Human fibroblasts as a relevant model to study signal transduction in affective disorders.

BACKGROUND: Previous studies have demonstrated a blunted beta adrenoceptor-linked protein kinase A (PKA) response in the 900xg supernatant fraction of human fibroblasts cultured from patients with major depression. RESULTS: Results of the present studies demonstrate a significant reduction in the B(max) value of [3H]cyclic AMP binding to the regulatory subunit of PKA in the supernatant fraction of fibroblasts from patients with major depression with no change in the K(d) values. The data are consistent with the previous observation that the maximal stimulation of PKA by cyclic AMP is reduced without a change in the EC(50) value. The blunted beta adrenoceptor-mediated PKA response in fibroblasts from patients with major depression is reflected in a significant reduction in the isoproterenol-stimulated phosphorylation of the nuclear transcription factor CREB. Both, the isoproterenol-mediated phosphorylation of nuclear CREB and the activation of the stably transfected luciferase reporter gene, pAD neo2-C12-BGL, were inhibited by the beta(2) adrenoceptor antagonist ICI 118551, thus indicating that the gene activating action of isoproterenol in human fibroblasts is mediated via the beta(2) adrenoceptor cascade. The low EC(50) value of 1 nM isoproterenol for activation of gene expression in stably transfected human fibroblasts appears to be a reflection of the amplification mechanism occurring via the beta adrenoceptor-cyclic AMP-PKA-CREB transduction cascade. CONCLUSIONS: The results support the notion that human fibroblasts represent a relevant model for studying processes of signal transduction in patients with affective disorders.

Anger as a predictor of aggression among incarcerated adolescents.

This study examined the validity of trait anger as a predictor of aggressive behavior among juvenile offenders. Two standard self-report anger scales were administered to 65 recently incarcerated male adolescents. These youths were followed prospectively for physical and verbal aggression during 3 months of subsequent incarceration. Anger scores were not correlated with participant history of violent offending or staff ratings of anger. However, anger scores from both instruments were predictive of subsequent physical and verbal aggression. For example, the Trait Anger scale successfully classified 66% of juvenile offenders into high and low aggressive groups; receiver operating characteristic analysis obtained an effect size of .72. These results support the predictive validity of self-reported anger in identifying juvenile offenders at risk for institutional aggression.

Composite assessment of gestational age: a comparison of institutionally derived and published regression equations.

OBJECTIVES: This study was undertaken to evaluate (1) the applicability of previously reported regression equations for gestational age assessment to our patient population in Pittsburgh and (2) whether the addition of radius length or its substitution for one of the other fetal measurements could improve the prediction of gestational age. STUDY DESIGN: Five fetal parameters--biparietal diameter, head circumference, abdominal circumference, femur length, and radius length--were measured in a prospective cross-sectional study of gestational age assessment in 265 pregnant women between 13 and 43 weeks' gestation. RESULTS: The regression equation derived for each fetal parameter was found to be quite similar to previously published reports. Although the coefficient of determination was only minimally affected, the variability improved with the institutionally derived regression equation. CONCLUSION: The incorporation of several fetal measurements into a composite assessment of gestational age generally enhances the accuracy of the prediction. The addition of a second long bone to a gestational age assessment does not significantly improve results.

Torsionally and hydrophobically modified 2,3-diarylindenes as estrogen receptor ligands.

2,3-Diarylindenes are ligands for the estrogen receptor which display intrinsic fluorescence. In order to optimize the receptor binding affinity of these compounds while preserving their desirable fluorescence properties, a series of torsionally modified analogues were prepared. A fluorine or methyl group was introduced on either of the two phenyl substituents ortho to their attachment site to the indene nucleus, in order to increase the out-of-plane twist of the appended rings. The analogues were prepared by the benzylation of appropriate deoxybenzoins, followed by Friedel-Crafts cyclic alkylation-dehydration. Comparison of the X-ray crystal structure of one analogue with unsubstituted analogues confirms the torsional perturbation effected by the ortho substituent. The torsional disposition of the C-2 aryl group in the substituted diphenylindenes is further investigated by UV (absorbance maxima and molar absorptivities), fluorescence (Stokes' shift), and NMR (chemical shifts). These spectroscopic measurements indicate increasing twisting between the C-2 aryl substituent and the indene system according to the following order: 3-ring o-Me-indene 9f less than diphenylindene 15 = 20 degrees less than 3-ring o-F-indene 9c less than 1-Me-indene 16 less than 2-ring o-F-indene 9b less than 2-ring o-Me-indene 9e = 63 degrees. The binding affinity of these analogues to the estrogen receptor was evaluated by a competitive radiometric receptor binding assay. While o-fluoro or o-methyl substitution on the 3-ring increases binding only slightly, binding of the o-fluoro 2-ring analogue is increased ca. 6-fold and the o-methyl analogue 11-fold, giving, in the latter case, a compound with an affinity equivalent to that of estradiol. The increase in binding affinity afforded by ortho substitution correlates with the increase in the torsion angle of the C-2 aryl ring. A thermodynamic evaluation of the receptor fit (Andrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648) indicates that, for the o-methyl 2-ring analogue, the effect of the ortho substitution on increasing receptor binding appears to be a combination of increased surface area due to the substituent itself, together with a change in surface area of the ligand that results from the increased torsion of the two aryl rings. An o-fluoro substituent on the 2-ring provides a compromise between the relative planarity required for high fluorescence intensity and the molecular shape needed for increased estrogen receptor binding affinity.(ABSTRACT TRUNCATED AT 400 WORDS)

Sonographic imaging of the fetal azygous vein. Normal and pathologic appearance.

