Inversion (X)(p11.4q22) associated with Norrie disease in a four generation family.

We report on a 4-generation family in which Norrie disease occurs together with a pericentric inversion of the X chromosome in all affected males and carrier females. The breakpoint in the short arm of the X chromosome appears to be at the purported location of the Norrie disease gene. This is the second report of an association between Norrie disease and a chromosome aberration involving Xp11, and the first report of a specific gene disruption, thus physical gene location, due to a pericentric chromosome inversion.

Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. A case-control study.

To evaluate the consistency, strength, and independence of the relation of carotid atherosclerosis to coronary atherosclerosis, we quantified coronary artery disease risk factors and extent of carotid atherosclerosis (B-mode score) in 343 coronary artery disease patients and 167 disease-free control patients. In univariable analyses, there was a strong association between coronary status and extent of carotid artery disease in men and women older than and younger than 50 years (p less than 0.001 for men and women greater than 50 years, p less than 0.001 for women less than or equal to 50 years, p = 0.045 for men less than or equal to 50). The relation remained strong after control for age in men and women older than 50 years and in women younger than 50 (p less than 0.001 for men and women greater than 50 years, p = 0.003 for women less than or equal to 50) but did not persist after control for age in men younger than 50. Logistic models that included coronary disease risk factors, with or without B-mode score, as independent variables and presence or absence of coronary disease as the outcome variable indicated that the extent of carotid atherosclerosis was a strong, statistically significant independent variable in models for men and women older than 50 years of age. Next, we examined the usefulness of B-mode score as an aid in screening for coronary artery disease in men and women older than 50 years. Classification rules, both including and excluding B-mode score, were developed based on logistic regression and, for comparison, recursive partitioning (decision trees). The performance of these rules and the bias of their performance statistics were estimated. The improved classification of the study sample when B-mode score was incorporated in the rule was statistically significant only for men (p = 0.015). However, the addition of B-mode score was found to 1) increase the median discrimination score for both sex groups based on the logistic model, and 2) yield better sensitivities and specificities for rules based on recursive partitioning. Thus B-mode score is strongly, consistently, and independently associated with coronary artery disease in patients older than 50 and is at least as useful as well-known risk factors for identifying patients with coronary artery disease.

Restriction fragment polymorphism of the cynomolgus monkey major histocompatibility complex.

Among old world monkeys, the major histocompatibility complex (MHC) is defined only in the rhesus (Macaca mulatta), cynomolgus (Macaca fascicularis) and pigtailed (Macaca nemistrina) species. However, little is known about the organization of class I and class II MHC genes or the extent of polymorphism in macaques. In the present study, human and murine class I and class II gene probes were used to analyze the leukocyte antigen (CyLA) system of unrelated and related cynomolgus monkeys. Restriction fragment length polymorphism (RFLP) analysis with a HLA-B7 cDNA probe supports the serologic evidence indicating the existence of a family of class I loci of which several are highly polymorphic. As in the human MHC, the class II beta genes are more polymorphic than class II alpha genes. In a pedigree study, RFLP patterns correlated with CyLA haplotypes as deduced from CyLA-A,B,C and complement factor B(Bf) phenotypes. The RFLP data are consistent with three expressed class I gene loci as well as nonclassical MHC genes potentially related to Qa/T1a in mice. We conclude that the RFLP analysis with cross-hybridizing DNA probes augments the information obtained by serotyping and sets the stage for gene mapping and structural analysis of the CyLA region.

Risk factors for extracranial carotid artery atherosclerosis.

We related risk factors, cardiovascular symptoms, and coronary status to the extent of extracranial carotid atherosclerosis as measured by B-mode ultrasonography in 376 volunteers hospitalized for elective coronary angiography. In a first analysis, we correlated risk factors and cardiovascular symptoms with carotid atherosclerosis. Univariate analysis showed that relations between many continuous risk factors and carotid atherosclerosis were graded and consistent for men and women. Multivariate analysis identified 6 significant variables (age, hypertension, pack-years smoked, and inversely, plasma concentrations of high density lipoprotein cholesterol and uric acid, and Framingham Type A score) that together accounted for 35% of the variability in extent of carotid atherosclerosis. In a second multivariate analysis, addition of coronary status (presence or absence of coronary stenosis as evaluated by coronary angiography) to the roster of candidate independent variables produced a new equation that accounted for an additional 5% of the variability in carotid atherosclerosis extent. Although much of the variability in extent of carotid atherosclerosis remains unexplained, these data define an association between coronary and carotid atherosclerosis that depends partly on shared exposure of both arteries to the same risk factors. They are also consistent with the concept that as yet undiscovered risk factors and/or genetic (e.g., arterial wall) factors common to both arterial beds also contribute to the relation between coronary and carotid atherosclerosis in human beings.

The major histocompatibility complex of primates.

