A study of cardiovascular risk in heterozygotes for homocystinuria

Early atherosclerotic-like lesions and thromboemobolic problems are prominent in homocystinuric patients. Recent evidence suggested that mild homocyst(e)inemia, such as is present in heterozygotes for homocystinuria due to cystathionine synthase deficiency, may cause a marked excess in early ischemic heart disease. To evaluate the risk due to mild homocyst(e)inemia, the frequencies of heart attacks and strokes in parents and grandparents of homocystinuric children were assessed in the present study. No statistically significant increases in the incidence of heart attacks or strokes were consistently detected. The data available are sufficient to virtually exclude an increase in the cardiovascular risk for homocystinuria heterozygotes of as much as fivefold compared to controls, and to make very improbable a relative risk of as much as threefold. Less than 5% of homocystinuria heterozygotes are likely to have a fatal or nonfatal heart attack by age 50. These results fail to suggest that mild homecyst(e)inemia is an important contributory factor in the overall incidence of cardiovascular disease.     

Elimination of interference component in Wigner-Ville distribution for the signal with 1/f spectral characteristic

Human populations are thought to metabolize coumarin almost exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leu160His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A6*2 allele. On administration of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excreted in the 0-8-hr urine, rather, approximately 50% of the dose was eliminated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hydroxylation. His immediate family members, who were heterozygous for the CYP2A6*2 allele, excreted little 2-hydroxyphenylacetic acid and mainly 7-hydroxycoumarin, when similarly tested. These findings raise a question regarding human risk evaluations for environmental coumarin exposures, since 7-hydroxylation is regarded as a detoxication pathway, but 3-hydroxylation as the process required to lead to macromolecular covalent binding of coumarin. Persons homozygous for the CYP2A6*2 allele may constitute 1-25% of various populations.     

MCMI-III as a treatment outcome measure for psychiatric inpatients

The Million Clinical Multiaxial Inventory-III (MCMI-III) recently was introduced to replace and update the MCMI-II. A sample of 97 psychiatric inpatients were administered the MCMI-III shortly following admission, and again 7-10 days later. Changes in the personality and symptom scales generally paralleled those found in previous work with the MCMI-II, although the mean retest interval was considerably shorter than in the earlier study. However, some differences between the two instruments were observed, confirming the need for ongoing cross-validation work on the MCMI-III as an instrument that is distinct from the MCMI-II.     

Transforming growth factor beta 1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice

We have examined the effect of transforming growth factor beta 1 (TGF-beta 1) overexpression in human breast cancer cell tumorigenicity in athymic mice. Estrogen-dependent MCF-7 cells were stably transfected with pSVTGF beta 1. A clone was isolated which overexpressed TGF-beta 1 mRNA and secreted > 10-fold more TGF-beta activity into the tissue culture medium. Similar to the parent line, the MCF-7/TGF-beta 1 cells were relatively insensitive to exogenous TGF-beta 1 and exhibited low levels of TGF-beta receptors. Clonogenicity in soft agarose, doubling time, morphology, and sensitivity to 17 beta-estradiol and the antiestrogen tamoxifen were not altered in the transfected cells. Inoculation s.c. of MCF-7/TGF-beta 1 cells in ovariectomized nude mice resulted in 100% tumor formation which was totally abrogated by i.p. administration of the neutralizing anti-TGF-beta 2G7 IgG2B. The parent cells formed tumors only after estrogen supplementation. By immunohistochemistry, higher levels of TGF-beta 1 protein were detected in MCF-7/TGF-beta 1 tumors than in estrogen-induced parent MCF-7 tumors. Administration of 1 microgram TGF-beta 1 i.p. daily for 3 weeks after tumor cell inoculation transiently supported estrogen-independent growth of parent MCF-7 tumors in castrated nude mice. These data indicate that overexpression of TGF-beta 1 in human breast cancer cells can contribute to their escape from hormone dependence.     

A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women

Using specimens from a population-based case control study among women ages 18 to 44 years in western Washington, we assessed the relationship between carriership of a genetic clotting factor II variant (20210 G-->A) and myocardial infarction (MI). The factor II variant was previously shown to be present in 1% to 2% of the population, to increase the levels of factor II, and to be associated with venous thrombotic disease. Personal interviews and blood samples were obtained from 79 women with a first myocardial infarction and 381 control women identified through random-digit telephone dialing. Polymerase chain reaction (PCR) method was used to determine the factor II genotypes. The factor II 20210 G to A transition was present more often in women with MI (5.1%) than among control women (1.6%). The age-adjusted odds ratio for MI was 4.0 (95% confidence interval 1.1 to 15.1). The relative risk was high when another major cardiovascular risk factor was also present, such as smoking (odds ratio 43.3, 95% confidence interval 6.7 to 281), and the risk seemed limited to those with other risk factors. These results, in which the effect of major coronary risk factors is enhanced fourfold to sixfold by the prothrombin variant, are similar to those previously reported for another genetic clotting abnormality, factor V Leiden. We conclude that factor II 20210 G to A increases the risk of myocardial infarction in young women, especially in the women with other major risk factors for coronary heart disease.