Zahnanomalien in der Neuropädiatrie

Dental anomalies in children with neuropediatric disorders are easy to diagnose and can be essential in the diagnosis of different entities. They are present in well-known disorders as Incontinentia pigmenti, but also in rare diseases as in Kohlschütter-Tönz syndrome or the recently described ataxia, delayed dentition and hypomyelination. Anomalies of dental shape, enamel and in this case also teeth color, dental number and eruption are all encountered. Knowledge of these abnormalities is important for both clinical geneticist and child neurologist.     

Genetik der koronaren Herzkrankheit und des Herzinfarkts

Because of their high prevalence, cases of coronary artery disease (CAD) and myocardial infarction (MI) are frequently found when asking for a patient’s family history. It is common knowledge that a positive familial history constitutes a risk factor for CAD in its own right, in addition to smoking, increased alcohol intake, diabetes, obesity, hypertension, and hyperlipidemia. Nevertheless, for correct risk assessment it is crucial to accurately distinguish between sporadic and true familial cases of CAD and MI. Familial disposition is present when at least one male first-grade relative under the age of 55 or one female first-grade relative under the age of 65 has/had been diagnosed with myocardial infarction or significant coronary artery disease. In the review presented here, we compile the relevant epidemiological and genetic studies that constitute the scientific basis of this risk assessment. Furthermore, a short overview of the state of the art of genetic CAD/MI research is given.     

L‐fucose influences chemotaxis and biofilm formation in Campylobacter jejuni

Campylobacter jejuni and Campylobacter coli are zoonotic pathogens once considered asaccharolytic, but are now known to encode pathways for glucose and fucose uptake/metabolism. For C. jejuni, strains with the fuc locus possess a competitive advantage in animal colonization models. We demonstrate that this locus is present in > 50% of genome‐sequenced strains and is prevalent in livestock‐associated isolates of both species. To better understand how these campylobacters sense nutrient availability, we examined biofilm formation and chemotaxis to fucose. C. jejuni NCTC11168 forms less biofilms in the presence of fucose, although its fucose permease mutant (fucP) shows no change. In a newly developed chemotaxis assay, both wild‐type and the fucP mutant are chemotactic towards fucose. C. jejuni 81‐176 naturally lacks the fuc locus and is unable to swim towards fucose. Transfer of the NCTC11168 locus into 81‐176 activated fucose uptake and chemotaxis. Fucose chemotaxis also correlated with possession of the pathway for C. jejuni RM1221 (fuc+) and 81116 (fuc‐). Systematic mutation of the NCTC11168 locus revealed that Cj0485 is necessary for fucose metabolism and chemotaxis. This study suggests that components for fucose chemotaxis are encoded within the fuc locus, but downstream signals only in fuc + strains, are involved in coordinating fucose availability with biofilm development.     

Reversible oxidative modification as a mechanism for regulating retroviral protease dimerization and activation

Human immunodeficiency virus protease activity can be regulated by reversible oxidation of a sulfur-containing amino acid at the dimer interface. We show here that oxidation of this amino acid in human immunodeficiency virus type 1 protease prevents dimer formation. Moreover, we show that human T-cell leukemia virus type 1 protease can be similarly regulated through reversible glutathionylation of its two conserved cysteine residues. Based on the known three-dimensional structures and multiple sequence alignments of retroviral proteases, it is predicted that the majority of retroviral proteases have sulfur-containing amino acids at the dimer interface. The regulation of protease activity by the modification of a sulfur-containing amino acid at the dimer interface may be a conserved mechanism among the majority of retroviruses.     

The role of the ACTH receptor in adrenal tumors: identification of a novel microsatellite marker.

