Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Responses to speech signals in the normal and pathological peripheral auditory system.

The responses to single (/a/ and /i/) and double vowel (/a,i/) stimuli of normal guinea pig cochlear nerve fibres are compared with those from animals with a cochlear hearing loss. When the threshold losses are sufficient to exclude the higher harmonics of the /i/, the temporal representation of the second and higher formants is lost. Smaller threshold elevations allow a representation of the second formant when the vowel /i/ is presented alone. However, under double vowel stimulation wider auditory filters allow the capture of the synchrony of high characteristic frequency fibres by lower frequencies thereby losing the higher formants of the /i/ and also much of the information about its fundamental frequency.

A method for monitoring end-tidal CO2 during neurophysiological experiments on small laboratory animals.

The Hewlett Packard Model 47210A Capnometer, intended for monitoring expired CO2 in human patients, can be modified for use in acute neurophysiological studies on small animals. The airway adaptor which would normally be attached to an endotracheal tube is modified and its internal volume is reduced to 0.2 ml, and is incorporated into a guinea pig head-holder. We have verified that the modification does not alter the Capnometer's accuracy. There is no significant increase in resistance in the airway when the adaptor is in place, and the waveform of instantaneous CO2 shows rapid changes on inspiration and expiration with well-resolved peaks and troughs. Measurement of arterial pCO2 suggests that the Capnometer and modified airway adaptor form an accurate system for obtaining a continuous record of end-tidal CO2 in small guinea pigs.

Mixed conductive and sensorineural hearing loss in LP/J mice.

Air and bone conduction thresholds for the detection of a compound action potential response were measured in mice of the LP/J inbred strain, which has been proposed as a possible model for human otosclerosis. Thresholds were compared with control data from CBA/Ca mice. Evidence of a mixed sensorineural and conductive hearing loss was obtained in LP/J mice. Few signs of hair cell degeneration or middle-ear bony lesions were found in 20-day old mice, although they generally showed raised thresholds to both air and bone conducted stimuli. The reason for the observed sensorineural component of the hearing loss at this age is not clear, since endocochlear potentials were normal in mice of this strain. By 225 days of age, hair cell loss was extensive and there was clearly excess bone growth in all middle-ear specimens studied, particularly on the incus and the cochlear wall facing the middle ear. Microbiological analysis of LP/J specimens revealed no evidence of a middle-ear infection specific to these mice which might explain the pathology.

The effects of paracetamol on frusemide ototoxicity.

Paracetamol (acetaminophen) is currently one of the most widely used drugs. In large doses, paracetamol is both nephrotoxic and hepatotoxic, and this toxicity may arise through the production of free radicals. Recently, there has been a revival of interest in the hypothesis that aminoglycoside antibiotics are ototoxic because they facilitate free-radical production. Aminoglycosides interact strongly with loop diuretics, producing enhanced ototoxicity. The object of the present study was to determine whether paracetamol would also interact with a loop diuretic. Pigmented guinea pigs received a dose of 500 or 1000 mg/kg paracetamol via an intragastric cannula. Compound action potentials (CAP) were recorded every 10 min for 2 h. Paracetamol alone had no effect on CAP thresholds, but significantly enhanced the CAP decrement induced by frusemide given intraperitoneally 1 h after paracetamol. This enhancement was larger in animals receiving 1000 mg/kg paracetamol. Repetition of these drug doses in recovery experiments indicated that all threshold shifts recovered within 7 days.