A transgenic minipig models of Huntington’s disease

Background: Some promising treatments for Huntington\u2019s disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. Objective: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1\u2013548 under the control of human HTT promoter. Methods: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. Results: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTTmRNAand protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old siblings showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. Conclusions: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study

Noise Susceptibility of Cochlear Implant Users: The Role of Spectral Resolution and Smearing

The latest-generation cochlear implant devices provide many deaf patients with good speech recognition in quiet listening conditions. However, speech recognition deteriorates rapidly as the level of background noise increases. Previous studies have shown that, for cochlear implant users, the absence of fine spectro-temporal cues may contribute to poorer performance in noise, especially when the noise is dynamic (e.g., competing speaker or modulated noise). Here we report on sentence recognition by cochlear implant users and by normal-hearing subjects listening to an acoustic simulation of a cochlear implant, in the presence of steady or square-wave modulated speech-shaped noise. Implant users were tested using their everyday, clinically assigned speech processors. In the acoustic simulation, normal-hearing listeners were tested for different degrees of spectral resolution (16, eight, or four channels) and spectral smearing (carrier filter slopes of −24 or −6 dB/octave). For modulated noise, normal-hearing listeners experienced significant release from masking when the original, unprocessed speech was presented (which preserved the spectro-temporal fine structure), while cochlear implant users experienced no release from masking. As the spectral resolution was reduced, normal-hearing listeners’ release from masking gradually diminished. Release from masking was further reduced as the degree of spectral smearing increased. Interestingly, the mean speech recognition thresholds of implant users were very close to those of normal-hearing subjects listening to four-channel spectrally smeared noise-band speech. Also, the best cochlear implant listeners performed like normal-hearing subjects listening to eight- to 16-channel spectrally smeared noise-band speech. These findings suggest that implant users’ susceptibility to noise may be caused by the reduced spectral resolution and the high degree of spectral smearing associated with channel interaction. Efforts to improve the effective number of spectral channels as well as reduce channel interactions may improve implant performance in noise, especially for temporally modulated noise