Sonologists should be familiar with the frequency of resolution and the ultrasonic appearance of the normal fetal azygous vein. In this study, 66 consecutive uncomplicated pregnancies were scanned to determine the frequency of imaging the fetal thoracic azygous vein. Between 21.7 and 30 gestational weeks, the azygous vein could be imaged in 50% of the cases and measured 1-2 mm in caliber. In the last 10 weeks of pregnancy, the azygous vein could be imaged in 98% of the cases and measured 2-4 mm. A case of fetal azygous continuation of the inferior vena cava is shown where the vein was abnormally dilated to a caliber of 8 mm.

Hydroxylated 2,3-diarylindenes: synthesis, estrogen receptor binding affinity, and binding orientation considerations.

In order to develop high affinity, fluorescent ligands for the estrogen receptor based on 2-arylindenes, it is important to understand how this non-steroidal estrogen is oriented within the binding site and to know how hydroxyl substituents affect binding. To investigate these issues a series of dihydroxyl-substituted 2,3-diphenylindenes were prepared by the cyclization of appropriately substituted alpha-benzyldesoxybenzoins, and their binding affinities for the estrogen receptor measured by a competitive radiometric binding assay. Introduction of a p-hydroxyl group in the 2-phenyl ring of two 2,3-diphenyl-6-hydroxyindene systems causes a 3-fold increase in binding affinity, whereas, p-hydroxylation in the 3-phenyl ring of these systems causes a 2-fold reduction in binding affinity. The parallel change in binding affinity in these two systems suggests a consistent binding orientation of the 2,3-diarylindene systems, which, on the basis of earlier studies, has the indene system corresponding to the A/B-ring system of estradiol. This orientation model and the enhanced affinity of the p-hydroxy 2-ring derivatives are suggestive of a new hydrogen bonding site below the D-ring binding site. Changes in receptor binding affinity upon hydroxylation in triphenylacrylonitrile ligands for the estrogen receptor, reported by others, do not show such parallelism, suggesting that different derivatives may not be bound in congruent orientations. A m-hydroxyl substituent in ring-3 of the 2,3-diarylindene has very little effect on receptor binding. In designing fluorescent 2,3-diarylindene ligands for the estrogen receptor, 3-ring hydroxylation may be useful in reducing non-specific binding and in modifying electron donation to the fluorophore with only modest or no reduction in binding affinity. p-Hydroxylation of the 2-ring, although increasing receptor binding, is not consistent with the electron accepting nature required of this ring.

Different roles of alpha-noradrenergic receptor subtypes in regulating lordosis.

Ovariectomized guinea pigs were given free estradiol (E) at hr 0 and 28, and progesterone (P) at hr 39. Experiment 1: The alpha-1 noradrenergic antagonist prazosin, but not the alpha-2 noradrenergic antagonist idazoxan, prevented display of lordosis behavior when administered systemically 30 min prior to E injections at either hr 0 or 28, or 30 min prior to both injections. Experiment 2: Multiple injections of idazoxan (i.e., 30 min prior to and 60 and 120 min after each E injection) failed to prevent display of lordosis. Experiment 3: E-primed animals were given a single injection of idazoxan 1 hr before P, or 5 hr after P. In those animals given idazoxan 1 hr before P, display of lordosis was not prevented. However, in animals given idazoxan once lordosis display had begun (i.e., 5 hr after P) ongoing lordosis behavior was blocked. These data suggest differential roles of alpha-noradrenergic receptor subtypes in regulation of lordosis: noradrenergic transmission through the alpha-1 subtype may mediate hormone-priming processes leading to lordosis, whereas transmission through the alpha-2 subtype may modulate ongoing lordosis responses.

Thigh circumference in the detection of intrauterine growth retardation.

Intrauterine growth retardation (IUGR) is associated with an increase in perinatal mortality as well as long-term neurobehavioral morbidity. Despite the increasing sophistication of antenatal fetal assessment, the diagnosis of growth retardation remains difficult. Since the fetal effects of growth inhibition are variable, no one ultrasonic parameter can diagnose with certainty the growth-retarded fetus. The reduction of thigh circumference with IUGR is secondary to the muscle wasting that is characteristic of this disease process. The sensitivity (77.8%) and specificity (75%) of thigh circumference may make it a useful additional sonographic parameter in the evaluation of fetal growth retardation.

Sonographic evaluation of the cervix during ovulation induction.

With the induction of ovulation, clomiphene citrate and human menopausal gonadotropin have the potential to stimulate the endocervical glands. We have found that the degree of mucus production can occasionally be quite large and hence is detectable by sonographic evaluation as an anechoic cervical mass. The incidence of this specific ultrasonic finding was found to be approximately 5%. This physiologic process should be differentiated from disease states affecting the cervix.