Some properties of the specific androgen-binding activities in cultured human genital skin fibroblasts. Specific 5 alpha-dihydrotestosterone (DHT)-binding activity in the cytosol (C) and 0.4 M KCl-extractable nuclear fraction (N) of cultured human fibroblast cell strains developed from preputial (n = 12) and labium majus (n = 12) skin were analyzed by gel exclusion chromatography, sucrose gradient sedimentation, and thermostability. Both fractions had activities that were excluded from Sephacryl S-200 columns; another component (mol wt, 20,000) was present in the N fraction. The C was more thermostable than a homologous N activity, and addition to the former of KCl to 0.4 M had no effect. There was large, overlapping variation in thermostability of the C and N activities among strains from either site, sister strains developed from a single skin biopsy, and even among serial subcultures within a strain; likewise, the variable sedimentability of the C (4-7S) and N (3.2-5.9S) activities prevented their consistent discrimination. Each type of variation occurred despite excellent intraexperimental replication. The thermostability of a given N activity varied directly with its sedimentation coefficient. By cluster analysis, the data relating thermostability of a given N activity with the percentage of 0.4 M KCl-resistant nuclear activity segregated into two populations; within each population these two measurements were related inversely. We suggest that these coordinate behaviors of the N activity reflect intrinsic properties of the androgen-receptor system in normal genital skin fibroblasts which may be useful for defining qualitative aberrations of the system in receptor-positive forms of congenital androgen insensitivity.


Radioimmunoassay of reverse triiodothyronine. rT3 RIA standard curves were generated using rT3 standards from various sources. The rT3 antiserum and the method of free and bound hormone separation used were the same in all assays. The slopes of rT3 RIA curves differed considerably; standard curves generated with Henning (Berlin) rT3 standard had the steepest slope. Because of the differences in slopes of standard curves, bound to free estimates, when extrapolated from standard curves generated with various rT3 standards, resulted in 2- to 3-fold differences in rT3 assay values in the same sera. Circulating rT3 concentration in human sera was 20 ng/100 ml when Henning rT3 standard was used in the assay, whereas with Jorgensen's rT3 standard, a value of 42 ng/100 ml was noted. As the rT3 antiserum and assay conditions used were identical in all comparisons (except rT3 standards), the 2- to 3-fold differences in rT3 values noted in the same sera suggested variability in potency of rT3 standards. The differences in rT3 values in the same sera (resulting from extrapolation from standard curves using different rT3 standards) were of the same magnitude as that noted in normal human sera in various studies, suggesting that the reported rT3 variations in sera of euthyroid individuals may also be due to differences in rT3 standards employed in the assay.


Heterogeneous human prolactin from a giant pituitary tumor in a patient with panhypopituitarism. A patient with hypopituitarism and an unusually large chromophobe adenoma which secreted an enormous amount of human PRL (hPRL) provided us with a unique opportunity to study the heterogeneity of hPRL. Serum samples obtained before and after surgery as well as pituitary extract were studied. Each sample contained three distinct hPRL peaks on gel filtration designated as big medium, and small. The hPRL moiety of each peak fraction was stable in size, immunoreactivity, and bioreactivity, indicating that the polymorphic hPRL components, once formed, were not interconvertible. As the relative proportion of medium and small hPRL components in all blood samples obtained before surgery and in the pituitary tumor extracts were similar, it seems that these two forms of hPRL originate from the tumor. However, there was a lack of correlation between big, medium, and small hPRL in samples obtained before and 1 yr after surgery. Also, increasing amounts of radioactive substance similar to increasing amounts of radioactive substance similar to big PRL were formed by exposure of 125I-labeled small PRL to progressively larger concentrations of serum. Thus, only small and possibly medium PRL are secretory products.


Effect of flutamide on cortisol metabolism. The effect of flutamide on cortisol metabolism was studied in eight patients with prostate cancer. Flutamide markedly decreased the formation of 3 alpha, 17,21-trihydroxypregnane-11,20-dione (THF), and the 11-oxy-17-ketosteroid metabolites by 72%, 50%, and 46% respectively; however, 3 alpha, 11 beta, 17,21-tetrahydroxy-5 alpha- pregnan-20-one was increased by 46%. The 24-h mean plasma cortisol concentration was not altered. The cortisol production rate decreased by an average of 53% (from 32.7 to 15.5 mg/24 h). The effect of the drug on plasma cortisol kinetics was studied in three patients. This showed that flutamide increased the t1/2 (from 80 to 108 min) but decreased the distribution volume (from 17.8 to 13.8 liters) and the MCR (from 222 to 130 liters/24 h). The changes in THE and THF formation and in the t1/2 and MCR of [C]cortisol are similar to the effects observed in patients with intrahepatic cholestasis. It is suggested that in the case of flutamide these changes were also due to a cholestasis-producing effect of the drug on the liver. As the clinical response to the drug did not correlate with the cortisol metabolic changes, its therapeutic effect was probably not mediated by its effects on cortisol metabolism.


Parathyroid hormone secretion in magnesium deficiency. The effect of an acute elevation of the serum magnesium concentration on the concentrations of serum immunoreactive parathyroid hormone (IPTH) were studied in hypocalcemic hypomagnesemic patients, hyperparathyroid patients, and normal individuals. Basal serum IPTH concentrations in the hypomagnesemic patients ranged from undetectable to 3 times the upper limit of normal. All hypomagnesemic patients were observed to have an immediate rise in the serum IPTH concentration after magnesium administration regardless of the basal IPTH concentration. In contrast, normal individuals and patients with primary and secondary hyperparathyroidism responded to magnesium administration with either a decrease or little change in the serum IPTH concentration. These date indicate that an acute stimulation of PTH secretion induced by magnesium is characteristic of the magnesium-deficient state. The consistency of this response suggests that impaired PTH secretion is a significant factor contributing to the hypocalcemia of magnesium deficiency.


Metabolism of cortisol-21 glucosiduronate in man. The metabolism of cortisol-21-glucosiduronate has been studied in two subjects. Urinary excretion was about 65% in both subjects, with cortisol glucosiduronate as the principal metabolite accompanied by small amounts of 11 beta, 17,21-trihydroxypregnane-3,20-dione (THF) glucosiduronate. The absence of the other normal metabolites of cortisol [17,21-dihydroxypregnane-3,11-20-trione (THE), 3 alpha, 11 beta, 17, 20xi, 21-pentahydroxypregnane, and 3 alpha, 17, 20xi, 21-tetrahydroxypregnan-11-one] indicates that negligible hydrolysis at C-21 occurred and that an unoccupied C21 position is required for oxidation at C-11 and reduction at C-20. The limited conversion to THF suggests that a pathway through cortisol-21-glucosiduronate does not contribute significantly to the differences in specific activity of urinary THF and THE observed after administration of labeled cortisol.


Extraadrenal effects of metyrapone in man. [14C]Cortisol was injected iv into three subjects during a control period and while receiving metyrapone. The plasma kinetics of the tracer cortisol and the patterns of its urinary metabolites were measured. Metyrapone caused an increase in the volume of distribution of cortisol (34%) and in the MCR (75%); the half-life was decreased by 25%. There were marked changes in the urinary metabolite pattern: 3 alpha,11 beta,17,21-tetrahydroxy-5 alpha-pregnan-20-one, 3 alpha,17,21-trihydroxy-pregnane-11,20-dione(THE), pregnane-3 alpha,11 beta,17,20 alpha,21-pentol, plus pregnane-3 alpha,11 beta,17,20 beta-21-pentol (cortol), and 3 alpha,17,20 alpha,21-tetrahydroxypregnan-11-one (cortolone) all decreased by an average of 62%, 44%, 38%, 45%, and 25% respectively. In contrast, there was an increase of 296% in 3 alpha,17,20 beta,21-tetrahydroxypregnan-11-one (beta-cortolone). To account for these effects it is postulated that metyrapone has the following extraadrenal actions: 1) it inhibits the back reduction of cortisone to cortisol and 2) it stimulates the 20-ketosteroid reductase that converts THE to beta-cortolone.


Urinary 5 alpha-androstane-3 alpha,17 beta-diol radioimmunoassay: a new clinical evaluation. A rapid specific and reliable RIA for urinary 5 alpha-androstane-3 alpha,17 beta-diol (Adiol) is described using chromatographical purification and a specific antibody. Values are reported under some physiological and pathological conditions in 179 individuals. In 43 normal adult men, the mean (+/-SD) urinary Adiol excretion was 193 +/- 77 micrograms/24 h, and in 29 normal women it was 44 +/- 23 micrograms/24 h. These values are significantly different (P less than 0.01). In 49 hirsute women, urinary Adiol Excretion was elevated (137 +/- 51 micrograms/24 h) and significantly different from this value in normal women (P less than 0.01). The urinary Adiol excretion in 10 postmenopausal women was very low (less than 5 micrograms/24 h). In normal adult subjects, the theoretical contribution to urinary Adiol of the major secreted androgens was calculated. Whereas dehydroisoandrosterone and dehydroisoandrosterone sulfate yield the same amount of urinary Adiol in both sexes, testosterone is the main precursor of Adiol in men and androstenedione is the main precursor in normal premenopausal and hirsute women. However, the amount of Adiol recovered in the 24-h urine depends not only on the secretion rate of androstenedione and testosterone but is also related to the testosterone 5 alpha-reductase activity present in androgen target cells, especially in sexual skin.


