In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg vinpocetine three times a day (tid) for 30 days, then 5 mg tid for 60 days. Matching placebo tablets were given to another 42 patients for the 90 day trial period. Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug.

We have used four restriction fragment length polymorphisms (RFLPs) of the human low density lipoprotein receptor (LDL-R) gene, detected by the restriction enzymes Ava ILPVM IL and ApaU (5' and 3'), to study the effect of variation at this gene locus in determining plasma cholesterol and LDL cholesterol levels. Two hundred eighty-nine nonmolipidemic individuals were studied from the Liguria region of Italy. The Pvu M RFLP was significantly associated with differences in plasma total and LDL cholesterol levels, explaining 9.6% of the sample variance in LDL cholesterol levels. The other RFLPs, which are in strong linkage disequilibrium with the Pvu II RFLP, were associated with smaller effects on LDL cholesterol. The Pvu II allele, distinguished by the presence of the variable cutting site (P2 allele), was associated with lower levels of total and LDL cholesterol, and the frequency of the P2 allele was significantly reduced in individuals with LDL cholesterol levels higher than the 75th percentile. The frequency of the P2 allele was significantly higher in the group of individuals over 65 years old, and in this gronp the P2 allele was also associated with a similar reduction in LDL cholesterol levels. Because of linkage disequilibrium, only four RFLP haplotypes were common in this sample. Of these, only the haplotype P2A2VI (relative frequency, 0.269) was associated with a reduction in LDL cholesterol (average excess, -11.5 mg/dl). Our data confirm, in the Italian population, the association observed with the Pvu H RFLP by others, and the higher relative frequency of the LDL cholesterol-lowering P2 allele in individuals over the age of 65 years suggests that the allele may be associated with increased survival. (Arteriosclerosis and Thrombosis 1991;ll:509-516)

The usefulness of the RFLPs of the LDL-receptor gene in early diagnosis of Familial Hypercholesterolemia (FH) was investigated in 122 FH-families. Four RFLPs, produced by digestion with the enzymes PvuII, ApaLI and AvaII/XbaI were able to detect the affected gene and to follow the inheritance of the disease in 72 out of 97 families (74%). In the remaining 25 families, unambiguous diagnosis was possible in 66% of the cases by use of PvuII, ApaLI and BstEII/EcoRI RFLPs. The RFLPs were also useful to distinguish true homozygotes from compound heterozygotes and to detect families where recombination events occurred or where hypercholesterolemia was not due to a defect of the LDL-receptor gene. In a normal population PvuII RFLP account for 9.6% of the total variance of the LDL cholesterol levels adjusted for confounding variables. The P2 allele was associated with lower LDL cholesterol concentrations (average excess -9.1 mg/dl). This finding allows us to presume there is a DNA sequence, close to the variable PvuII cutting site in intron 15, which could act as an enhancer of the LDL-receptor gene expression.

No abstract

Familial hypercholesterolemia (FH) is an autosomal dominant metabolic disorder caused by several different mutations in the low density lipoprotein (LDL) receptor gene. This large number of different mutations, often undetectable in Southern blotting, makes it impossible directly to diagnose the disease. However, restriction fragment length polymorphisms (RFLPs) can be used to follow the inheritance of the defective gene in FH families. In the present study, we report the use of three RFLPs, detected by PvuII, ApaLI and AvaII restriction enzymes, to determine the haplotypes of normal and defective LDL receptor genes in 61 families with FH and in 128 normal individuals. Two of the nine haplotypes were significantly more often associated with the affected genes, whereas one was significantly less frequent. Although none of the associations was strong enough to allow diagnosis in individuals, it was possible, using the three RFLPs, to identify the haplotype of the affected gene in 57 families and to carry out unequivocal diagnosis in 67% of the cases. In four families, PvuII and AvaII detected an abnormal fragment co-segregating with the disease, thus increasing the percentage of diagnosis to 73.4% of the cases.