Genetic variance in nonverbal intelligence: data from the kinships of identical twins.

The multiple relationships within kinships of adult monozygotic twins permit incisive analyses to be made of genetic and environmental effects on behavioral traits. Data from families of 65 monozygotic twin pairs yield evidence of genetic variance on the Block Design Test, a nonverbal measure of general intelligence.

Stability of dissolved and soluble Fe(II) in shelf sediment pore waters and release to an oxic water column.

Shelf sediments underlying temperate and oxic waters of the Celtic Sea (NW European Shelf) were found to have shallow oxygen penetrations depths from late spring to late summer (2.2-5.8 mm below seafloor) with the shallowest during/after the spring-bloom (mid-April to mid-May) when the organic carbon content was highest. Sediment porewater dissolved iron (dFe, <0.15 µm) mainly (>85%) consisted of Fe(II) and gradually increased from 0.4 to 15 µM at the sediment surface to ~100-170 µM at about 6 cm depth. During the late spring this Fe(II) was found to be mainly present as soluble Fe(II) (>85% sFe, <0.02 µm). Sub-surface dFe(II) maxima were enriched in light isotopes (δ56Fe -2.0 to -1.5‰), which is attributed to dissimilatory iron reduction (DIR) during the bacterial decomposition of organic matter. As porewater Fe(II) was oxidised to insoluble Fe(III) in the surface sediment layer, residual Fe(II) was further enriched in light isotopes (down to -3.0‰). Ferrozine-reactive Fe(II) was found in surface porewaters and in overlying core top waters, and was highest in the late spring period. Shipboard experiments showed that depletion of bottom water oxygen in late spring can lead to a substantial release of Fe(II). Reoxygenation of bottom water caused this Fe(II) to be rapidly lost from solution, but residual dFe(II) and dFe(III) remained (12 and 33 nM) after >7 h. Iron(II) oxidation experiments in core top and bottom waters also showed removal from solution but at rates up to 5-times slower than predicted from theoretical reaction kinetics. These data imply the presence of ligands capable of complexing Fe(II) and supressing oxidation. The lower oxidation rate allows more time for the diffusion of Fe(II) from the sediments into the overlying water column. Modelling indicates significant diffusive fluxes of Fe(II) (on the order of 23-31 µmol m-2 day-1) are possible during late spring when oxygen penetration depths are shallow, and pore water Fe(II) concentrations are highest. In the water column this stabilised Fe(II) will gradually be oxidised and become part of the dFe(III) pool. Thus oxic continental shelves can supply dFe to the water column, which is enhanced during a small period of the year after phytoplankton bloom events when organic matter is transferred to the seafloor. This input is based on conservative assumptions for solute exchange (diffusion-reaction), whereas (bio)physical advection and resuspension events are likely to accelerate these solute exchanges in shelf-seas.

Familiality of breast cancer and socioeconomic status in blacks.

Familial patterns of the occurrence of breast cancer were studied in a population-based case-control series of black women from the Cancer and Steroid Hormone study. The risks of breast cancer among relatives of breast cancer cases were compared to those of controls who were matched for age and locale. Using the term "proband" to indicate either case or control status, significant predictors of risk to the relatives of probands included case/control status of the proband and the number of years of education completed by the proband. Genetic segregation analysis of the case families using external risks generated from SEER data indicated that the familial aggregation was consistent with Mendelian recessive transmission of a single major gene. The use of internally estimated risks, which are much less stable than the SEER risks, no longer permitted discrimination among the major locus models examined. To avoid possible reporting bias, we also performed segregation analysis on families of probands who had completed at least 12 years of education. The results from this analysis reflected the results from the entire data.

Wax ester synthesis in the mouse preputial gland tumour.

The microsomal fraction from the mouse preputial gland tumour contains an acyltransferase which catalyzes the synthesis of wax esters. The enzyme is inhibited by moderate concentrations of free fatty acids (40 muM or more) but the inhibition is relieved by the addition of bovine serum albumin. The specific activity of the enzyme increases markedly between the 20th and 30th days of tumor growth. A number of other lipid synthesizing enzymes show similar trends for specific activity as related to tumour age.

Family study of agoraphobia. Report of a pilot study.

A family study of agoraphobia (n = 20), panic disorder (n = 20), and nonanxious controls (n = 20) showed the morbidity risk for all anxiety disorders to be 32% among first-degree relatives of agoraphobics, 33% among relatives of patients with panic disorder and 15% among relatives of controls. Relatives of agoraphobics were also shown to be at higher risk for alcohol disorders. Female relatives were found to be at greater risk for anxiety disorders, reflecting their increased susceptibility to these illnesses, and male relatives were at greater risk for alcohol disorders. The increased risk for anxiety disorders in the relatives of agoraphobics was not specific for agoraphobia but included panic disorder and other phobias as well. The findings indicate that agoraphobia is a familial disorder and that family data may help to determine whether agoraphobia is separate from other anxiety and phobic disorders.