Effect of starvation on the production and peripheral metabolism of 3,3',5'-triiodothyronine in euthyroid obese subjects. The effect of starvation on the peripheral metabolism of rT3 was evaluated in four obese euthyroid patients. During starvation, the serum rT3 concentration increased by 69% while the MCR of rT3 decreased in all four patients from control values of 96 +/- 23 (mean +/- SD) to 68 +/- 17 liters/70 kg . day, resulting in a slight increase in the mean production rate of rT3. These findings are in contrast to the marked decrease in T3 production rate associated with fasting, indicating that inner and outer ring deiodination of T4 can be varied independently.


Prolonged hyperprolactinemia in preterm infants. Serum PRL levels were followed serially in full term (FT; 39-41 weeks) and preterm (PT; 30-32 weeks) infants, from birth to 12 and 20 postnatal weeks, respectively. Values were higher in FT infants than in PT infants on day 1 after birth (267 +/- 20 vs. 156 +/- 8 ng/ml) but were similar in both by the age of 2-4 weeks (69 +/- 8 vs. 69 +/- 6 ng/ml). Between the ages of 4-12 weeks, the serum PRL in FT infants fell to near adult levels (24 +/- 2 ng/ml), but this fall was seen much later in PT infants, between 12-20 weeks postnatally (23 +/- 2 ng/ml). When values in FT and PT infants were compared at parallel postmenstrual ages in contradistinction to postnatal ages, a similar course of PRL was discernable in both groups. These data may provide indirect evidence for the establishment and maturation of inhibition of PRL secretion (i.e. PRL-inhibitory factor production) postnatally, between 44-52 weeks postmenstrually.


A new method of paired thyrotropin assay as a screening test for neonatal hypothyroidism. A simple and reliable method of paired TSH assay was developed and used in screening for neonatal primary hypothyroidism. In this method, a paired assay is first done. Equal parts of the extracts of dried blood spots on filter paper (9 mm diameter) from two infants 4-7 days old are combined and assayed for TSH by double antibody RIA. If the value obtained is over the cut-off point, the extracts are assayed separately for TSH in a second assay to identify the abnormal sample. Two systems, A and B, with different cut-off points were tested. On the basis of reference blood samples (serum levels of TSH, 80 microU/ml in system A and 40 microU/ml in system B), the cut-off point was selected as follows: upper 5 (A) or 4 (B) percentile in the paired assay and values of reference blood samples in the second individual assay. Four cases (2 in A and 2 in B) of neonatal primary hypothyroidism were found among 25 infants (23 in A and 2 in B) who were recalled from a general population 41,400 infants (24,200 in A and 17,200 in B) by 22,700 assays. This paired TSH neonatal hypothyroidism.


Effect of intraamniotic fluid thyroxine injection on fetal serum and amniotic fluid iodothyronine concentrations. Seven hundred micrograms of T4 were injected into the amniotic cavity 24 h before delivery of five pregnant women scheduled for elective cesarean section at term. T4, T3, and rT3 concentrations were measured by RIA in amniotic fluid obtained at the time of the injection and in amniotic fluid and cord serum samples collected at delivery. Iodothyronine concentrations also were determined on cord samples from 24 full term control infants. The geometric mean serum T4 concentration in the experimental infants was 27.2 micrograms/dl, almost 3 times that of the control population (10.3 micrograms/dl); serum rT3 concentrations were markedly elevated to a mean of 657 ng/dl, compared to 254 ng/dl in control infants. The mean serum T3 concentration was slightly but significantly increased to 61.3 ng/dl (control, 48.3 ng/dl; P less than 0.02). Amniotic fluid T4, T3, and rT3 concentrations all increased significantly. T4 injection into the amniotic fluid is an effective method of increasing fetal serum T4 concentrations. The preferential pathway of monodeiodination of the injected T4 in the human fetus is to rT3 rather than T3.


A radioimmunoassay for 3',5'-diiodothyronine. The present report describes a RIA for 3',5'-diiodothyronine (T2) that can be performed on unextracted serum and which has a lower limit of detectability of 2 ng/dl. Cross-reactivity with other iodothyronines was negligible, except for rT3 which began to demonstrate cross-reactivity when rT3 levels were elevated to 180 ng/dl. Employing this RIA for T2, we have determined that 83 healthy individuals had a mean  (+/-SE) serum T2 concentration of 5.0 +/- 0.3 ng/dl, thyrotoxic subjects (n = 12) had a mean T2 level that was elevated to 10.8 +/- 0.8 ng/dl, and each of 6 hypothyroid subjects had undetectable (less than 2 ng/dl) concentrations. Athyreotic patients (n = 8), receiving 0.4 mg T4 daily, had serum T2 concentrations of 15.0 +/- 3.0 ng/dl. Fasting in obese subjects was associated with an increase in serum T2 to 6.9 +/- 0.6 ng/dl from a basal level of 4.4 +/- 0.4 ng/dl in the fed state (P less than 0.01). Despite the fact that rT3 levels may be elevated in amniotic fluid and that rT3 is expected to represent the major source from which extrathyroidal T2 arises, T2 levels were low in amniotic fluid, being undetectable (less than 2 ng/dl) in 9 of 19 samples; the mean (+/-SE) T2 concentration in the 10 detectable samples was 5.4 +/- 1 ng/dl. These data indicate T2 is a normal component of serum and that the majority of serum T2 is probably derived from peripheral conversion. Furthermore, these observations suggest that situations associated with elevated rT3 levels (e.g. thyrotoxicosis and fasting) may also have increased T2 values.


Serum Neurophysins in familial central diabetes insipidus. Antibovine neurophysin antibodies (anti-bNpI and/or anti-bNpII) are present in certain patients with familial central diabetes insipidus; these are exogenous origin, as they are not present in patients who have not received treatment with crude posterior pituitary extracts over the years preceding the analysis. Immunoreactive neurophysins were detectable in the blood of five patients with familial central diabetes insipidus, and in two of them, the levels increased after a short period of water restriction. There is marked polymorphism of these neurophysins from one serum to another: neurophysin I was consistently absent, while neurophysin II, accessory neurophysins, and other immunoreactive substances not present in normal sera were sometimes present in variable amounts. Immunoreactive AVP was undetectable in the urine of all patients, while immunoreactive OT was found in three of them; the latter substance could, however, be arginine vasotocin. Data are presented suggesting that the association between the biosynthesis of neurophysin I and AVP on the one hand, and neurophysin II and OT on the other hand is maintained in patients with isolated AVP deficiency on the basis of a congenital defect.


The use of specific radioimmunoassays to determine the renal clearance rates of estrone and 17 beta-estradiol during the menstrual cycle. Specific RIAs requiring ether extraction only were established for estrone and 17 beta-estradiol both in plasma and in urine from the nonpregnant female. These assays were used to measure the renal clearance rates of estrone and of 17 beta-estradiol in eight ambulatory women in the follicular and in the luteal phases of the menstrual cycle. The mean (+/-SE) for the renal clearance rate of estrone was 0.71 +/- 0.058 ml/min in the follicular phase and 1.26 +/- 0.35 ml/min in the luteal phase. The mean (+/-SE) renal clearance rate of 17 beta-estradiol was 0.44 +/- 0.055 ml/min in the follicular phase and 0.29 +/- 0.043 ml/min in the luteal phase. There was no significant difference in the renal clearance rates of either estrone or of 17 beta-estradiol between the follicular and luteal phases of the cycle. The renal clearances of estrone and 17 beta-estradiol were highly correlated (r = 0.84; P less than 0.01). The renal clearance rate of estrone was significantly greater than that of 17 beta-estradiol in both phases of the cycle (P less than 0.01).


A specific radioimmunoassay for estrone sulfate in plasma and urine without hydrolysis. Estrone sulfate, quantitatively the most important estrogen in plasma, has previously been determined only after hydrolysis and chromatography. An antiserum raised against estrone glucosiduronate-bovine thyroglobulin was found to be suitable for the specific RIA of estrone sulfate both in plasma and urine. Plasma levels were measured after solvent extraction without hydrolysis or chromatography. The mean (+/-SE) was 972 +/- 79 pg/ml (range, 537-1581) in 15 women in the follicular phase, 1806 +/- 160 pg/ml (range, 814-3358) in 15 women in the luteal phase, and 922 +/- 62 pg/ml (range, 461-1238) in 13 men. The urinary excretion of estrone sulfate, measured after simple chromatographic separation, ranged from 0.8-7.9 micrograms/24 h in men and 5.1-18.7 micrograms/24h in nonpregnant women. This was generally one-seventh to one-half the simultaneous estrone glucosiduronate excretion rate. An approximate mean renal clearance of estrone sulfate calculated from the above values was 2.7 ml/min. The low clearance rate is taken to reflect extensive binding of estrone sulfate by plasma proteins. The splanchnic extraction of estrone sulfate measured in 6 patients undergoing hepatic vein catheterization for diagnostic purposes was 29.8 +/- 11.1%, indicating net uptake of this compound by the splanchnic area.


