risk assessments. The EU risk assessment process detected a high number of substances of concern. Furthermore priority chemicals may pose (potential) risks to the whole range of protection goals of the risk assessment. The predictability of the risk assessments for priority chemicals was investigated. Our a priori knowledge on possible risks of priority chemicals is found to be poor, especially for consumers. Both for environment and human health the (potential) risks were linked with a broad spectrum of use patterns. It is concluded that no industry category can in advance be excluded from performing risk assessments. For a great number of chemicals, additional testing was found to be needed to finalise the risk assessment. This evokes questions about the completeness of the current base-set, but also about the suitability of some of the submitted human health tests that should initially fulfil the base-set needs. The results of this evaluation are useful for future discussions on risk assessment processes for chemicals.Vanaf 1993 is de EG-Verordening 793/93 van kracht die zich richt op de risico's van 'bestaande stoffen'. Sindsdien worden er voor deze stoffen EU-risicobeoordelingen gemaakt. Het RIVM heeft een evaluatie-onderzoek gedaan naar de 'overall' uitkomsten van het werk tot nu toe. Het EU risicobeoordelingsproces heeft een groot aantal stoffen naar voren gebracht die aanleiding geven tot zorg. Dit gold maar liefst voor 34 van de 41 beoordeelde chemicalien. Een onderzoeksvraag betrof of de uitkomst van de risicobeoordeling altijd strookt met de verwachte risico's van een stof. Vooral bij de consument blijken veel 'onderschattingen' voor te komen. Stoffen komen blijkbaar in producten terecht waar ze totaal niet thuis horen. Verder is gekeken of er een relatie bestaat tussen de potentiele risico's van de stoffen en het type gebruik van de stof. Duidelijk werd dat de risico's gekoppeld zijn aan een zeer breed scala van gebruikscategorieen. De industrie is wettelijk verplicht om een zogenaamde basis-set van gegevens aan te leveren voor een stof. Ondanks deze basis-set bleek dat voor veel stoffen aanvullende testen noodzakelijk waren om de risicoschatting goed te kunnen afronden. Deze resultaten roepen vragen op over de juistheid en compleetheid van de huidige basis-set. De resultaten van dit onderzoek zijn bruikbaar bij de voorbereidende discussies voor een nieuw EU stoffenbeleid

Evaluatie van EU Risicobeoordelingen Bestaande Stoffen (EG Verordening 793/93)

Vanaf 1993 is de EG-Verordening 793/93 van kracht die zich richt op de risico's van 'bestaande stoffen'. Sindsdien worden er voor deze stoffen EU-risicobeoordelingen gemaakt. Het RIVM heeft een evaluatie-onderzoek gedaan naar de 'overall' uitkomsten van het werk tot nu toe. Het EU risicobeoordelingsproces heeft een groot aantal stoffen naar voren gebracht die aanleiding geven tot zorg. Dit gold maar liefst voor 34 van de 41 beoordeelde chemicalien. Een onderzoeksvraag betrof of de uitkomst van de risicobeoordeling altijd strookt met de verwachte risico's van een stof. Vooral bij de consument blijken veel 'onderschattingen' voor te komen. Stoffen komen blijkbaar in producten terecht waar ze totaal niet thuis horen. Verder is gekeken of er een relatie bestaat tussen de potentiele risico's van de stoffen en het type gebruik van de stof. Duidelijk werd dat de risico's gekoppeld zijn aan een zeer breed scala van gebruikscategorieen. De industrie is wettelijk verplicht om een zogenaamde basis-set van gegevens aan te leveren voor een stof. Ondanks deze basis-set bleek dat voor veel stoffen aanvullende testen noodzakelijk waren om de risicoschatting goed te kunnen afronden. Deze resultaten roepen vragen op over de juistheid en compleetheid van de huidige basis-set. De resultaten van dit onderzoek zijn bruikbaar bij de voorbereidende discussies voor een nieuw EU stoffenbeleid.An evaluation was performed on the first group (41) of completed risk assessments for chemicals of the EU priority lists (Existing Chemicals; EC Regulation 793/93). The evaluation focussed on the conclusions of the risk assessments. The EU risk assessment process detected a high number of substances of concern. Furthermore priority chemicals may pose (potential) risks to the whole range of protection goals of the risk assessment. The predictability of the risk assessments for priority chemicals was investigated. Our a priori knowledge on possible risks of priority chemicals is found to be poor, especially for consumers. Both for environment and human health the (potential) risks were linked with a broad spectrum of use patterns. It is concluded that no industry category can in advance be excluded from performing risk assessments. For a great number of chemicals, additional testing was found to be needed to finalise the risk assessment. This evokes questions about the completeness of the current base-set, but also about the suitability of some of the submitted human health tests that should initially fulfil the base-set needs. The results of this evaluation are useful for future discussions on risk assessment processes for chemicals.DGM-SA