Relationship between panic disorder and agoraphobia. A family study.

A family study of patients with agoraphobia (n = 40), panic disorder (n = 40), and nonanxious controls (n = 20) showed that the morbidity risk for panic disorder was increased among the relatives of agoraphobics (8.3%) and the relatives of patients with panic disorder (17.3%). The morbidity risk for agoraphobia was also increased among the relatives of agoraphobics (11.6%) but not the relatives of panic disorder patients (1.9%). Male relatives of agoraphobics were shown to be at higher risk for alcohol disorders (30.8%). No greater risk for primary affective disorders was found among the relatives of agoraphobic or panic disorder patients or among the relatives of probands with secondary depression compared with relatives of probands without secondary depression. Probands and relatives with agoraphobia reported an earlier onset of illness, more persistent and disabling symptoms, more frequent complications, and a less favorable outcome than probands and relatives with panic disorder. The findings suggest that agoraphobia is a more severe variant of panic disorder. They also lend support to the separation between anxiety disorders and affective disorders.

Black-white differences in risk of developing retinopathy among individuals with type 2 diabetes.

OBJECTIVE: To assess racial differences in risk of developing retinopathy among individuals with type 2 diabetes, after taking into account differences in the distribution of risk factors for retinopathy. RESEARCH DESIGN AND METHODS: The participants were 105 individuals with type 2 diabetes, aged 40-69 years, who had no evidence of retinopathy at the time of a diabetic eye disease screening project. After an average of 4 years of follow-up, the subjects were reevaluated using nonmydriatic funds photography. RESULTS: Retinopathy occurred more often among black than white participants (50 vs. 19%). This difference could not be explained by differences in risk factors for retinopathy or potential confounders (odds ratio [95% CI] 2.96 [1.00-8.78] after adjustment for level of glycosylated hemoglobin, systolic blood pressure, type of diabetes treatment, and sex). CONCLUSIONS: These results are consistent with the concept that racial differences in risk of developing retinopathy exist among individuals with type 2 diabetes and that these differences may be caused by differential (genetic) susceptibility to the adverse effects of increased levels of blood glucose and/or blood pressure. Discovery of the etiology of this differential susceptibility would allows us to identify and target secondary prevention efforts to individuals with type 2 diabetes who are at increased risk of retinopathy.

Racial differences in the relationship between blood pressure and risk of retinopathy among individuals with NIDDM.

OBJECTIVE: To assess whether the prevalence of retinopathy differs between blacks and whites with diabetes and to examine differences between blacks and whites in the relationship between risk factors for and prevalence of retinopathy. Population data suggest diabetic retinopathy is either more prevalent or more severe in blacks than in whites. RESEARCH DESIGN AND METHODS: We analyzed data from a screening study for retinopathy among patients with diabetes, conducted in Maryland from 1986-1990. RESULTS: After adjusting for age, duration of diabetes, type of treatment for diabetes, and presence or absence of high blood pressure, black men with NIDDM were approximately 23% more likely to have retinopathy than other race-sex groups (not statistically significant). We also found a different relationship between systolic blood pressure and retinopathy prevalence in blacks than in whites among individuals with NIDDM. Among blacks, the risk increased as systolic blood pressure increased, even within the normal range, and reached statistical significance at > 150 mmHg. Among whites, the risk was increased only among those with high systolic blood pressure (> 140 mmHg) and did not reach statistical significance. CONCLUSIONS: Our data are consistent with the hypothesis that differences exist between blacks and whites in risk of diabetic retinopathy, and that the effect of blood pressure on risk of retinopathy differs between blacks and whites.

Monoclonal antibody (II2C) to human lactoferrin inactivates the myelopoietic suppressive effect of human lactoferrin in vitro.

A mouse monoclonal antibody was prepared against purified and fully iron-saturated human breast milk lactoferrin (LF). This antibody was of the IgG1 subclass, and recognized LF biosynthesized in low-density normal human bone marrow cells and LF stored in normal human polymorphonuclear neutrophils. This antibody did not recognize purified and iron-saturated human transferrin. The antibody inactivated the suppressive effects of purified and iron-saturated human milk LF and LF present in crude extracts of normal polymorphonuclear neutrophils against the release of granulocyte-macrophage colony-stimulating factors from mononuclear blood leukocytes in vitro.

Identification of two susceptibility loci for vascular fragility in the Brown Norway rat.