Regulation by plasma lipoproteins of progesterone biosynthesis and 3-hydroxy-3-methyl glutaryl coenzyme a reductase activity in cultured human choriocarcinoma cells. The regulation of both the activity of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase [mevalonate-NADP+ oxidoreductase (CoA-acylating) EC 1.1.1.34] and the secretion of progesterone by human plasma lipoproteins has been investigated in human choriocarcinoma cells in culture. HMG CoA reductase activity was computed from the rate of formation of [14C]mevalonolactone from [14C]HMG CoA. The activity of HMG CoA reductase was expressed as nanomoles of mevalonolactone formed/min . mg solubilized cell protein. An inverse relationship was found between the presence of lipoprotein in the culture medium and the activity of HMG CoA reductase in these cells. In cells maintained in the presence of lipoprotein-enriched culture medium containing 840 micrograms cholesterol/ml, the average activity of HMG CoA reductase was 0.25 nmol/min . mg protein. After removal of lipoprotein, the activity of HMG CoA reductase increased to 1.3 nmol/min . mg protein. The average activity of HMG CoA reductase in cells maintained in lipoprotein-deficient culture medium was 1.5 nmol/min . mg protein but fell to 0.3 nmol/min . mg protein after addition of lipoprotein to the medium. When cells were maintained in the presence of lipoprotein, the rates of section of progesterone and pregnenolone into the culture medium were 2-8 times greater than the rates of secretion of these steroids by cells maintained in the absence of lipoprotein. On the basis of these results, it is concluded that lipoproteins control the rate of cholesterol biosynthesis in cultured choriocarcinoma cells by regulating the activity of HMG CoA reductase, and control the rate of synthesis of progesterone by providing the precursor, cholesterol. We suggest that progesterone synthesis by the trophoblast of the human placenta may also be regulated by the uptake of lipoprotein from maternal blood.


Plasma immunoreactive relaxin levels in pregnant and nonpregnant women. Immunoreactive relaxin was measured in plasma samples obtained from human volunteers utilizing the RIA procedure of Sherwood et al., as modified by O'Byrne and Steinetz for heterologous plasma samples. Immunoreactive hormone was not detected in samples obtained from men, and only rarely in plasma of nonpregnant women. Immunoreactive relaxin was present as early as the fourth week of pregnancy and was detectable throughout the course of gestation. Immunoreactive relaxin tended to be higher early in pregnancy, and there was no peak just before parturition as occurs in many other species. Our results are at variance with those of Bryant and coworkers, who reported high levels of immunoreactive relaxin in men and nonpregnant as well as pregnant women. The possible reasons for this discrepancy are presented.


Low serum triiodothyronine and high serum reverse triiodothyronine in old age: an effect of disease not age. Serum concentrations of T4, T3, T3, free T4, free T3, and TSH were determined in four groups of adult subjects: group A, 27 healthy young volunteers (aged 18-29 yr); group B, 24 carefully selected healthy elderly subjects (aged 70-90 yr); group C, 41 subjects living at a municipal nursing home for the elderly (aged 70-90 yr); and group D, 35 hospitalized patients (aged 70-90 yr). Identical levels of iodothyronines in serum were found in the young and in the elderly healthy subjects. Moderate and severe disease induced alterations in iodothyronine concentrations in serum comparable to those reported earlier. Serum T3 and free T3 levels were low and serum rT3 levels were high in groups C and D subjects; serum free T4 was elevated in group D, while serum T4 was low. Serum TSH was lower in the healthy elderly subjects than in the young subjects. Serum TSH was higher in the elderly sick subjects (groups C and D) than in the healthy subjects (group B). We conclude that advanced age per se is not accompanied by alterations in free or total serum iodothyronine levels.


Twenty-four-hour plasma prolactin patterns in prepubertal and adolescent boys. The concentration of PRL was measured every 20 min for 24 h in six prepubertal and three adolescent boys. In both groups, PRL secretory episodes occurred throughout the 24-h period. In all subjects, the mean concentration of PRL was significantly higher during sleep than during wakefulness; the mean concentration during the entire 24-h period, during sleep or during wakefulness, was not different between the prepubertal subjects and the adolescents. These data suggest the absence of an ontogenetic change for PRL secretion in boys. During acute sleep-wake reversal, two of three pubertal boys showed significantly higher PRL during daytime sleep than during nocturnal wakefulness. This suggest that PRL release in adolescent boys is linked with sleep, rather than with clock time.


Brain growth-promoting activity in human serum: relationship to growth hormone and somatomedin. Brain growth-promoting activity and somatomedin activity were assessed in serum collected from patients with pituitary disorders of GH secretion. Brain growth-promoting activity correlated with somatomedin activity in serum, and both rose in response to GH administration.


Basal and human chorionic gonadotropin-stimulated 17 alpha-hydroxyprogesterone and testosterone levels in Klinefelter's syndrome. In nine patients with Klinefelter's syndrome, mean basal plasma levels of testosterone (302 +/- 145 ng/100 ml) and its major precursor, 17 alpha-hydroxyprogesterone (17-OHP; 86 +/- 46 ng/100 ml), were significantly lower (P less than 0.01 to less 0.05) than in eight eugonadal men (605 +/- 180 and 136 +/- 39 ng/100 ml, respectively). The ratio of 17-OHP to testosterone, however, was comparable in both groups (0.29 +/- 0.09 vs. 0.24 +/- 0.08; P less than 0.10). In the Klinefelter patients, basal plasma testosterone and 17-OHP levels were positively correlated (rs = 0.87). Administration of hCG for 3 days raised plasma testosterone and 17-OHP levels in both groups. In the Klinefelter patients, the plasma 17-OHP rise exceeded the testosterone increment, leading to a statistically significant increase (0.48 +/- 0.19) of the 17-OHP to testosterone ratio, whereas this ratio remained virtually unchanged in the control subjects (0.20 +/- 0.06). Together, these findings indicate that in the basal state testicular steroidogenesis is globally attenuated, whereas short term hCG stimulation shows that the later steps in the biosynthesis of testosterone may be rate limiting in Klinefelter's syndrome.


Studies of the human testis. XI. Leydig cell clusters and levels of intratesticular testosterone and 20 alpha-dihydroprogesterone. Testosterone concentration in testes of 23 men, ages 51 to 90, was determined as 490 +/- 172 ng/g tissue (M +/- S.D.) and 20 alpha-dihydroprogesterone concentration as 10.0 +/- 2.3 ng/g tissue (M +/- S.D.) in 18 men of the same patient group. Leydig cells were estimated by the number of Leydig cell clusters per tubule. There was a high correlation (r = 0.88, p less than .001) of the Leydig cell index with intratesticular testosterone. It is proposed that the Leydig cell cluster index provides a direct index of steroid biosynthetic activity in the human testis as reflected in intratesticular testosterone levels. Although there was no significant correlation of 20 alpha-dihydroprogesterone levels in the testis with either the Leydig cell index or intratesticular testosterone, the high level of 20 alpha-dihydroprogesterone compared to peripheral levels suggests its production by the testis.


The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. Three patients with insulin resistance caused by autoantibodies to the insulin receptor were investigated serially over a 3-yr period. Major changes in carbohydrate metabolism, insulin receptor status, and titer of antireceptor antibodies were observed in each case. In one patient, normalization of glucose tolerance, insulin sensitivity, and receptor binding were associated with a spontaneous fall in the titer of antireceptor antibody. A second, more severely affected patient had two entirely distinct phase to her illness. The first, or hyperglycemic phase, was characterized by insulin resistance, negligible insulin binding to receptors on circulating monocytes, and high titers of circulating antireceptor antibodies. The second phase was characterized by refractory hypoglycemia, in association with proliferation of membrance insulin receptors; these occurred despite persistence of high titers of antireceptor antibody. An unusual heptic lesion, diffuse adenomatosis, was observed during this phase. A third patient showed features of both of the other patients, with spontaneous fall in antibody titer as well as a later phase of receptor proliferation. These studies demonstrate that patients with antibodies to insulin receptors may have a fluctuating clinical course. There may be spontaneous changes in antibody titers as well as independent changes in receptor concentration. Hypoglycemia and hepatic proliferation are newly recognized clinical sequelae in patients with this syndrome.


Effects of dexamethasone on fetal and maternal thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels. The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (+/- SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 +/- 0.9 and 13.0 +/- 0.9) were not significantly different (P less than 0.05) from those of the control patients (13.9 +/- 1.5 and 10.4 +/- 0.6, respectively). The mean (+/- SE) maternal plasma concentrations of T3 and rT3 (nanograms per dl) of dexamethasone-treated patients (204 +/- 6 and 82 +/- 11) were not significantly different (P less than 0.05) from those of the control patients (201 +/- 26 and 72 +/- 6, respectively). However, the mean (+/- SE) concentrations of T3 and rT3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 +/- 13 and 360 +/- 35) were 3- and 2-fold and significantly higher (P less than 0.05) than those of the control group (39 +/- 6 and 195 +/- 19, respectively). No significant differences (P less than 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 +/- 0.5 and 3.0 +/- 1.0) and those of the control group (2.8 +/- 0.5 and 6.9 +/- 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3, or TSH were observed between the two groups of patients (P less than 0.05). The increase of T3 and rT3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy.


Direct conversion of testosterone to dihydrotestosterone glucuronide in man. Tritiated testosterone and [14C]dihydrotestosterone (DHT) were administered by constant iv infusion into five young and five elderly men undergoing diagnostic cardiac catheterization. The radioactivity concentrations of free and conjugated DHT in arterial and hepatic vein blood samples were then determined. The analysis of the 3H:14C ratio of free DHT in arterial and hepatic vein blood showed that in both groups, the 3H:14C ratio of free DHT was the same in arterial and hepatic vein blood, indicating that splanchnic tissue is not the source of blood DHT from testosterone. This is in agreement with data that the transfer constant across the liver ([rho]T-DHT SD) was undetectable. In both young and elderly men, a significant increase of the 3H concentration of DHT glucuronide in hepatic vein blood was observed, indicating that the splanchnic compartment could be the site of production of DHT glucuronide. The 3H:14C ratio of DHT glucuronide was much higher than that of free DHT in both groups, suggesting that DHT glucuronide is derived from the blood testosterone pool, and most of the DHT from testosterone seems to be conjugated before mixing with blood DHT. This study indicates that a large fraction of DHT produced in the liver from testosterone is efficiently conjugated or further metabolized, and this results in the lack of splanchnic production of free DHT in men.


