Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene.

BACKGROUND: Cutis laxa is an acquired or inherited condition characterized by redundant, pendulous and inelastic skin. Autosomal dominant cutis laxa has been described as a benign disease with minor systemic involvement. OBJECTIVE: To report a family with autosomal dominant cutis laxa and a young girl with sporadic cutis laxa, both with variable expression of an aortic aneurysmal phenotype ranging from mild dilatation to severe aneurysm or aortic rupture. METHODS AND RESULTS: Histological evaluation of aortic aneurysmal specimens indicated classical hallmarks of medial degeneration, paucity of elastic fibres, and an absence of inflammatory or atherosclerotic lesions. Electron microscopy showed extracellular elastin deposits lacking microfibrillar elements. Direct sequencing of genomic amplimers detected defects in exon 30 of the elastin gene in affected individuals, but did not in 121 normal controls. The expression of mutant elastin mRNA forms was demonstrated by reverse transcriptase polymerase chain reaction analysis of cutis laxa fibroblasts. These mRNAs coded for multiple mutant tropoelastins, including C-terminally truncated and extended forms as well as for molecules lacking the constitutive exon 30. CONCLUSIONS: ELN mutations may cause severe aortic disease in patients with cutis laxa. Thus regular cardiac monitoring is necessary in this disease to avert fatal aortic rupture.

Alzheimer's dementia produces a loss of discrimination but no increase in rate of memory decay in delayed matching to sample.

Patients diagnosed with senile dementia of the Alzheimer type (SDAT) were compared with control subjects on a computerized delayed matching to sample task. Performance was assessed with a measure of discriminability at zero delay and a measure of rate of forgetting--these are the two parameters of an exponential function derived from extensive animal testing. The SDAT group showed significantly poorer discriminability at zero delay than controls but equivalent rates of forgetting over a 32-sec delay. These data suggest that SDAT may have little effect on the decay rate of the short term (or 'primary') memory trace and may instead affect encoding, initial storage or retrieval mechanisms. The effects of SDAT on this task are consistent with previous results with anticholinergic agents in rats.

Low dose scopolamine affects discriminability but not rate of forgetting in delayed conditional discrimination.

The effect of scopolamine on remembering was examined in a delayed conditional discrimination procedure with rats. Remembering was quantified by a negative exponential function fitted to estimates of discriminability derived from a signal detection type of analysis. This function had two parameters: a measure of initial discriminability of the sample stimuli in the absence of a memory requirement (at zero delay) and a measure of rate of forgetting. Eight rats were trained on an auditory delayed conditional discrimination task until they were showing stable performance. Each rat then received doses of 0, 0.005, 0.014, 0.042, 0.125 and 0.375 mg/kg scopolamine IP in a saline vehicle. There was a highly significant, largely linear, decrease in initial discriminability. This was obvious even at the lowest dose of scopolamine. Poorer memory, as demonstrated by an increase in b, was only apparent at the highest dose. Significant changes in per cent of correct responses were also only obtained at higher doses. These results show that initial discriminability and rate of forgetting are pharmacologically as well as theoretically independent. They suggest that the measure of initial discriminability used here is a particularly sensitive measure of at least some types of cholinergic dysfunction; and they also suggest that effects of scopolamine in other working memory tasks could be more a result of changed stimulus processing than of impairment of memorial processes.

Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination.

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.

Chlordiazepoxide reduces discriminability but not rate of forgetting in delayed conditional discrimination.

Benzodiazepine and anticholinergic drugs interfere with septo-hippocampal function in similar but not identical ways. They also share a number of common behavioural effects and, in particular, both classes of drug interfere with spatial memory in the Morris Water Maze--a test which is very sensitive to hippocampal dysfunction. We have previously shown that the anticholinergic drug scopolamine impairs discriminability, but not rate of forgetting, in delayed conditional discrimination. In the present study forgetting was quantified by fitting a negative exponential function to estimates of discriminability derived from a signal detection analysis of data from an auditory delayed conditional discrimination task. Chlordiazepoxide produced a highly significant decrease in discriminability which was monotonically related to the logarithm of dose in the range 0.67-18.0 mg/kg IP. The rate of forgetting was not increased. These data confirm the pharmacological independence of changes in discriminability and rate of forgetting; demonstrate that in this task chlordiazepoxide has similar effects to scopolamine; and suggest that the effects of chlordiazepoxide in other working memory tasks could be more a result of changed stimulus processing than impairment of memorial processes.

Defensive burying: effects of diazepam and oxprenolol measured in extinction.

When a rat is shocked via a prod in a chamber with sawdust on the floor it will typically push the flooring material with snout and forepaws towards and over the prod. We administered diazepam (.5 and 1.0 mg/kg) and oxprenolol (10 and 20 mg/kg) the day following shock exposure, and observed the complete suppression of burying by diazepam, and some suppression with oxprenolol. These effects are independent of interference with initial association of shock and prod, and of changes in general activity.