TY  - JOUR
A1  - Üçeyler, Nurcan
A1  - Homola, György A.
A1  - González, Hans Guerrero
A1  - Kramer, Daniela
A1  - Wanner, Christoph
A1  - Weidemann, Frank
A1  - Solymosi, László
A1  - Sommer, Claudia
T1  - Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease
N2  - A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males – females; normal – impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.
KW  - Arterial Diameters
KW  - ischemic stroke
KW  - magnetic resonance imaging
KW  - stroke
KW  - cerebral arteries
KW  - renal system
KW  - central nervous system
KW  - blood flow
KW  - lesions
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112614
ER  - 
TY  - JOUR
A1  - Shityakov, Sergey
A1  - Förster, Carola
T1  - In silico predictive model to determine vector-mediated transport properties for the blood-brain barrier choline transporter
JF  - Advances and Applications in Bioinformatics and Chemistry
N2  - The blood–brain barrier choline transporter (BBB-ChT) may have utility as a drug delivery vector to the central nervous system (CNS). We therefore initiated molecular docking studies with the AutoDock and AutoDock Vina (ADVina) algorithms to develop predictive models for compound screening and to identify structural features important for binding to this transporter. The binding energy predictions were highly correlated with r2=0.88, F=692.4, standard error of estimate =0.775, and P-value<0.0001 for selected BBB-ChT-active/inactive compounds (n=93). Both programs were able to cluster active (Gibbs free energy of binding <−6.0 kcal*mol-1) and inactive (Gibbs free energy of binding >−6.0 kcal*mol-1) molecules and dock them significantly better than at random with an area under the curve value of 0.86 and 0.84, respectively. In ranking smaller molecules with few torsional bonds, a size-related bias in scoring producing false-negative outcomes was detected. Finally, important blood–brain barrier parameters, such as the logBBpassive and logBBactive values, were assessed to predict compound transport to the CNS accurately. Knowledge gained from this study is useful to better understand the binding requirements in BBB-ChT, and until such time as its crystal structure becomes available, it may have significant utility in developing a highly predictive model for the rational design of drug-like compounds targeted to the brain.
KW  - virtual screening
KW  - Gibbs free energy of binding
KW  - diffusion
KW  - molecular docking
KW  - drug delivery vector
KW  - central nervous system
KW  - blood–brain barrier choline transporter
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120200
VL  - 7
ER  -