TY  - JOUR
A1  - Hopp, Sarah
A1  - Albert-Weissenberger, Christiane
A1  - Mencl, Stine
A1  - Bieber, Michael
A1  - Schuhmann, Michael K.
A1  - Stetter, Christian
A1  - Nieswandt, Bernhard
A1  - Schmidt, Peter M.
A1  - Monoranu, Camelia-Maria
A1  - Alafuzoff, Irina
A1  - Marklund, Niklas
A1  - Nolte, Marc W.
A1  - Sirén, Anna-Leena
A1  - Kleinschnitz, Christoph
T1  - Targeting coagulation factor XII as a novel therapeutic option in brain trauma
JF  - Annals of Neurology
N2  - Objective: 
Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. 

Methods: 
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. 

Results: 
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. 

Interpretation: 
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.
KW  - Molecular-weight heparin
KW  - Thrombus formation
KW  - Cerebral-ischemia
KW  - in-vivo
KW  - Intravascular coagulation
KW  - Hemodynamic depression
KW  - Head-injury
KW  - Rats
KW  - Model
KW  - Mice
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188800
VL  - 79
IS  - 6
ER  - 
TY  - JOUR
A1  - Dekant, Wolfgang
A1  - Bridges, James
T1  - Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence
JF  - Regulatory Toxicology and Pharmacology
N2  - Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility.
KW  - n-hexyl phthalate
KW  - male rats
KW  - dicyclohexyl phthalate
KW  - Diisononyl phthalate
KW  - in-vivo
KW  - 2-Generation reproduction
KW  - testosterone production
KW  - sexual development
KW  - risk-assesment
KW  - fetal testis
KW  - weight of evidence
KW  - classification and labeling
KW  - reproductive and developmental toxicity
KW  - quantitative assessments
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186750
VL  - 81
ER  -