A trait of vascular fragility, characterized by the formation of abrupt defects within the elastic laminae of the abdominal aorta, has been identified in Brown Norway (BN) rats. These lesions are greatly exacerbated in F(1) rats from a BN x New Zealand genetically hypertensive (GH) intercross, implying that the genetic background provided by the GH rat influences lesion severity. The F(2) progeny of the BN x GH intercross were used to identify susceptibility loci for the lesions as well as exacerbating loci. Two major quantitative trait loci (QTLs) for number of internal elastic lamina lesions were identified on rat chromosomes 5 and 10, with the maximum "log of the odds ratio" (LOD) scores at D5Rat119 (LOD 5.0) and at D10Mit2 (LOD 4.5), respectively, together contributing 33.5% to the genetic variance. Further analysis revealed that the chromosome 10 locus exhibits a dominant mode of inheritance, with BN alleles being associated with increased lesion number (P < 0.0002) compared with GH homozygotes. This locus was in epistasis to a modifier locus on rat chromosome 2 at D2Mit14 (LOD score 2.12). A second major locus was identified on chromosome 5, exhibiting a semidominant mode of inheritance, again with the BN allele being significantly associated with increased lesion number (P < 0.0001). Furthermore, a locus influencing lesion severity was identified on chromosome 3 wherein GH alleles associated with increased severity. This is the first study to identify susceptibility loci for vascular elastic tissue fragility.

Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk.

The association between glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk has been controversial in the published literature. To examine this controversy, 12 case-control studies of GSTM1 status and lung cancer risk were identified in the published English literature. These studies included a total of 1593 cases and 2135 controls. We conclude that GSTM1 deficiency is a moderate risk factor for lung cancer development with an odds ratio of 1.41 (95% confidence interval = 1.23-1.61; P < 0.0001) by using Mantel-Haenszel methods for stratified analysis. This increased risk is evident for all the major histological subtypes of lung cancer. Although the increased risk is small, GSTM1 deficiency accounts for approximately 17% of lung cancer cases because of the high prevalence of GSTM1 deficiency.

Volumetric MRI changes in basal ganglia of children with Tourette's syndrome.

To define the site of pathology in Tourette's syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS+ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.

Heart mass and blood pressure have separate genetic determinants in the New Zealand genetically hypertensive (GH) rat.

OBJECTIVE: To determine associations between cardiovascular parameters and genotype in 205 F2 rats of both sexes and lineages from reciprocal crosses made between rats of the New Zealand genetically hypertensive (GH) and Brown Norway (BN) rat strains. METHODS: Systolic tail blood pressure, mean arterial blood pressure, pulse rate, heart mass, body mass and relative heart mass were determined for each rat in the age range 17-19 weeks, and DNA polymorphisms were examined for the guanylyl cyclase A (GCA), angiotensin converting enzyme (ACE) and renin (REN) genes. RESULTS: The phenotypic data indicated the presence of genes on the X and Y chromosomes that affected blood pressure. The GH GCA allele, in males only, and the GH ACE allele, in females only, both cosegregated with increased blood pressure. The ACE effect was confined to rats of one lineage only, namely those with GH grandfathers. A cosegregation of the GH REN allele with decreased blood pressure was also detected in females with BN grandfathers. In contrast, the GH REN allele cosegregated with a smaller heart in males only, whereas the GH ACE allele cosegregated with a larger heart both in males and in females. In males this was the consequence of a decrease in body mass with no change in absolute heart mass, whereas in females there were changes in both of these parameters. CONCLUSIONS: The results show that cardiac hypertrophy and blood pressure have independent genetic determinants in the GH rat, and indicate the importance of sex in determining the phenotypic expression of genes underlying cardiovascular pathology.

Segregation analysis of hypospadias: a reanalysis of published pedigree data.

Little is known about the cause of hypospadias, one of the most common urogenital anomalies in males. Familial clustering of hypospadias is well recognized, with heritability estimated to be about 70% under a simple multifactorial threshold model. Neither alternative genetic mechanisms nor shared environmental factors within families have been explored fully. To learn more about possible genetic mechanisms, we used 2 methods of segregation analysis to analyze a set of published family data. These analyses are based on the families of 103 probands with hypospadias, who were ascertained through surgery departments in Denmark [Sørensen, 1953]. Urogenital examinations were performed on 95% (n = 1,510) of available male relatives, and 2.2% were found to have hypospadias. Within the probands' nuclear families, 12% of nonproband sons of normal fathers were affected. Using the mixed model of inheritance, both the autosomal dominant (AD) and codominant models fit these data better than either autosomal recessive (AR) or multifactorial models. Using the regressive logistic models, both AD and AR models were equally likely, and a model of nonMendelian sibship clustering gave a better fit to these data. These inconsistent findings illustrate the difficulties commonly encountered in segregation analysis. Using 2 different statistical approaches, we found 2 different explanations, both of which differ from the autosomal recessive model originally suggested by Sørensen [1953]. Hypospadias in these families is almost certainly heterogeneous. Determining the cause of familial clustering of hypospadias will require careful delineation of persons with recognized syndromes from uncomplicated cases and detailed information on potential prenatal risk factors.

