Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.

Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver.

Many metabolic processes occur simultaneously in the liver in different locations along the porto-central axis of the liver units. These processes are often regulated by hormones, one of which is thyroid hormone which for its action depends on the presence of the different isoforms of the thyroid hormone receptor (TR). These are encoded by two genes: c-erbA-alpha encoding TRalpha1 and TRalpha2 and their respective Delta isoforms, and c-erbA-beta which encodes TRbeta1, TRbeta2 and TRbeta3. We recently found a zonal (pericentral) expression of and a diurnal variation in the TRbeta1 isoform in rat liver. We were therefore also interested to see whether TRalpha1 and TRalpha2 expression showed similar characteristics. For this reason we raised both polyclonal and monoclonal antibodies against TRalpha1 and TRalpha2 isoforms and characterised these. Antibody specificity was tested using Western blots and immunohistochemistry in liver of TR isoform-specific knockout animals. Using these antibodies we found that the TRalpha1 and TRalpha2 isoforms are zonally expressed around the central vein in rat liver. The experiments show that the portal to central gradient of TRalpha1 is broader than that of TRbeta1. Moreover, the expression of the TRalpha2 protein showed a diurnal variation with a peak in the afternoon when the animals are least active whereas no such variation was found for the TRalpha1 protein. From our data it appears that both the TRalpha1 and TRalpha2 isoforms show a zonal distribution in liver. This finding, together with the observed diurnal rhythm, has major implications for interpreting and timing experiments concerning the TR and its downstream actions in liver.

[Disorder attribution in psychiatric problems of adolescents. A pilot study of inventory validation of disorder attribution of psychiatric problems in adolescents]. / Störungskonzepte für psychische Probleme bei Jugendlichen. Pilotstudie zur Validierung eines Fragebogens zu Störungskonzepten bei psychischen Problemen von Jugendlichen (SPPJ).

OBJECTIVES: The first Questionnaire on Disorder Concepts for Mental Problems in Adolescents (SPPJ) was developed on the basis of the attributional theory (health locus of control) and validated in a population of 54 adolescents with mental disorder hospitalized primarily as in-patients. METHODS: Analysis of consistency, correlation with the test for locus of control in health and illness (KKG-Test), scale intercorrelation, correlation with the Frankfurt Self-Concept Scales, therapy cooperation and prognosis. RESULTS: The SPPJ distinguishes between causal attributions and locus of control and proves to be a reliable measuring instrument that delivers satisfactory correlations to the statement of general measuring instruments (KKG-Test). Contrary to our expectations there is no significant positive correlation between internal locus of control and cooperation and prognosis. An external, powerful-others causal attribution has a negative effect upon cooperation, while an external powerful-others locus of control has a positive effect upon it. CONCLUSIONS: Adolescent self-assessment of mental problems is a defined research subject different from illness or health concept variables in adults or concerning bodily illness. Adolescents who are less inclined to blame others for their problem and who value professional competence are probably more accepting of interventions and more compliant. Further research in this area is necessary. On the basis of the attributional theory more attention must be paid to the substantial difference between locus of (treatment) control and causal attributions.