Inhibitory effect of human follicular fluid upon the maturation of porcine oocytes in culture. Human follicular fluid (hFFl) was harvested from follicles (5-15 mm) of human ovaries obtained at laparotomy. Addition of native hFFl, or a low molecular weight fraction of it, to the culture medium was found to inhibit the spontaneous maturation of cumulus-enclosed porcine oocytes. It was also found that hFFl inhibited progesterone secretion by the cumulus cells. The results extend earlier observations in other mammalian species, indicating that in the human, also, a specific oocyte maturation inhibitor is responsible for keeping the oocyte in meiotic arrest.


Gamma-amino-beta-hydroxy butyric acid stimulates prolactin and growth hormone release in normal women. The influence of gamma-amino-beta-hydroxy butyric acid (GABOB) treatment on pituitary function has been investigated in this study. Different doses (50 x 100 mg) of GABOB were iv injected into three and six normal women, respectively. PRL and GH plasma levels were measured before and after the injection. The treatment with 150 mg GABOB, performed in another two normal women, was interrupted because of side-effects (loss of consciousness etc.) due to the treatment. The treatment with 50 mg GABOB did not induce significant variations of the two hormones; however, significant increases of PRL (P less than 0.05) and GH (P less than 0.01) plasma levels were observed after injection with 100 mg GABOB. The present data suggest that gamma-amino butyric acid (GABA) itself of GABAergic drugs might play an important role in the control of hypothalamic-pituitary function.


L-dopa absorption and the pituitary-hypothalamic axis. Administration of oral L-dopa is often used as a neuropharmacological probe to evaluate the pituitary hypothalamic axis. The effect of gastrointestinal absorption of L-dopa on the changes in plasma GH, PRL, and body temperature which occur after ingestion of this amino acid is unknown. Plasma L-dopa, GH, PRL, and rectal and skin temperatures were measured in 14 male volunteers after oral administration of 1.0 g measured in 24 men after random administration of L-dopa and a placebo. L-Dopa levels rose to 1.85 +/- 1.33 microgram/ml (mean +/- SD), but maximum plasma levels occurred at variable times from 30-230 min after drug administration. Plasma GH levels increased to 23.7 +/- 14.7 ng/ml, while PRL levels fell to 46.7 +/- 12.3% of the mean basal values. Rectal temperature decreased significantly in 3 of the men after L-dopa ingestion. Plasma GH levels after L-dopa correlated with the absorption of the drug (P less than 0.05) and inversely with the basal level of GH before L-dopa administration. There was no correlation between the basal PRL level or basal body temperature and the magnitude of the fall in PRL or body temperature after L-dopa administration. The variability of responses in GH, PRL, and body temperature after oral L-dopa ingestion is not the result of differences in  absorption in the amino acid alone, and indicate either that there is a different sensitivity in the mechanisms that stimulate GH secretion and lower plasma PRL and body temperature, or that L-dopa acts at different sites to bring about each of these changes.


Nomifensine: diagnostic test in hyperprolactinemic states. Nomifensine, an antidepressant agent which activates dopamine (D) neurotransmission mainly by inhibiting DA reuptake in the central nervous system, was administered either to puerperal lactating women or to subjects with nonpuerperal hyperprolactinemia. In 10 postpartum women and in 7 women with no evidence of PRL-secreting tumor, oral administration of nomifensine (100 or 200 mg, respectively) induced in the following 5 h a clear-cut inhibition of plasma PRL levels; in 10 patients with PRL-secreting tumors, the drug did not lower plasma PRL levels. In 2 of these patients nonsupressibility of plasma PRL levels to nomifensine was the only indication of the existence of a pituitary microadenoma. It is proposed that acute nomifensine testing may be a valid neuropharmacological tool for discriminating between individuals with and without pituitary adenoma.


Specific 5 alpha-dihydrotestosterone receptors in human gingiva. The cytoplasm of normal human male and female gingiva contains a receptor capable of specifically binding 5 alpha-dihydrotestosterone (DHT). This binding has a high affinity for DHT (Kd, approximately 2.2 x 10-9 M) and a low capacity (approximately 190 fmol/mg protein). The binding is extremely heat sensitive and exhibits a pattern of competition similar to that obtained with DHT receptors from other target tissues. The demonstration of a specific DHT receptor in human gingiva provides the first direct biochemical evidence that this tissue may function as a target organ for androgens. There was no correlation between the Kd in normal tissue and gingival hyperplasia or between the Kd or number of binding sites and the age or sex of the patient. However, there sites and the age or sex of the patient. However, there was a significant difference (P less than 0.0005) between the amount of DHT-binding sites per mg protein in normal tissue as compared to gingival hyperplasia (drugs or pregnancy).


LH and melatonin secretion patterns in pubertal boys. Four normal pubertal boys had plasma LH and melatonin measured at 20-minute intervals for 24-hours. All four subjects showed a significant augmentation of LH and melatonin during nocturnal sleep. There was also a significant correlation between the LH and melatonin levels (P less than 0.001). These data indicate that the peripheral concentrations of melatonin which occur during sleep are insufficient to prevent spontaneous LH secretion during puberty.


Small bowel rupture due to blunt abdominal trauma. Fourteen men with traumatic rupture of the small gut are analysed. Seven had alcohol intoxication. The diagnosis was made pre-operatively in eight. Ileal ruptures were the commonest, (11 of 14). Two patients died.


Anaemia in pregnancy--a report of two trials. In two separate trials, 140 cases of Pregnancy Anaemia were investigated in the University Teaching Hospital, Lusaka. The distribution of anaemia was as follows: Iron deficiency 118 (84.2%); dual deficiency 15 (19.7%); haemolytic five (35%); and megaloblastic 2 (1.4%). Anaemia with megaloblastic change was more common in the second study.


A review of autopsies at the University Teaching Hospital, Lusaka, 1975. Findings in all clinical autopsies performed in 1975 are presented. The autopsy rate for all deaths was 17%, it was only 10% in childhood deaths, but rose to nearly 34% if stillbirths and neonatal deaths are excluded. The main causes of death are classified in major fields. In adults neoplasms were the commonest cause of death with acute infections and cardiac diseases following in order of importance. The value of the clinical autopsy is briefly discussed.


Blood supply and position of the vermiform appendix in Zambians. The arterial blood supply, position, and length of the appendix were studied 103 Zambian cadavers. In 39.8%, more than one appendicular artery was found. In position, 43.6% were pelvic, and 20.3% retro-cecal. The average length of the appendix was 12.0 cm in males, and 11.4 cm in females. The prevalence of the dual blood supply and pelvic position, may partly explain the recorded rarity of appendicitis among Africans.


The treatment of sepsis in superficial burns: effect of 1% Silver Sulphadiazine. One hundred patients with superficial burns were treated by the exposure method under ordinary ward conditions. Topical 1% Silver Sulphidiazine ("Flamazine") was used under controlled conditions. The exposure technique, with judicious local cleaning, resulted in spontaneous healing in 42% of cases. Topical "Flamazine" was used in 58% of cases. It was found to be soothing, giving patients instant relief of pain. It arrested crack and fissure formation with bleeding, especially in burnt areas in the neck and about major joints. It expedited healing; an astringent effect was also observed. It was concluded that the exposure technique, with topical "Flamazine", was beneficial in the treatment of superficial burns, obviating the routine daily bathing of the burnt.


A clinical study of Osteomyelitis and septic arthritis. Sixty-nine cases of Osteomyelitis, and 27 of septic arthritis have been presented. 69/96 (71%) were children below 12. The sites frequently involved were tibia, femur and humerus. Septic arthritis commonly involved the knee. The commonest organism was Penicillin - resistant Staphylococcus aureus. Though we sought but failed to establish that overt clinical malnutrition was aetiologically important, since 54% were well-fed children, the virulence of the sepsis in which an entire bone shaft may die is disturbing but unexplained. Whereas arthrotomy plus antibiotics gave uniformly good results for septic arthritis, in osteomyelitis, no single treatment regime was outstanding. We would recommend the tetracyclines, (eg. "Reverin"), in addition to appropriate surgery, as a routine.


Initial management of pulmonary tuberculosis in Lusaka, 1976. The records of 395 patients diagnosed in the Lusaka UTH as having pulmonary tuberculosis (TB) in 1976 were examined. A total of 4,308 patient days were spent by 319 TB patients on treatment at UTH: average 12 beds a day. Thirty (8%) absconded from the UTH: 80% were later transferred to Kabwe or Kafue Gorge. Initial diagnosis was made by smear only in 71% of cases; the known resistance rate in Zambia is about 25%. Treatment was variable: 86% were started on streptomycin and thiazine, about 50% of sputum-negative cases on triple regimes, and old cases were also sometimes restarted on streptomycin and thiazine. Ways of advancing TB control in Lusaka were suggested.


Hepatitis B surface antigenaemia: incidence and significance in Zambian blood donors. Forty-eight (5.0%) of 966 healthy Zambian blood donors were positive for hepatitis B surface antigen (HBsAg) when tested by the turkey erythrocyte passive haemagglutination (TEPHA) method. Twenty-six were investigated in detail, but only one blood donor was found to have liver disease, and this was thought unlikely to be causally related to HBsAg (alcohol-induced fatty infiltration). It is recommended however, that blood donors should be screened for HBsAg. Positive individuals should be rejected but their serum tested for aspartate transaminase (AST), and, if elevated, a liver biopsy performed. This ideal policy is not practicable in all tropical hospitals.