In vitro, the growth inhibiting effect of ACTH on adrenocortical cells is well documented, even though there are reports of opposite effects under defined cell culture conditions. In vivo, activation of the ACTH receptor (ACTHR) has a trophic effect on the adrenal cortex, while the effects on proliferation are still under discussion, especially since other POMC derived peptides have been characterized. However, ACTH is thought to act as a differentiation factor with inhibiting effects on tumor growth. In undifferentiated adrenocortical carcinomas, ACTHR expression is frequently lost, which is associated with extensive tumor growth. We describe a new microsatellite marker within the intron of the ACTHR gene termed ACTHRint1. In a series of 114 patients with various adrenal and non-adrenal tumors, the rate of heterozygosity was 100 %. Only one out of 57 patients with adrenocortical adenoma showed LOH at the ACTHR locus, whereas 4 of 10 carcinomas had loss of one allele. Patients suffering from tumors with LOH showed a more aggressive disease course and had earlier recurrences with poor prognosis. These data confirm earlier findings that adrenocortical carcinomas frequently show loss of ACTHR expression, which is associated with a more aggressive tumor growth. However, whether the ACTHR is directly involved in tumor growth or acts a marker of differentiation that is lost in more advanced tumor stages is still not clear.     

Reconciliation in wild white-faced capuchins (Cebus capucinus)

The likelihood of reconciliation (defined as preferential peaceful contact among former opponents following conflicts) has been predicted to vary positively with relationship value and compatibility, and negatively with relationship security. Long-term data on wild white-faced capuchins (Cebus capucinus) indicate that dyads consisting of an adult female and an alpha male have high value and compatibility, but low security. Two studies of C. capucinus postconflict (PC) behavior were carried out at Lomas Barbudal Biological Reserve, Costa Rica. One study consisted of 30-min PC and matched control (MC) follows. The second study extracted PC and MC periods from long follows, yielding PC/MC periods averaging 105 min. In study 2, but not study 1, significantly more PC/MC pairs were attracted (former opponents affiliated with each other sooner in the PC period than in the MC period) than were dispersed (former opponents affiliated with each other sooner in the MC period than in the PC period). Reconciliation in study 2 could not be explained as a by-product of former opponents' tendency to seek affiliative contact with conspecifics generally, or of the spatial proximity of opponents following conflicts. Attempted reconciliation was less likely to be followed by renewed aggression when reconciliation attempts were delayed following conflicts. The data were insufficient for a formal test of differences in conciliatory tendency (the difference between the number of attracted and dispersed PC/MC pairs, divided by the total number of pairs) among dyad types to be conducted.     

Generation of a vector system facilitating cloning of DMBT1 variants and recombinant expression of functional full-length DMBT1

Deleted in malignant brain tumours 1 (DMBT1) codes for a approximately 340kDa glycoprotein with highly repetitive scavenger receptor cysteine-rich (SRCR) domains. DMBT1 was implicated in cancer, defence against viral and bacterial infections, and differentiation of epithelial cells. Recombinant expression and purification of DMBT1 is an essential step for systematic standardized functional research and towards the evaluation of its therapeutical potential. So far, DMBT1 is obtained from natural sources such as bronchioalveolar lavage or saliva, resulting in time consuming sample collection, low yields, and protein preparations which may substantially vary due to differential processing and genetic polymorphism, all of which impedes functional research on DMBT1. Cloning of DMBT1 cDNAs is hampered because of the size and the 13 highly homologous SRCR exons. In this study, we report on the setup of a vector system that facilitates cloning of DMBT1 variants. We demonstrate applicability of the vector system by expression of the largest DMBT1 variant in a tetracycline-inducible mammalian expression system using the Chinese hamster ovary cell line. Yields up to 30 mg rDMBT1 per litre of cell culture supernatant could be achieved with an optimized production procedure. By harnessing the specific bacteria-binding property of DMBT1 we established an affinity purification procedure which allows the isolation of more than 3 mg rDMBT1 with a purity of about 95%. Although the glycosylation moieties of rDMBT1 are different from DMBT1(SAG) isolated from saliva, we demonstrate that rDMBT1 is functionally active in aggregating Gram-positive and Gram-negative bacteria and binding to C1q and lactoferrin, which represent two known endogenous DMBT1 ligands.     

Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors

We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.