The turnover of cholesterol in the brain is thought to occur via conversion of excess cholesterol into 24S-hydroxycholesterol, an oxysterol that is readily secreted from the central nervous system into the plasma. To gain molecular insight into this pathway of cholesterol metabolism, we used expression cloning to isolate cDNAs that encode murine and human cholesterol 24-hydroxylases. DNA sequence analysis indicates that both proteins are localized to the endoplasmic reticulum, share 95% identity, and represent a new cytochrome P450 subfamily (CYP46). When transfected into cultured cells, the cDNAs produce an enzymatic activity that converts cholesterol into 24S-hydroxycholesterol, and to a lesser extent, 25-hydroxycholesterol. The cholesterol 24-hydroxylase gene contains 15 exons and is located on human chromosome 14q32.1. Cholesterol 24-hydroxylase is expressed predominantly in the brain as judged by RNA and protein blotting. In situ mRNA hybridization and immunohistochemistry localize the expression of this P450 to neurons in multiple subregions of the brain. The concentrations of 24S-hydroxycholesterol in serum are low in newborn mice, reach a peak between postnatal days 12 and 15, and thereafter decline to baseline levels. In contrast, cholesterol 24-hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate with age. We conclude that the cloned cDNAs encode cholesterol 24-hydroxylases that synthesize oxysterols in neurons of the brain and that secretion of 24S-hydroxycholesterol from this tissue in the mouse is developmentally regulated.

The synthesis of dihydrotestosterone is catalyzed by steroid 5a-reductase isozymes, designated types 1 and 2. Mutation of type 2 results in male pseudohermaphroditism, in which the external genitalia are phenotypically female at birth. Two striking and unexplained features of this disorder are that external genitalia of affected males undergo virilization during puberty and that these individuals have less temporal hair regression. The tissue-specific and developmental expression patterns of the 5a-reductase isozymes were investigated by immunoblotting. The type 1 isozyme is not detectable in the fetus, is transiently expressed in newborn skin and scalp, and permanently expressed in skin from the time of puberty. There was no qualitative difference in 5a-reductase type 1 expression between adult balding vs. nonbalding scalp. The type 2 isozyme is transiently expressed in skin and scalp of newborns. Type 2 is the predominant isozyme detectable in fetal genital skin, male accessory sex glands, and in the prostate, including benign prostatic hyperplasia and prostate adenocarcinoma tissues. Both isozymes are expressed in the liver, but only after birth. These results are consistent with 5a-reductase type 1 being responsible for virilization in type 2-deficient subjects during puberty, and suggest that the type 2 isozyme may be an initiating factor in development of male pattern baldness. (J. Clin. Invest. 1993. 92:903-910.) Key words: dihydrotestosterone* sexual differentiation * benign prostatic hyperplasia* prostate cancer * male pattern baldness

516Ventricular septal defect (VSD) is the most common congenital heart malformation and can be detected during the prenatal and postnatal period, in childhood, and in adulthood. Spontaneous closure of VSD can be determined through a variety of methods-echocardiography, Doppler color flow imaging, angiography, auscultation, and cardiac catheterization-and can be proven by pathological evidence at necropsy. There are two major types of VSD, membranous and muscular, as well as the perimembranous variety, which comprises variable portions of the adjacent muscular septum but lacks the membranous septum. VSD appears either as an isolated cardiac defect without other abnormalities or with several complex malformations. It has long been recognized that VSD can close spontaneously, but the incidence of spontaneous VSD closure is still uncertain. Since necropsy study of the hearts with VSD has rarely been reported, information on morphological features of spontaneous VSD closure remains limited. In addition, the mechanisms for spontaneous VSD closure are not fully understood. Herein, we present a brief review of the incidence of spontaneous VSD closure, morphological characteristics of the closure, and the main mechanisms responsible for the closure. INCIDENCE OF SPONTANEOUS VSD CLOSURETh e incidence of spontaneous ventricular septal defect (VSD) closure varies greatly, depending on the age and gender of subjects at spontaneous closure, the size and site of the defect, the types of defect, as well as the population studied, methods employed, and length of follow-up period. Table 1 presents available data on the incidence of spontaneous VSD closure.Age and gender. Age has been found to have a significant infl uence on the incidence of spontaneous VSD closure, whereas gender seems less likely to aff ect the incidence. Although spontaneous VSD closure can occur at any agegestation, infancy, childhood, adolescence, and adulthood (1)-it occurs most commonly during the fi rst 6 months of life (2), during the fi rst year (3, 4), or soon after the fi rst year of life (5). Afterward, the occurrence of closure declines progressively and occurs less commonly after the age of 10 (5). It has been documented that the incidence of the close increases with age, from 24% at 18 months of age to 50% at 48 months and 75% at 120 months (6). However, in older children, at 3.5 years old, the incidence declines sharply to 44% and then rises to 66% at 7 years and 75% at 10.5 years (6). A similar trend has been found in other reports, which showed 57% (109/190) of cases closed before 3 years of age, 89% (169/190) closed before 8 years of age (7), and 4% to 10% closed after the age of 17 (8, 9). During adulthood, the incidence of spontaneous VSD closure remarkably declines. One study showed that of 188 adults with VSD, 19 patients' (10%) VSD closed spontaneously between the age of 17 and 45 years, and the incidence of closure was greater in the 17-to 24-year age group than the 25-to 34-year group, the 35-to 44-year group, and the ≥45-year group (8)...

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Lipomatous hypertrophy of the interatrial septum ("massive fatty deposits in the atrial septum") may represent an incidental autopsy finding or may be associated with atrial arrhythmias, obstructive symptoms, or sudden death. Antemortem diagnosis is becoming much more common. In a literature review and in a review of our 12 cases, this condition was found to occur more frequently in obese middle-aged or elderly subjects, who frequently demonstrated atherosclerotic coronary artery disease. The unencapsulated mass generally occurred anterior or superior to the fossa ovalis, and histologically was characterized by mature fat with varying quantities of fetal fat, inflammation and fibrosis, and entrapment of myocardial fibers with cytologic atypia. Cases were included that had a minimum atrial septal thickness of 1.0 cm. The septum ranged up to 7.0 cm in maximum thickness (2.6 cm average). In our cases, no deaths were directly attributed to this disorder. It is important that forensic pathologists become more generally aware of this condition. To further delineate the true pathological significance, the atrial septum should be routinely examined by palpation and sectioning to determine its thickness and fat content.