Adverse reactions to methyldopa with particular reference to hypotension. Of 26,294 consecutive patients monitored in a comprehensive drug surveillance program, 1067 (4 per cent) received methyldopa for treatment of hypertension. Adverse reactions attributed to methyldopa were reported in 149 patients (14 per cent), the most frequent being hypotension. Life-threatening adverse effects were reported in nine patients (6 per cent of reactors)--the major problems being hypotension associated in several patients with signs of cardiac or cerebral ischemia. Hypotension attributed to methyldopa was more frequent in younger patients, in those with uremia, in lighter subjects, and in those receiving a high daily dose. Marked interaction between these factors was demonstrated and eightfold differences in the frequency of hypotension were observed in different sub-groups of methyldopa recipients. Adverse effects other than hypotension were reported infrequently and did not correlate well with the previously mentioned factors. The findings suggest that methyldopa therapy should be commenced cautiously in younger patients, in the non-obese, and in those with impairment of renal function as manifest by elevated blood urea nitrogen levels.


An evaluation of the results of left ventricular aneurysmectomy: use of a simplified method for analysis of the left ventriculogram. Twenty-three patients underwent left ventricular aneurysmectomy without coronary artery bypass or other surgical procedure. Fourteen patients (Group 1) benefitted from surgery, and nine fared poorly (Group 2), including the four postoperative deaths. Among the 19 survivors, 17 had postoperative catheterizations. Pre- and postoperative left ventriculograms in the right anterior oblique projection were analyzed by planimetry of the aneurysmal and non-aneurysmal areas. This method provided data favorably altered by surgery in the improved patients and unchanged in the others. None of the preoperative ventriculographic measurements effectively separated the postoperative patient groups. The poor results in the Group 2 patients were of heterogeneous origin arising from pre-, peri- and postoperative factors. The more important factors were the largest and smallest aneurysms, surgically induced mitral insufficiency, and progressive coronary artery disease. Thus, the improvement in surgical results from better angiographic preoperative case selection is possible, but limited.


Coronary artery to pulmonary artery fistulas. Twelve patients with a total of 14 coronary artery to pulmonary artery fistulas were discovered at the time of diagnostic coronary angiography. Six patients had severe coronary artery disease, five patients had normal coronary arteriography, one patient had insignificant coronary artery disease, and one patient had rheumatic heart disease. Only two patients had characteristic continuous murmurs; one patient had a normal coronary angiogram, and the second patient had severe coronary artery disease. Ten fistulas originated from the left anterior descending artery, three from the right coronary artery, and one from the left circumflex artery. The fistulas were either composed of one large (five fistulas) or one or more small channels (seven fistulas) or poorly defined plexiform channels (two fistulas). Hydrogen studies performed in two patients were negative and dye dilution curves performed in all patients were normal. In only four out of the six patients with severe coronary artery disease, the fistulas originated from a diseased vessel and in each case the origin was proximal to the narrowing. The pathogenesis and functional role of these fistulas is largely unknown.


Migraine and the mitral valve prolapse syndrome. We believe there is a significant association between migraine and the prolapse mitral valve syndrome. Propranolol is the drug of choice in these patients for the treatment and prevention of migraine. Increased platelet aggregability may be the common pathophysiologic mechanism as relates to emboli from the valve and possibly in strokes related to migraine. Recognition of the association of the two syndromes will result in appropriate subacute bacterial endocarditis prophylaxis for patients at risk as well as prevention of improper medication to those patients with migraine who are at risk for stroke.


Leukocyte function after aortic valve replacement. Leukocyte function was studied in patients with prosthetic heart valves by oxygen consumption measurements during phagocytosis of polystyrene latex particles. The consumption reflects the phagocytotic capacity of the cells. In 38 patients with Starr-Edwards aortic ball valves the mean oxygen consumption was 3.95 nanoatoms per minute per 10(6) leukocytes, as compared to 4.15 in 50 healthy subjects, the difference not being statistically significant. The number of leukocytes per ml. of blood and the distribution of cell types was quite similar in the two groups, although slightly more younger cells were found in the patients. It is concluded that the capacity for phagocytosis is not significantly reduced after aortic ball valve implantation.


Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol. Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.


Hemodynamics of essential hypertension in young subjects. Cardiac output was determined in 42 young essential hypertensives (15 to 25 yrs); values ranged from 3.86 to 10.30 L./minute. These differences were not related to magnitude of volemia. Correlation of output to weekly blood pressure average (BPav) was not significant; its relationship to intraarterial pressure (BPia) was not significant in 21 patients aged 20 to 25 and of borderline significance in 13 aged 15 to 19. Blood pressure changes associated with the study (BPia--BPav) were also not consistently related to cardiac output. Six patients had systolic hypertension; only one had elevated stroke volume. These results outline as complex a picture in young essential hypertensives as in older subjects.


Exposure of concealed right bundle branch block in Wolff-Parkinson-White type B by pacing from the vicinity of the A-V node. In two infants with Wolff-Parkinson-White type B, right bundle branch block was concealed during sinus rhythm and pacing from close to the atrial entrance of the right-sided accessory pathway. However, pacing from the vicinity of the A-V node, the A-V node itself, and the His bundle exposed the right bundle branch block by producing exclusive ventricular activation through the normal, A-V nodal His-Purkinje pathway. In addition, pacing from close to the A-V node also resulted in fusion beats characterized by absence of delta waves with (pseudo) normal QRS complexes and short H-V intervals. False patterns of tachycardia-dependent and bradycardia-dependent block in the accessory pathway also occurred. These dynamic phenomena were attributed to the (peri-A-V nodal) pacing-related, relatively early arrival of excitation at the ventricles through the normal pathways coexisting with delayed arrival of excitation via the accessory pathway. The latter in turn was due to the longer intra-atrial conduction time from paced (peri-A-V nodal) site to atrial entrance of the accessory pathway.


The familial component in longevity--a study of offspring of nonagenarians: III. Intrafamilial studies. The effect of parental longevity on the length of survival of offspring has been examined according to selected demographic and environmental characteristics. The present study is based on 7,103 progeny, 20 years old or older. They were the sons and daughters of 1,766 men or women, 90 or more years old, who were alive in 1922-1930 at the time of ascertainment. The age at death of the other parent of the offspring is the basis of classification used in this analysis. A positive relationship was found between age at death of the non-proband parent and the age at death of the offspring. This relationship existed regardless of similarities or differences in the characteristics analyzed.


Familial correlations of longevity: an isolate-based study. Familial correlations for age at time of death have been computed in a French Canadian isolate. We show that parent-offspring correlations as well as sib correlations are of the same order of magnitude as that between spouses for various age groups at death. It is suggested that heritability of survival is nearly zero. Observed variability in survival is interpreted as the effect of environmental differences acting upon age-dependent genes.


The G and BBB syndromes: case presentations, genetics, and nosology. Hypertelorism and hypospadias are described in four unrelated boys; bilateral cleft lip and cleft palate were also present in two of the boys and mild mental retardation in another. These features are compatible with both the G and BBB syndromes. When present, laryngotracheoesophageal anomalies or respiratory and swallowing difficulties are characteristic features of the G syndrome; otherwise facial features may be useful in distinguishing the G and BBB syndromes. Cases 1 and 2 had anteverted nares and a broad and flat nasal bridge, and Case 1 had shortened palpebral fissures, all consistent with the G syndrome. In contrast, Cases 3 and 4 had a high and broad nasal bridge as previously described in the BBB syndrome. The father of Case 1 had mild hypertelorism and first-degree hypospadias, demonstrating autosomal dominant inheritance in the G syndrome. The mothers of Cases 2, 3, and 4 all had mild hypertelorism consistent with autosomal dominant inheritance and partial male-sex limitation, as previously proposed for both the G and BBB syndromes.


Phenotypic overlap of the BBB and G syndromes. Three males with similar malformations including hypertelorism, telecanthus, cleft lip and palate, and hypospadias, have been evaluated. One also had a laryngotracheoesophageal cleft and therefore was considered to have the G syndrome. The other two had no stridor, aspiration, or difficulty swallowing, and were considered to have the BBB syndrome. Both disorders are associated with multiple malformations and can be most readily distinguished by the presence of laryngoesophageal abnormalities in the G syndrome and differences in facial features evident later in childhood. The BBB syndrome appears to be inherited as an X-linked disorder with the affected female showing only telecanthus and hypertelorism. The G syndrome exhibits autosomal dominant inheritance with males more severely affected, although a few few females have had serious malformations in addition to telecanthus and hypertelorism. In the family with the G syndrome evaluated for this report, the mother of the affected infant had telecanthus, hypertelorism, and anosmia, the latter a feature not previously noted in this disorder.


Alkaptonuria in the Trencín District of Czechoslovakia. For several years the Clinical Genetics Research Laboratory at Martin, Czechoslovakia, has been studying alkaptonuria (AU) in the northern part of the District of Trencín in Slovakia. These affected individuals are part of a group of 103 alkaptonurics originated mostly in the mountainous parts of Slovakia. We report results of pedigree analyses; population and affected-family biochemical urine screening; estimation of inbreeding coefficient, of exogamy rate and of average marital distance and of calculation of the frequency of the AU allele, and of homozygotes and heterozygotes in this portion of the Trencín District. Twelve homozygotes were found, but seven originated from a single hamlet in which a founder effect - genetic drift and inbreeding - are thought to account for the high prevalence of AU.


