Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1711-0) contains supplementary material, which is available to authorized users.

BackgroundNovel extracorporeal procedures are constantly being developed and evaluated for use in patients with sepsis. Preclinical evaluation of such procedures usually requires testing in large animal models. In the present work, the safety and efficacy of a recently developed ADVanced Organ Support (ADVOS) system in a newly developed large animal two-hit model of liver failure combined with endotoxemia were tested.MethodsAfter establishing the model in more than 50 animals, a randomized study was performed. An inflammatory cholestatic liver injury was initially provoked in pigs. Three days after surgery, endotoxin was gradually administered during 7½ h. Animals were randomized to receive standard medical treatment either with (ADVOS group, n = 5) or without ADVOS (control group, n = 5). The ADVOS treatment was started 2½ h after endotoxemia and continued for 7 h. Survival, cardiovascular, respiratory, renal, liver, coagulation, and cerebral parameters were analyzed.ResultsThree days after surgery, cholestatic injury resulted in hyperbilirubinemia [5.0 mg/dl (IQR 4.3–5.9 mg/dl)], hyperammonemia [292 μg/dl (IQR 291–296 μg/dl)], leukocytosis [20.2 103/μl (IQR 17.7–21.8 103/μl)], and hyperfibrinogenemia [713 mg/dl (IQR 654–803 mg/dl)]. After endotoxemia, the ADVOS procedure stabilized cardiovascular, respiratory, and renal parameters and eliminated surrogate markers as bilirubin [2.3 (IQR 2.3–3.0) vs. 5.5 (IQR 4.6–5.6) mg/dl, p = 0.001] and creatinine [1.4 (IQR 1.1–1.7) vs. 2.3 (IQR 2.1–3.1) mg/dl, p = 0.01]. Mortality: All animals in the ADVOS group survived, while all animals in the control group expired during the 10-h observation period (p = 0.002). No adverse events related to the procedure were observed.ConclusionsThe ADVOS procedure showed a promising safety and efficacy profile and improved survival in a sepsis-like animal model with dysfunction of multiple organs. An amelioration of major organ functions (heart and lung) combined with removal of markers for kidney and liver function was observed.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-017-0144-3) contains supplementary material, which is available to authorized users.

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This preliminary clinical investigation of the pharmacokinetic behavior of the main metamizole (dipyrone) metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) in calves undergoing umbilical surgery is part of an already published main study. A single intravenous dose of metamizole was added to ketamine/xylazine/isoflurane anesthesia. Eight Simmental calves weighing 90 ± 10.8 kg and aged 47.6 ± 10.4 days received 40 mg/kg metamizole intravenously 10 minutes prior to general anesthesia. Blood samples were collected over 24 hours and analyzed for 4-MAA and 4-AA. Meloxicam was additionally given twice: 2.5 hours pre- and 20.5 hours postsurgically. The pharmacokinetic profile of 4-MAA was best fitted to a two-compartment model and was characterized by a fast distribution half-life and slow elimination half-life (t½alpha = 5.29 minutes, t½beta = 9.49 hours). The maximum concentration (Cmax 101.63 μg/mL) was detected at the first measurement time point 15 minutes after administration. In contrast, 4-AA showed fast, high and biphasic plasma peak concentration behavior in five calves (2.54–2.66 μg/mL after 15–30 minutes, and 2.10–2.14 μg/mL after 2–3.5 hours) with a t½beta of 8.87 hours, indicating a rapid distribution and subsequent redistribution from well-perfused organs. Alternatively, three calves exhibited a slower and lower monophasic plasma peak concentration (1.66 μg/mL after 6.5 hours) with a t½beta of 6.23 hours, indicating slow accumulation in the intravascular compartment. The maximum concentration and area under the plasma concentration curve (AUC) of 4-AA were lower than those of 4-MAA. This metabolic behavior supports our already published data on clinical monitoring and plasma cortisol concentrations (PCCs). Compared to those of saline controls, lower PCCs correspond to the t½alpha of 4-MAA. Data on Tmax and t½beta also match these clinical observations. However, further studies are required to assess the exact analgesic mechanism and potency of the metamizole metabolites in calves.