Search for a gene x environment interaction: G x E hunt

We developed a method to identify gene x environment interactions (G x Es). To test this method in the simulated data (Problem 2, GAW11), we first identified an environmental factor (E1) that was associated with the simulated disorder. We stratified affected sibling pairs (ASPs) into two groups, those concordant for the presence of E1 and those concordant for the absence of E1. We then localized genes on chromosomes 3 and 5 using identity-by-descent (IBD) sharing rates among ASPs. Because the stratified IBD sharing rates are independent of the environmental factor if there is no G x E, we inferred the existence of a G x E near loci 3G44 and 3G45 by testing whether the proportion of ASPs sharing no alleles IBD differed among the two groups.     

The effects of idazoxan on reaction times, eye movements and the mood of healthy volunteers and patients with upper respiratory tract illnesses.

An experiment was carried out to determine whether idazoxan, a drug which increases the turnover of central noradrenaline, removes the malaise (reduced alertness, slower psychomotor performance) associated with upper respiratory tract illness (URTI). Eighty-one volunteers were tested when healthy and 17 returned to the laboratory when they developed URTIs. Those who remained healthy were then recalled as a control group. Volunteers were tested before and after receiving either idazoxan (40mg) or a lactose placebo. Idazoxan removed the URTI-induced slowing in a simple reaction time task and this group performed at a comparable level to the healthy group. No significant stimulant effect of idazoxan was found in the healthy subjects. The results suggest that at least part of the malaise induced by URTIs may reflect reductions in central noradrenaline and that this can be reversed by compounds such as idazoxan.     

Antihyperglycaemic effect of saccharin in diabetic ob/ob mice

1. The effect of chronic saccharin (benzosulphimide) consumption on glucose homeostasis was examined in normal lean +/+ mice and genetically obese hyperglycaemic insulin-resistant ob/ob mice.
2. Consumption of a 5% (w/v) sodium saccharin solution for 7 weeks prevented the development of hyperglycaemia, improved glucose tolerance (area under curve decreased by 51%), reduced the extent of hyperinsulinaemia (by 21%), and reduced excessive weight gain (by 18%) in ob/ob mice.
3. Consumption of 5% (w/v) sodium saccharin temporarily decreased hyperphagia at the beginning of treatment, decreased hepatic glycogen content (by 47%), increased abdominal muscle glycogen content (by 82%), but did not significantly alter the hypoglycaemic response to exogenous insulin in ob/ob mice.
4. Consumption of a 1% (w/v) sodium saccharin solution did not prevent the development of hyperglycaemia in ob/ob mice.
5. Normal lean +/+ mice consuming 5% (w/v) sodium saccharin solution showed a marginal decrease (by 8%) in glycaemia, and glucose tolerance was improved (area under curve decreased by 30%) without a significant change in the insulin response to glucose or the hypoglycaemic effect of exogenous insulin.
6. The results suggest that chronic consumption of saccharin can defer the development of hyperglycaemia and improve glucose homeostasis in insulin-resistant ob/ob mice through a mechanism that is independent of insulin.

     

Sedative antidepressants impair visual detection mechanisms in humans

The safety of sedative antidepressants is a topical issue in the treatment of depression, with driving impairment being of particular concern. We have recently completed a study with normal male volunteers comparing the actions of dothiepin (a traditional, sedating antidepressant) with those of fluvoxamine (one of the selective serotonin re-uptake-inhibiting SSRI class of newer antidepressants) on psychomotor functions relevant to driving. We set out to investigate whether these drugs impair visual selective attention (focused and divided) by employing the 'odd-ball' task. Subjects were required to respond to letters of the alphabet (T for target and other letters for non-targets) that were presented at the centre and/or periphery of the computer screen. The task has been shown to be useful in detecting differences between drugs in their effects on selective attention. Preliminary results show that dothiepin delayed responses to single targets compared with fluvoxamine and placebo. There was also preliminary evidence that it mainly affected response times to peripheral targets. Furthermore, there was preliminary evidence that both drugs delayed responses to central targets compared with placebo on the divided attention trials. Finally, response accuracy in detecting peripheral targets was greater under placebo compared with fluvoxamine and dothiepin. The impairment produced by dothiepin is presumably a consequence of the central blockade of cholinergic muscarinic or histaminergic H1 receptors. It could contribute to the reported association between the tricyclic class of antidepressants and road traffic accidents, and would be worth further investigation in depressed patients taking both classes of drug.     

A comparison between propranolol and hypothermia in preventing ischemic contracture of the left ventricle (stone heart).

Ischemic contracture of the left ventricle ("stone heart") was studied utilizing a previously described stone heart model. Our studies suggest that beta-adrenergic blockade is not quantitatively as important as hypothermia in protecting ischemic myocardium. On the basis of reduced fibrillatory activity and a slight protective effect shown by electron microscopy, it would appear that combining propranolol with hypothermia may be superior to either used singly.     

Section II: General orthopaedics. Anterior cervical fusion for trauma.

Anterior bone grafts of 24 injured cervical spines were reviewed with respect to early postoperative instability and eventual malunion. Spinal redislocation or graft extrusion occurred in 21% representing failure to attain early stability. In 38%, the late complication of kyphotic malunion occurred, averaging 21%. The Yale instability criteria were fulfilled in 15 cases and mechanical complications developed in 87% of these. When posterior instability was present, the mechanical complication rate rose to 92%. Early stabilization of most neck injuries is not achieved by the anterior bone graft and its use as a means of "stabilization" is unsubstantiated by clinical experience.