Cystinuria genotypes predicted from excretion patterns. Genotypes of 17 patients with cystinuria were predicted from data based on excretion rates of the families' obligate carriers. The methodology differed from that used by other investigators as it did not employ intestinal biopsy studies or loading dose measurements. The Type I form was more common than either Type II or Type III and frequently occurred in combination to give compound heterozygous genotypes with the Type III form.


Normal intelligence in two children with Carpenter syndrome. Previous reports have noted a constant association between the Carpenter syndrome (acrocephalopolysyndactyly, type II) and mental retardation. We report two patients with this condition with normal intelligence. These observations indicate that mental deficiency is not necessarily a component of the Carpenter syndrome and that early surgical correction of the craniosynostoses may improve the chances of normal mentality.


Cerebral gigantism and primary hypothyroidism: pleiotropy or incidental concurrence. An 8.5-month-old baby girl had cerebral gigantism and primary hypothyroidism with generalized large muscles (the Kocher-Debré-Semelaigne syndrome). The significance of this association remains to be determined.


X-linked mental retardation: transmission of the trait by an apparently unaffected male. A pedigree is presented in which an apparently unaffected man transmitted the gene for X-linked mental retardation to at least four of his 12 daughters. None of his 12 sons was mentally retarded. These findings may be explained by a somatic mutation and germinal mosaicism in the father or by a half chromatid mutation in maternal gametes.


Autosomal dominant Fanconi syndrome with early renal failure. The "idiopathic" Fanconi syndrome occurs mostly sporadically, occasionally as an autosomal recessive trait. However, few instances of autosomal dominant inheritance have been reported. We described a father and son with the Fanconi syndrome, ie, with renal glycosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and bone disease. No other causes of the Fanconi syndrome were found. Both father and son developed end stage renal disease. Aminoaciduria in excess of that seen in renal insufficiency is shown by comparison with published data for amino acid excretion in uremia. Renal transplantation in the father has improved kidney function with no evidence of Fanconi syndrome. This family is unique in that there are no other reports of autosomal dominant Fanconi syndrome with progression to early renal failure.


Spreading of inactivation in an (X;14) translocation. In the KOP translocation, t(X;14)(q13;q32), virtually the entire long arm of the X has been translocated to the end of the long arm of chromosome 14. Meiotic secondary nondisjunction in a female balanced carrier of the translocation has led to a son with two der(14) or 14-X chromosomes. The normal X chromosome is late replicating in the mother. One of the two 14-X chromosomes is late replicating in the son, with heavy terminal labeling of all but the centromeric end of the chromosome. This suggests that genetic inactivation has spread from the Xq segment of the translocation chromosome to at least two thirds of the segment derived from chromosome 14, and that the remaining proximal segment of chromosome 14 is possibly still genetically active. These findings provide an explanation for the phenotype: Klinefelter syndrome plus a few mild malformations that are sometimes seen in this syndrome but are also seen in duplication of the proximal portion of chromosome 14. Although the proband has a duplication of virtually an entire chromosome 14, 14(pter leads to q32), the phenotypic effect of the autosomal duplication has been mostly nullified by the spread of inactivation.


Genetic aspects of the BOR syndrome--branchial fistulas, ear pits, hearing loss, and renal anomalies. A pedigree of branchio-oto-renal dysplasia (the BOR syndrome) is reported, including the documentation by serial audiometric studies of the onset and rapid progression of hearing loss in the twin sister of an affected child. The literature on this syndrome is analyzed to derive some figures for use in genetic counseling of such families. Branchio-oto-renal dysplasia is an autosomal dominant disorder in which affected individuals may have preauricular pits, lachrymal duct stenosis, hearing loss, branchial fistulas or cysts, structural defects of the outer, middle, and inner ear, and renal anomalies, which may range from mild hypoplasia to complete absence. Not all features of the syndrome are expressed in all carriers of the gene, but few carriers lack all the features, and the pits, branchial clefts, and hearing loss, are frequently expressed. Those offspring of affected persons who have pits or fistulas are likely (about 80%) to have hearing loss of varying degrees of severity. A minority of heterozygotes (about 7%) may have hearing loss without pits or fistulas. The risk of severe renal malformation is probably fairly low. Whether families that show dominant inheritance of pits, clefts, and deafness without renal anomalies represent variants of the BOR syndrome or a separate entity (the BO syndrome), is still not clear. At present, any individual with preauricular pits and branchial clefts deserves both otologic and renal investigation.


Mental retardation and osteosclerosis.

Mental retardation and osteosclerosis. We report a girl with profound mental retardation who, at 3 years of age, began to show a progressive osteosclerosis on bone roentgenograms. The bony changes were slightly suggestive of osteopetrosis from which they differed by a number of unusual features.


Anatomical analysis of the developmental effects of aneuploidy in man--the 18-trisomy syndrome: II. Anomalies of the upper and lower limbs. We report the anatomical variations of the limbs in eight infants with the trisomy-18 syndrome that were dissected and studied in detail. In each case, the upper limbs showed defects which further define the specific influence of this aneuploidy on the development of its preaxial (radial) component, and the tendency towards reduction defects. Abnormalities included muscle variations concentrated along the radial margin of the forearm and hand, the absence of the definitive musculocutaneous nerve in all of the limbs, and reductions of the radial artery in four of the bodies. Pathogenetic mechanisms explaining the observed defects are discussed, and include: 1) a defect in peripheral nerve development; or 2) tissue necrosis. The characteristic flexion deformities of the fingers seem to be due to a displacement of the tendons of extensors digitorum and digiti minimi. The lower limbs did not show a consistent pattern of defects, except for the absence of some muscles (psoas minor, the tendon of flexor digitorum brevis to digit V), and the presence of several supernumerary muscles. These variations are discussed as possible nonspecific effects of 18-trisomy on development. The additional anatomical data from this and the first paper in this series [Bersu and Ramirez-Castro, 1977] provide a more detailed picture of the trisomy-18 phenotype which may be useful in corroborating an unconfirmed clinical diagnosis of the syndrome.


The Rieger syndrome.

The Rieger syndrome. Fourteen patients with hypodontia and the ocular features of the Rieger syndrome were examined for the presence of systemic anomalies. A periumbilical defect that consisted of failure of the periumbilical skin to involute was seen in ten of the thirteen evaluated for the defect. Three others had scars over the umbilical area and had a history of surgery for herniation. In addition, four males in one family and one male from another family had hypospadias. None of several other anomalies reported to be components of the Rieger syndrome by other authors was detected in the fourteen patients. The mode of inheritance in the familial cases studied was compatible with autosomal dominance. The results of this study indicate that the Rieger syndrome is an autosomal dominant syndrome whose cardinal features are hypodontia, goniodysgenesis, and failure of the periumbilical skin to involute properly.


Genetics of acheiropodia ("The handless and footless families of Brazil"): X. Roentgenologic study. The main radiologic findings from four unrelated cases and two sibs with acheiropodia are presented and discussed. On the basis of such analysis, a clinical and radiologic description of the anomaly is given. The presence of one or more fingers and of a small bone (Bohomoletz bone) in the upper stumps is discussed. These unusual findings in bone structure were assumed to be due to a variability in the expression of the acheiropodia gene. Radiologic studies of some of the acheiropods' normal parents failed to reveal even mild manifestations of the gene in the heterozygous state. No recognizable pattern was found in the dermal ridges on the end of the acheiropods' upper or lower stumps.


Size and pericentric inversion heteromorphisms of secondary constriction regions (h) of chromosomes 1, 9, and 16 as detected by CBG technique in Caucasians: classification, frequencies, and incidence. Eighty normal Caucasians were studied by CBG technique for estimation of size and inversion heteromorphisms of chromosomes 1, 9, and 16. Size heteromorphisms were classified into one of five sizes using 16p as a reference standard: very small, small, intermediate, large, and very large. Inversion heteromorphisms were also classified into 5 categories - eg, no inversion; partial inversion - minor; half inversion; partial inversion - major; and complete inversion. The frequencies of size heteromorphisms for chromosomes 1, 9, and 16 were 11.3%, 47.5%, and 7.5%, respectively. Thirty-four chromosomes were found to have inversions. Of these, 16 were in chromosome 1, and 18 were in chromosome 9. No inversions were found in chromosome 16. An increase in the size of the h region was more frequently associated with inversion, suggesting that there is a possible relationship between size and inversion. For example, there were 118 chromosomes that were classified as "intermediate" by size; 23 (19.5%) had inversions. In contrast, there were 225 that were "small" in size, and only 10 (4.4%) had inversions. There was no significant difference between males and females for size and position heteromorphisms.


Hypoplastic left heart in a patient with 45,X/46,XX/47,XXX mosaicism. Recurrence risks for primary congenital heart lesions are well defined. An infant with hypoplastic left heart syndrome is observed to have a short neck with a full skin fold on the right side, unilateral single palmar crease, and whorls on all ten fingers. She was found to have the Ullrich-Turner syndrome with mosaicism 45,X/46,XX/47,XXX. We believe the cardiac malformation was secondary to her aneuploidy. This could have important implications for prediction of recurrence risks to the parents. Chromosomal tests may be indicated for infants were severe congenital cardiac lesions, based on subtle clinical findings.


