No abstract

Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene.

Genomic microarrays have been implemented in the diagnosis of patients with unexplained mental retardation. This method, although revolutionizing cytogenetics, is still limited to the detection of rare de novo copy number variants (CNVs). Genome-wide single nucleotide polymorphism (SNP) microarrays provide high-resolution genotype as well as CNV information in a single experiment. We hypothesize that the widespread use of these microarray platforms can be exploited to greatly improve our understanding of the genetic causes of mental retardation and many other common disorders, while already providing a robust platform for routine diagnostics. Here we report a detailed validation of Affymetrix 500k SNP microarrays for the detection of CNVs associated to mental retardation. After this validation we applied the same platform in a multicenter study to test a total of 120 patients with unexplained mental retardation and their parents. Rare de novo CNVs were identified in 15% of cases, showing the importance of this approach in daily clinical practice. In addition, much more genomic variation was observed in these patients as well as their parents. We provide all of these data for the scientific community to jointly enhance our understanding of these genomic variants and their potential role in this common disorder.

When the heart-lung preparation is made from a dog treated with reserpine, catechol amines such as noradrenaline and isoprenaline have a greater effect on the rate of the heart than they have in a preparation from a normal dog. Other sympathomimetic amines such as tyramine and ephedrine, on the other hand, are found to have lost their action. Since treatment with reserpine has been shown to cause the store of noradrenaline in the heart to disappear, and the infusion of noradrenaline into the preparation made from a reserpine-treated animal restores the action of tyramine. it is concluded that substances like tyramine and ephedrine normally act by liberating noradrenaline from the store, and do not act directly. Cocaine, like reserpine, increases the effect of noradrenaline and decreases the effect of tyramine on tne heart rate; it appears to block the release of noradrenaline from the store in the heart.Observations have recently been made (Burn and Rand, 1958c) on the action of sympathomimetic amines on the blood pressure of the spinal cat and on the vessels of the perfused hindleg of the dog. Experiments were performed on normal animals, and on animals treated with reserpine. In animals treated with reserpine the effect of the catechol amines such as noradrenaline, adrenaline and dopamine was greater than usual, the tissues being supersensitive to them. However, the effect of other amines such as tyramine and ephedrine was almost abolished. Since it had been shown (Burn andRand, 1957, 1958b) that reserpine causes the dispersal of the noradrenaline in the vessel wall, the conclusion was drawn that tyramine and similar amines act by releasing noradrenaline, and that they differ from the catechol amines which act directly.We now describe a study of the action of sympathomimetic amines on the heart rate. METHODObservations were made in the heart-lung preparation of the dog, at a temperature between 36.5°and 37°. One dog was bled under ether anaesthesia. The second dog was first anaesthetized with ether and chloralose was then injected intravenously. The heart-lung preparation was then made. The venous reservoir was immersed in a thermostatically controlled water bath, with an overflow from the reservoir so that the venous pressure was constant. The heart rate was measured from the electrocardiogram recorded on a Cossor electrocardiogaph model 1314. The artificial resistance was set to maintain a pressure of 110 mm. and the systemic outflow was usually about 750 ml./min. Dogs usually weighed 12 to 15 kg. Those treated with reserpine were given 5 mg. on two successive days by intraperitoneal injection and were used on the third day. The solution of reserpine was prepared in 20% (w/v) ascorbic acid. RESULTSTyramine and Phenylethylamine.-Tyramine hydrochloride was tested, as were the other amines, by injecting a dose into the tube carrying blood to the superior vena cava and observing the height and duration of the rise in heart rate which

The actions of nicotine, hexamethonium, and ethanol on the hypothalamo-hypophysial system have been investigated in the rat. The antidiuretic action of nicotine was not inhibited by ethanol, nor by doses of hexamethonium which were sufficient to block both its pressor and convulsant actions. Hexamethonium itself had an antidiuretic action the mechanism of which has been investigated. Nicotine caused a release of oxytocin into the blood which was not blocked by ethanol nor significantly reduced by hexamethonium. The results suggest that any synapse which exists at the supraoptic nuclei is dissimilar in its pharmacological properties to synapses at autonomic ganglia.