The major histocompatibility complex (MHC) encodes cell surface glycoproteins that function in self-nonself recognition and in allograft rejection. Among primates, the MHC has been well defined only in the human; in the chimpanzee and in two species of macaque monkeys the MHC is less well characterized. Serologic, biochemical and genetic evidence indicates that the basic organization of the MHC linkage group has been phylogenetically conserved. However, the number of genes and their linear relationship on the chromosomes differ between species. Class I MHC loci encode molecules that are the most polymorphic genes known. These molecules are ubiquitous in their tissue distribution and typically are recognized together with nominal antigens by cytotoxic lymphocytes. Class II MHC loci constitute a smaller family of serotypes serving as restricting elements for regulatory T lymphocytes. The distribution of class II antigens is limited mainly to cell types serving immune functions, and their expression is subject to up and down modulation. Class III loci code for components C2, C4 and Factor B (Bf) of the complement system. Interspecies differences in the extent of polymorphism occur, but the significance of this finding in relation to fitness and natural selection is unclear. Detailed information on the structure and regulation of MHC gene expression will be required to understand fully the biologic role of the MHC and the evolutionary relationships between species. Meanwhile, MHC testing has numerous applications to biomedical research, especially in preclinical tissue and organ transplantation studies, the study of disease mechanisms, parentage determination and breeding colony management. In this review, the current status of MHC definition in nonhuman primates will be summarized. Special emphasis is placed on the CyLA system of M. fascicularis which is a major focus in our laboratory. A highly polymorphic cynomolgus MHC has been partially characterized and consists of at least 14 A locus, 11 B locus, 7 C locus class I allelic specificities, 9 Ia-like class II antigens and 6 Bf (class III) variants.

A critical analysis of paternity determination using HLA and five erythrocyte antigen systems.

Five hundred and thirty-seven cases of disputed paternity in North Carolina were tested for five erythrocyte polymorphisms, HLA antigens, or both. The data were analyzed to evaluate the ability of the tests to exclude the alleged father or to include the alleged father as the biological father. Incompatibility between the phenotypes of the alleged father, and those of the mother and child, were found in 40.6% of black males and 30.3% of white males (P less than 0.005). The rates of exclusion appeared to vary between countries in which the cases originated, although the significance of the differences could not be determined because of the small sample size. Using a Bayesian approach and 0.5 as the prior probability of paternity, we calculated the posterior probability of paternity for HLA and five erythrocyte systems combined as well as for HLA and erythrocyte systems separately. The probability of paternity values based on the combined HLA and RBC tests exceeded 95% in 299 of the 345 nonexcluded cases as compared to only 218 cases based on HLA tests alone and 36 cases based on erythrocyte tests alone. We conclude that in approximately 10% of paternity cases in the population served by this laboratory, the information obtained is inconclusive. To resolve these cases, additional polymorphisms and/or a panel of genetic tests systems which can provide greater than 95% probability of exclusion is required.

Complement components C3, C4, and Bf in six nonhuman primate species.

The extent of cross reactivity between antisera to human complement proteins [the third (C3) and fourth (C4) components and factor B (Bf)] and these proteins in the sera of six species of nonhuman primates was examined. Strong cross reactivity was found with these antisera and the specific complement proteins from rhesus monkeys, stumptailed macaques, cynomolgus macaques, patas monkeys, African green monkeys, and squirrel monkeys. Although molecular differences were apparent as indicated by differences in antigenic determinants and electrophoretic mobility, the antisera developed against human C3, C4, and Bf could be used to identify and to characterize these proteins in the nonhuman primate species examined.

Pregnancy effects on nonhuman primate high density lipoprotein.

The concentration of cholesterol in high density lipoproteins (HDL) has been showed to be dramatically decreased during pregnancy in Macaca nemestrina. HDL were isolated from females of this species at various stages of pregnancy to determine if pregnancy also alters their composition and size. The chemical compositions of the HDL were determined nad found different in pregnant animals; the mass ratio of surface (coat) to center (core) constituents was higher, suggesting that the average size of HDL decreased during pregnancy. When measured chromatographically, the average size of HDL was found to decrease during pregnancy. This change in HDL size was accompanied by a minor alteration in apolipoprotein distribution.

Influence of dietary fats and an oral contraceptive on plasma lipids, high density lipoproteins, gallstones, and atherosclerosis in african green monkeys.

Twenty-nine African green monkeys were fed diets for 22 months containing 0.79 mg cholesterol/kcal and 40% of calories as either safflower oil or butter with or without the addition of an estrogen- and progestin-containing oral contraceptive. Plasma cholesterol concentrations ranged from 199 to 250 mg/dl. Animals consuming the safflower oil diet had plasma cholesterol concentrations that averaged 61 mg/dl lower than those consuming butter. At least 72% of this lowering was due to a reduction in low density lipoproteins. Triglyceride concentrations were also slightly lower in animals consuming the safflower oil diet. The oral contraceptive lowered total plasma cholesterol concentrations in both diet groups by an average of 41 mg/dl with 54% of this lowering (22 mg/dl) due to a reduction in high density lipoprotein cholesterol. This effect occurred only during the 3 weeks while the contraceptive was being administered and was not apparent 1 week after stopping the drug. Animals consuming safflower oil had bile that was more lithogenic and had more gallstones than did those consuming butter. Addition of the oral contraceptive caused a slight increase in bile lithogenicity, but this increase was not statistically significant. There was no significant interaction between the oral contraceptive and either of the diets to exacerbate cholelithiasis. At the plasma cholesterol concentrations achieved only minimal amounts of atherosclerosis developed and there were no indications of differences due to diet or oral contraceptive in the extent of atherosclerosis.