The X-linked syndrome of macroorchidism and mental retardation: further observations. We report six males with the syndrome of macroorchidism and mental retardation. The trait is inherited as though X-linked, or possibly autosomal dominant male-limited. We also found no evidence of gonadal dysfunction. Associated abnormalities were abnormal EEG (3/4), seizures (2/6), and one instance each of cervical vertebral fusion, cataract, esophoria, and abnormal cutaneous pigmentation. One woman with a 50% a priori risk of bearing the mutant gene had mental retardation and seizures. Results of Xg blood-group typing were uninformative for the purpose of linkage analysis.


Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: studies of seventy autopsied cases. Postmortem histological examination of the thyroid gland and measurement of serum antithyroid antibodies were performed in 70 patients without overt thyroid disease. Lymphocytic infiltration, antithyroglobulin hemagglutination antibody (TGHA), and antithyroid microsomal hemagglutination antibody (MCHA) were found in 12, 2, and 9 cases, respectively. The incidence of lymphocytic infiltration in females was three times that in males. Ten of the 12 cases with lymphocytic infiltration had positive antibodies (either TGHA or MCHA), while 10 of 11 patients with positive antibodies showed lymphocytic infiltration. Thus, the correlation between morphological and serological findings was highly significant at P less than 0.001. The incidence of a small thyroid gland of less than 15 g in weight was higher in patients with lymphocytic infiltration and/or positive antibodies than in patients with a normal thyroid gland. These data suggest that positive serum antithyroid antibodies in subjects without overt thyroid disease may indicate the existence of lymphocytic infiltration in the thyroid gland, that is presumably subclinical autoimmune thyroiditis.


Effect of protein binding on transfer and metabolism of cortisol in perfused human placenta. The transfer and metabolism of cortisol and cortisone and the effect of protein binding on these processes have been investigated in vitro in the perfused human placenta. The clearance of cortisol in buffer, expressed as a fraction of the antipyrine transfer rate (clearance index), was 0.50 +/- 0.05 SEM in either direction. Extensive conversion to cortisone (85%) occurred during transfer. Addition of corticosteroid-binding globulin (CBG) in amounts sufficient to bind 50% of the cortisol reduced the clearance (0.40 +/- .026) insignificantly, whereas human serum albumin (HSA) in amounts sufficient to bind 50% of the cortisol reduced the clearance to 0.28 +/- 0.012 (P less than 0.001) even though the association constant for albumin is approximately 1000-fold less. The percent of conversion to cortisone did not change significantly with protein binding. The clearance index of cortisone from a protein-free perfusate was 0.74. With CBG and albumin in the same concentrations as used in the cortisol experiments, the binding of cortisone to CBG was 23% and its clearance was 0.70; with albumin, the binding was 45% and the clearance index was 0.45. The addition of albumin and CBG to the same perfusate resulted in a cortisol clearance equal to that obtained with perfusate containing only albumin. Binding to albumin may be more significant than binding to CBG in controlling the transfer rate of cortisol to the fetus.


Riedel's struma associated with subacute thyroiditis, hypothyroidism, and hypoparathyroidism. Riedel's struma with dense fibrous invasion of surrounding muscle and fat was found in a patient who had clinical subacute thyroiditis superimposed on primary hypothyroidism. Riedel's struma may sometimes be an uncommon stage in the more common subacute form of thyroiditis, although in our patient an unusual coincidence of subacute thyroiditis and Riedel's struma is also possible. Of interest in our patient was the development of spontaneous primary hypoparathyroidism; parathyroid function returned to normal concomitant with the spontaneous resolution of the goiter after partial resection. This patient also represents another instance of hyperthyroidism developing in a previously hypothyroid patient.


Subhourly variability of circulating third trimester maternal steroid concentrations as a source of sampling error. Seven plasma samples from five normal third trimester pregnant women, drawn every 5 and 15 min at similar times on 2 days, 2 days apart, were measured in quadruplicate for estradiol (E2), estriol, progesterone, 16 alpha-hydroxyprogesterone, and 17 alpha-hydroxyprogesterone (17P). The mean of the 22 samples obtained from each subject for each steroid was used as a reference mean. Individual determinations were converted to percentages of the reference mean which was normalized to 0%. All pregnancies were uncomplicated, and all mean values were within the normal range for gestational age. Variability about the reference mean for single samples, however, range from a low of -80% to a high of 150%. The single sample, 95% confidence intervals for individual steroids pooled from the five subjects (110 determinations) range from +/- 36% (E2) to +/- 60% (17P). Mean percentage coefficients of variation between 5-min and 15-min sampling sequences were compared by analysis of variance. There is no significant difference between the mean percentage coefficients of variation of a 5-min as opposed to a 15-min sampling sequence for any of the hormones measured. The 95% confidence interval width around the reference mean is a function of the number of samples obtained. Because the 95% confidence interval width from 110 measurements decreases approximately as 1/ square root n with increasing sampling size, the decrement progressively diminishes. For E2, the least variable steroid, a one-sample 95% confidence interval width of +/- 36% decreases to approximately +/- 18% with four samples or approximately +/- 12% with nine samples. For 17P, the most variable steroid, a one-sample 95% confidence interval width of +/- 60% decreases to approximately +/- 30% with four samples or approximately +/- 20% with nine samples. Multiple sampling with plasma pooling is required for the accurate study of steroid concentrations in individual subjects in late pregnancy.


Evidence that triiodothyronine and reverse triiodothyronine are sequentially deiodinated in man. We have demonstrated that in patients given a single iv injection of T3, rT3, or, to a lesser extent, T4, all labeled with 125I in the outer or phenolic ring, chromatography of serum on columns of Sephadex G-25 superfine revealed the presence of a labeled material, separate from the administered hormone and from both iodide and iodoprotein. This peak has been termed pre-T3 because it elutes just before the T3 peak. Identification of the various compounds in pre-T3 was carried out by cation exchange chromatography. Pre-T3 generated from [125I]T3 consistently contained labeled compounds with the chromatographic behavior of 3,3'-diiodothyronine and 3'-monoiodothyronine, while pre-T3 generated from [125I]rT3 contained labeled products with the chromatographic mobility of 3',5'-diiodothyronine, 3,3'-diiodothyronine, and 3'-monoiodothyronine. In addition, pre-T3 also contained the glucuro- and sulfoconjugates of these several labeled products. These studies demonstrate that T3 and rT3 undergo progressive and probably sequential deiodination in the peripheral tissues, resulting in the formation of a variety of diiodothyronines and monoiodothyronine, as well as their glucuro- and sulfoconjugates.


Appearance of labeled metabolites in the serum of man after the administration of labeled thyroxine, triiodothyronine (T3), and reverse triiodothyronine (rT3). Chromatography of serum on columns of Sephadex G-25 superfine after the iv administration of 125I-labeled T4 consistently yielded labeled iodide, iodoprotein, T3, and a labeled peak that eluted from the column before the T3, termed "pre-T3." Much larger quantities of pre-T3 were generated after the iv administration of 125I-labeled T3 and rT3. The ratio of [125I]pre T3:[125I]T3 and [125I]pre T3:[125I]rT3 plateaued at approximately 10 h and 2 h, respectively, after the iv administration of the labeled hormone, and averaged approximately 15% in euthyroid subjects. As pre-T3 behaves like its precursors in the TCA precipitation-ethanol extraction or anion exchange chromatographic procedures used to separate labeled iodide and iodoprotein from administered labeled T3 and rT3, concentrations of labeled hormone measured by these techniques will be in error, because pre-T3 will be included. Thus, the MCR of labeled T3 and rT3 measured by Sephadex chromatography will always be higher than values obtained by the other two separative techniques and the magnitude of change will be similar to the ratio of pre-T3 to precursor T3 or rT3. The Sephadex chromatographic technique is laborious, but appears to be the method of choice where greatest accuracy of measurement is required. As the generation of pre-T3 from labeled T4 is sufficiently slow, the present chromatographic technique is not necessary in studying peripheral T4 turnover.


Contribution of human somatomedin activity to the serum growth requirement of human skin fibroblasts and chick embryo fibroblasts in culture. Although purified human somatomedins and related peptides have been shown to stimulate growth-related processes in cultured human skin fibroblasts, it is unknown whether the serum macromolecules required for the routine growth of human fibroblasts in culture include the somatomedins. To evaluate this question we have obtained sera from five GH-deficient patients before and after GH treatment and have compared these pre- and post-GH sera for their ability to stimulate [3H]thymidine incorporation into DNA and cell multiplication in the patients' own fibroblasts in culture. Subconfluent human fibroblasts demonstrated a dose-dependent increase in thymidine incorporation and cell number when exposed to human sera. Pre- and post-GH sera were equipotent. Partial purification of somatomedin activity by boiling sera at pH 5.5 diminished the level of thymidine incorporation to 10-20% of the level achieved with unboiled sera but did not unmask a difference between pre- and post-GH sera. In contrast to the results in human fibroblasts, boiled post-GH sera were 2- to 5-fold more potent than pre-GH sera in stimulating thymidine incorporation in chick embryo fibroblasts. Mixing experiments failed to demonstrate inhibition of thymidine incorporation by boiled pre-GH sera. Boiled post-GH sera also were twice as active as boiled pre-GH sera in stimulating multiplication of chick embryo fibroblasts and confirmed that thymidine incorporation reflected DNA synthesis. GH added directly to chick embryo fibroblasts did not stimulate thymidine incorporation. We conclude that despite the presence of specific receptors for somatomedin-like peptides on human skin fibroblasts, somatomedins are not a major component of the serum macromolecules required for the routine growth of human fibroblasts in culture. In contrast, in chick embryo fibroblasts, somatomedins do appear to constitute an important part of the serum macromolecules supporting cell growth.