Segregation analysis of Parkinson disease.

Parkinson disease (PD) is a prevalent movement disorder of unknown cause whose incidence rises with increasing age. Nearly 20% of PD is familial, a small subset of which exhibits autosomal dominant transmission. However, in most families, the inheritance is not clear. To determine the most likely mode of inheritance of PD, we performed complex segregation analyses using kindreds of 136 PD patients randomly ascertained from a clinic population. The hypotheses of a nontransmissible environmental factor, no major gene or type (sporadic), and all Mendelian inheritance (dominant, recessive, additive, decreasing) were rejected (P <0.001). Familial clustering of PD in this data set is best explained by a rare familial factor which a) is transmitted in a nonMendelian fashion, and b) influences the age at onset of PD. If confirmed, our results have immediate implications in gene-mapping studies which often search for genes that behave in a Mendelian fashion that affect susceptibility rather than age at onset and long term implications in understanding the pathogenesis of PD.

Using log-linear models to test for associations among congenital malformations.

Log-linear models can be used to test for pairwise associations and higher order interactions among anatomically distinct birth defects or congenital malformations. A log-linear model, including terms for every possible pairwise association among seven severe and easily detectable congenital malformations, was examined using data on 16,217 infants registered in the Metropolitan Atlanta Congenital Defects Program between 1968 and 1986. The resulting model showed clear patterns of strong association between some congenital malformations and not others, and the presence of 3-way interaction terms where the association between two malformations depended on the presence of a third. Examining a more parsimonious log-linear model showed overlapping patterns of pairwise association involving anal-rectal atresia and omphalocele, anal-rectal atresia and limb deficiency, and anal-rectal atresia and tracheaesophageal fistula. A second common pattern involved a triangular cluster with a hierarchical relationship among the three malformations (where there was a strong association between the first and second malformations and between the first and third malformations, but the association between the second and third was only seen in the absence of the first). Three such overlapping triangular clusters were identified from these data: neural tube defects, oral clefts, and omphalocele; neural tube defects, oral clefts, and limb deficiency; and limb deficiency, diaphragmatic hernia, and neural tube defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1.

To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

SA gene and blood pressure cosegregation using Dahl salt-sensitive rats.

Based on the published cDNA base sequence for the (anonymous) SA gene, a polymerase-chain-reaction (PCR) product from the SA gene was obtained from a Dahl salt-sensitive rat kidney cDNA library. Compared to the published sequence, this product had a 102 base pair insert in the 3' end of the cDNA, probably as the result of alternate mRNA splicing. A StuI restriction fragment length polymorphism detected three alleles among various rat strains using this PCR SA gene probe. Alleles at the SA locus strongly cosegregated with blood pressure (P = .0012) in a salt-fed F2 population derived from crossing Dahl S and Lewis rats. In contrast, a cosegregation analysis of blood pressure and SA alleles in salt-fed F2 rats derived from a Dahl S x Wistar-Kyoto cross gave a negative cosegregation result. It is concluded that in certain genetic backgrounds the SA gene (or a closely linked gene) can contribute a significant component of genetic hypertension.

Amino Acid analysis by precolumn derivatization.

Amino acid analysis is of central importance to many areas of biological and medical research as a tool for characterization and quantitation of both free amino acids present in biological fluids, beverages, or food and proteins/peptides.

Identification of N-terminal amino acids by high-performance liquid chromatography.

1-Dimethylaminonaphthalene-5-sulfonyl chloride (dansyl chloride, Dns-Cl) has been widely used in protein chemistry for determination of the N-terminal amino acid of peptides. The dansyl chloride reacts with both α- and Σ-amino groups (Fig. 1). After derivatization the peptide is acid hydrolyzed releasing free amino acids, amino acids such as lysine and histidine with the dansyl group attached to their side chains, together with the derivatized N-terminal amino acid. Traditionally the Dns-amino acids have been separated by thin layer chromatography and viewed by fluorescence in UV light ( Chapter 23 in vol. 1 of this series). This procedure is time-consuming, however, and is not easily quantified. More recently, methods have been developed for separation of the Dns-amino acids by reverse-phase HPLC (1,2), thus allowing for automation of the separation and quantitation of the derivatives. In order to minimize the interference by reagent byproducts, the reaction conditions have been modified from those of the traditional method.