Adenosine thiamine triphosphate (AThTP) inhibits poly(ADP-ribose) polymerase-1 (PARP-1) activity.

Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD(+)) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD(+). Recent experimental studies demonstrate beneficial impacts of high-dose thiamine treatment of diabetic complications. These findings have led us to hypothesize that AThTP may modulate the activity of PARP-1. We have chemically synthesized AThTP and evaluated the effect of AThTP on recombinant PARP-1 enzyme activity. AThTP inhibited the PARP-1 activity at 10 µM, and a structural model of the PARP-1-AThTP complex highlighted the AThTP binding site. The results provide new insights into the pharmacological importance of AThTP as an inhibitor of PARP-1.

[Stapes surgery performed for congenital stapes foot plate fixation--comparison of prosthesis fixation to the malleus vs. the incus].

We report the surgical results of stapes surgery using the Schukneht-type wire piston prosthesis performed on 30 ears with fixation of the stapes footplate and absence of the long process of the incus. The prosthesis was reformed to avoid dislocation and fixed to the handle of the malleus. The surgical results in another 49 ears, the comparator group, in which the prosthesis was fixed to the long process of the incus because the anomaly was restricted to fixation of the footplate without other associated anomalies, were also analyzed for comparison. The mean postoperative air conduction hearing levels were 28.6dB in the subjects and 21.6dB in the comparator group, and the mean hearing improvements were 35.7dB and 29.7dB, respectively. The success rate of the operation, based on the criteria established by the Japan Otological Society, was 90% in the subjects and 98% in the comparator group. The mean postoperative air-bone gap in the subjects was 15.8dB, which was 4.3dB higher than that in the comparator group. The difference between the two groups was considered to be due to the difference in the effectiveness of the conduction mechanism after the surgery. We therefore concluded that the surgical procedure using the Schukneht-type wire piston prosthesis to fix the malleus handle is a useful surgical method that yields satisfactory results.