20 research outputs found
A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function
BACKGROUND:
The Holt-Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15-month-old patient being investigated for strict diagnostic criteria of HOS. -----
METHODS AND RESULTS:
Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T-box transcription factors playing major roles in morphogenesis and cell-type specification. The mutation located in the DNA-binding domain at position 920 (C→A) leads to an amino acid change at position 85 (proline → threonine). Three-dimensional analysis of the protein structure predicted a cis to trans change in the respective peptide bond, thereby probably provoking major conformational and functional alterations of the protein. The p.Pro85Thr mutation showed a dramatically reduced activation (97%) of the NPPA promoter in luciferase assays and failed to induce NPPA expression in HEK 293 cells compared to wild-type TBX5 protein. The mutation did not interfere with the nuclear localization of the protein. -----
CONCLUSION:
These results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient
Digitale Lehre in der Kunstgeschichte. Eine Handreichung
Der Arbeitskreis Digitale Kunstgeschichte will mit dieser Handreichung die Lehrenden in der Kunstgeschichte bei der Realisierung ihrer Veranstaltungen unterstützen und den Erfahrungsaustausch untereinander fördern. Die Handreichung führt kurz in die zentralen Fragen für eine erfolgreiche digital gestützte Lehre ein. Im Sinne einer kompetenzorientierten Lehre werden die spezifischen Besonderheiten der kunsthistorischen Lehre thematisiert und anschließend konkrete Hilfestellungen gegeben. Hier stehen vor allem die technische Infrastruktur, die didaktischen Formate und die kunsthistorischen Quellen und die Literatur im Internet im Vordergrund
Prostaglandin D2-supplemented “functional eicosanoid testing and typing” assay with peripheral blood leukocytes as a new tool in the diagnosis of systemic mast cell activation disease: an explorative diagnostic study
Background: Systemic mast cell activation disease (MCAD) is characterized by an enhanced release of mast cell-derived mediators, including eicosanoids, which induce a broad spectrum of clinical symptoms. Accordingly, the diagnostic algorithm of MCAD presupposes the proof of increased mast cell mediator release, but only a few mediators are currently established as routine laboratory parameters. We thus initiated an explorative study to evaluate in vitro typing of individual eicosanoid pattern of peripheral blood leukocytes (PBLs) as a new diagnostic tool in MCAD. Methods: Using the “functional eicosanoid testing and typing” (FET) assay, we investigated the balance (i.e. the complex pattern of formation, release and mutual interaction) of prostaglandin E2 (PGE2) and peptido-leukotrienes (pLT) release from PBLs of 22 MCAD patients and 20 healthy individuals. FET algorithms thereby consider both basal and arachidonic acid (AA)-, acetylsalicylic acid (ASA)-, and substance P (SP)-triggered release of PGE2 and pLT. The FET assay was further supplemented by analyzing prostaglandin D2 (PGD2), as mast cell-specific eicosanoid. Results: We observed marked PGE2-pLT imbalances for PBLs of MCAD patients, as indicated by a markedly enhanced mean FET value of 1.75 ± 0.356 (range: 1.14–2.36), compared to 0.53 ± 0.119 (range: 0.36-0.75) for healthy individuals. In addition, mean PGD2 release from PBLs of MCAD patients was significantly, 6.6-fold higher than from PBLs of healthy individuals (946 ± 302.2 pg/ml versus 142 ± 47.8 pg/ml; P < 0.001). In contrast to healthy individuals, PGD2 release from PBLs of MCAD patients was markedly triggered by SP (mean: 1896 ± 389.7 pg/ml; P < 0.001), whereas AA and ASA caused individually varying effects on both PGD2 and pLT release. Conclusions: The new in-vitro FET assay, supplemented with analysis of PGD2, demonstrated that the individual patterns of eicosanoid release from PBLs can unambiguously distinguish MCAD patients from healthy individuals. Notably, in our analyses, the FET value and both basal and triggered PGD2 levels were not significantly affected by MCAD-specific medication. Thus, this approach may serve as an in-vitro diagnostic tool to estimate mast cell activity and to support individualized therapeutic decision processes for patients suffering from MCAD
Charakteristika der staatlichen Einbindung von Eliten und Bevölkerung in Ideokratien
"This paper shows that ideocracies, especially communist ideocracies, have a specific pattern of cooptation and incorporation of elites and ordinary citizens, which is different from all other political regime types. Ideocracies dominate society through and through by a net of measures that make the citizens materially dependent on the state, from which the individual citizen cannot escape. The strong concentration of the distribution of goods and positions in the hands of the ideocratic state goes hand in glove with the great power to repress non - co - opted people. However, there are trade - offs in the ideocratic pattern of cooptation. The tendency of ideocracies to infantilize its citizens, may provoke reluctance even among otherwise politically indifferent citizens. Nevertheless, despite the trade - offs, the specific pattern of cooptation and incorporation of citizens and elites might help to explain why communist ideocracies were very durable in comparison to other types of political regimes." (author's abstract
Determination of plasma heparin level improves identification of systemic mast cell activation disease.
Diagnosis of mast cell activation disease (MCAD), i.e. systemic mastocytosis (SM) and idiopathic systemic mast cell activation syndrome (MCAS), usually requires demonstration of increased mast cell (MC) mediator release. Since only a few MC mediators are currently established as biomarkers of MCAD, the sensitivity of plasma heparin level (pHL) as an indicator of increased MC activation was compared with that of serum tryptase, chromogranin A and urinary N-methylhistamine levels in 257 MCAD patients. Basal pHL had a sensitivity of 41% in MCAS patients and 27% in SM patients. Non-pharmacologic stimulation of MC degranulation by obstruction of venous flow for 10 minutes increased the sensitivity of pHL in MCAS patients to 59% and in SM patients to 47%. In MCAS patients tryptase, chromogranin A, and N-methylhistamine levels exhibited low sensitivities (10%, 12%, and 22%, respectively), whereas sensitivities for SM were higher (73%, 63%, and 43%, respectively). Taken together, these data suggest pHL appears more sensitive than the other mediators for detecting systemic MC activity in patients with MCAS. The simple, brief venous occlusion test appears to be a useful indicator of the presence of pathologically irritable MCs, at least in the obstructed compartment of the body
Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks
Sensitivities of heparin, tryptase, chromogranin A levels in blood and <i>N</i>-methylhistamine excretion into urine for indication of an increased mast cell activity.
<p>Sensitivities of heparin, tryptase, chromogranin A levels in blood and <i>N</i>-methylhistamine excretion into urine for indication of an increased mast cell activity.</p
Mast cell mediators or their metabolites in blood or urine which currently can be determined as routine laboratory parameters.
<p>Mast cell mediators or their metabolites in blood or urine which currently can be determined as routine laboratory parameters.</p