Plasma concentrations of prostaglandins during late human pregnancy: influence of normal and preterm labor. Highly sensitive and specific RIA procedures have been used to measure prostaglandin concentrations in the peripheral circulation of late pregnant and parturient women. The concentrations of prostaglandin E (PGE) and prostaglandin F (PGF) in plasma samples assayed within 4 weeks of collection were not significantly different among the groups studied, the levels (mean +/- SEM, picograms per ml) were: late pregnancy (n = 13): PGE, 4.8 +/- 1.0; PGF, 6.2 +/- 0.5; early term labor (n = 5): PGE, 6.8 +/- 1.5; PGF, 7.9 +/- 0.7; late term labor (n = 5): PGE, 5.4 +/- 2.2; PGF, 12.4 +/- 3.5; and preterm labor (n = 7): PGE, 4.4 +/- 0.4; PGF, 6.9 +/- 1.4. The concentration of 13,14-dihydro-15-keto-prostaglandin F (PGFM) in late pregnancy was 59.0 +/- 7.8 pg/ml. During spontaneous term labor, the concentration of PGFM was significantly elevated (P less than 0.01) to 142.8 +/- 32.3 pg/ml in early labor and 282.7 +/- 55.3 pg/ml in late labor. The concentration of PGFM in plasma from patients in preterm labor (62.7 +/- 17.4 pg/ml) was not significantly different from that found during late pregnancy, but was significantly lower than levels found at term during early labor (P less than 0.05). The concentration of PGE increased significantly in frozen plasma samples stored for more than 4 weeks in all groups studied; the concentration of PGF was significantly elevated after storage only in the late pregnancy group (P less than 0.01). The plasma concentration of PGFM in all groups studied was unaffected by storage. It is concluded that measurement of PGFM concentrations is the most reliable method available of monitoring prostaglandins in the peripheral circulation and that great care must be exercised in the assay and interpretation of prostaglandin levels in human plasma.


Longitudinal studies of plasma aldosterone, corticosterone, deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone determined simultaneously in mother and child at birth and during the early neonatal period. I. Spontaneous delivery. In order to obtain the still lacking reference data of individual plasma steroids in the immediate postnatal period needed for the assessment of adrenocortical function in various neonatal maladaptation syndromes, aldosterone (A), corticosterone, deoxycorticosterone (DOC), progesterone (P), 17-hydroxyprogesterone (17-OHP), cortisol, and cortisone were simultaneously followed in the same human newborn in a single 250-500 microliters peripheral plasma sample obtained at constant times during the first week of life using a mechanized Sephadex LH-20 multicolumn chromatography and standardized RIAs. Mean concentrations in 12 spontaneously delivered full term newborns of either sex and in paired umbilical (UV) and peripheral maternal (MV) venous plasma are given in the table. Besides significant maternoumbilical gradients in each steroid, DOC, P, 17-OHP, and cortisone, originating predominantly from the fetoplacental unit, disappear rapidly with steadily increasing half-lives. A, corticosterone, and cortisol, however, remain elevated in comparison with later infancy, with the exception of a marked "glucocorticoid dip" in cortisol and corticosterone levels between 2 and 12 h after birth.


Content of chorionic gonadotropin in human fetal tissues. As part of a study on the physiological role of hCG in the human fetus, the hCG concentrations in homogenates of various fetal tissues were measured using a hCG beta subunit RIA. The mean concentrations (picograms of hCG per mg wet tissue +/- SEM; n greater than 10, unless otherwise indicated) found in human fetuses of 12-20 weeks were: ovary, 46.9 +/- 4.3; testis, 8.2 +/- 1.7; kidney, 20.3 +/- 2.8; thymus, 11.5 +/- 1.2; adrenal, 2.6 +/- 0.4; lung, 3.4 +/- 0.7; liver, 1.8 +/- 0.2; spleen, 1.4 +/- 0.4 (n = 5); muscle, 2.4 +/- 0.8 (n = 6); and meconium, 356 +/- 104. That the immunoreactive material measured behaved like hCG was determined by RIA of the supernatants. Parallelism was demonstrated between dilution curves for the tissue homogenates and the hCG standard for all tissues except meconium. A rat Leydig cell in vitro bioassay was used to demonstrate that there was hCG biological activity in the supernatants in ovarian, thymic, and renal tissues. The mean ratios of biological to immunological activities were 5.3 in kidney (n = 4), 1.6 in thymus (n = 3), and 1.3 in ovary (n = 2). Blood content of the tissues was determined from measurements of hemoglobin levels and it was found that for the ovary, testis, kidney, and thymus, hCG concentrations were higher than could be explained by the presence of circulating hCG in the tissues. These results, together with our previous results of the binding and effects of hCG in the human fetal testis, support the fact that the fetal testis is a target organ for hCG in the stimulation of steroidogenesis. The presence of high levels of hCG in the ovary, thymus, kidney, and meconium poses questions for further study of the possible physiological role of hCG.


Split xenon detector for tomochemistry in computed tomography. The design of a split high-pressure xenon detector array for tomochemistry in computed tomography (CT) is described. Each detector produces a signal from the front primarily due to low energy photons and a signal from the back primarily due to high energy photons. Two methods are described whereby these signals are used to determine the photoelectric and Compton coefficients. From these, the electron density and average atomic number can be determined for each pixel in the image. These methods were tested by computer simulations of scans of a simple phantom, and the resulting Compton and photoelectric images are presented and compared with a conventional CT image. It was found that electron density and atomic number can be determined to an accuracy of better than 4%. The sensitivity to noise was studied, and it was found that the standard deviation of the mean of a 5 X 5 pixel region in the conventional image is about a factor of 3 lower than in the same region in the Compton image and about a factor of 40 lower than in the photoelectric image.


Computed tomography scanning for the measurement of bone mineral in the human spine. An investigation into the feasibility of using X-ray computed tomography (CT) to measure disease induced changes in bone mineral content of the human spine is described. A theoretical study of this type of measurement has been made using a mathematical model of osteomalacia. The measured EMI number changes linearly with the mineral content, and the sensitivity is shown to be 1.2 EMI units (EU: 500 scale)/1% change in mineral content in vertebral bone. The physical sensitivity to an equal mineral change in cortical bone is found to be 8.6 times greater. The mineral selectivity of the CT method is such that only about half the change in the EMI number arising from progressive osteomalacia reflects change in actual mineral content, while half is due merely to changes in bone density that accompany demineralization. In addition, the perturbing effects of beam hardening on measurement accuracy are evaluated and shown to be significant. Finally, an experimental measurement indicates that in practice the reproducibility of such measurements would be about 1 EU, and it is shown that the measured parameter correlates well with the calculated total linear attenuation coefficients.


Measurement of lung density by computed tomography. Computed tomography scanners can be calibrated to provide reproducible measurements for a quantitative analysis of lung density. Typical histograms for inspiration and expiration are presented. The reproducibility of the method is demonstrated as well as the limitations caused by artifacts and incomplete inspiration. This method is suggested for follow-up studies of patients with diseases affecting the entire lung. Early detection of interstitial lung disorders also seems possible.


Detection of subcutaneous metastases by computed tomography. Subcutaneous fat provides excellent contrast for water density tissue. Five patients with subcutaneous metastases visualized on computed tomography (CT) scans are presented. In some cases, CT proved to be the optimal diagnostic modality for visualizing these lesions and documenting their response to therapy.


Computed cranial tomographic findings in cerebral sinovenous occlusion. Eleven patients with angiographically and/or pathologically verified cerebral sinovenous occlusions not directly caused by trauma were studied by computed cranial tomography (CCT). Static radionuclide brain scans and dynamic radionuclide flow studies were also obtained in four patients; in two, findings diagnostic of lateral sinus thrombosis were noted. These comprised a "negative on dynamic, hot on static" image, as well as a "hot on static with nonfilling on angiography." Computed cranial tomography findings included visualization of the thrombosed vein ("cord sign") or sinus ("empty triangle" or "delta sign"), multiple focal bilateral parasagittal hemorrhages, intense tentorial enhancement, gyral enhancement indistinguishable from infarct, solitary intracerebral hematoma, small ventricles, and normal scan. Excluding the patients with underlying meningioma, all three of whom survived, seven of the remaining eight patients expired during the acute phase of their illness, an 88% mortality. This group includes one patient who had normal CCT findings, albeit without contrast enhancement, who was diagnosed as pseudotumor cerebri. The need for full neuroradiological evaluation, including angiography, is thus stressed if this highly fatal yet treatable condition is not to remain undiagnosed.


Malformation of the cerebral cortex with heterotopia of the gray matter. Developmental malformation of the cerebral cortex with heterotopia of the gray matter is a rare condition. It can present as unilateral megalencephaly, a localized mass, or focal cortical dysplasia. Four histologically confirmed cases are described in this report, and the findings from computed tomography as well as from other radiological diagnostic procedures are discussed.


The value of computed tomography in the diagnosis of intracranial lipomata. Intracranial lipomata can be found in both symptomatic and asymptomatic patients. The tumors, which are rare, can be diagnosed by computed tomography without further investigative procedures.


Quantitative estimation of tumor volume on computer assisted tomography. With the use of computer assisted tomography (CAT), the volume of intracranial hemorrhages can be calculated. The present work outlines a method that, based on EMI scan printouts, makes possible a calculation of the volume of hemorrhages, tumors, or other pathological changes detectable on CAT with a high degree of accuracy, even when the pathological changes are irregular in shape. Thus, there have been divergences between the estimations of volume of meningiomas using this method and the measure of the volume of the enucleated meningiomas within the range of 0 to +5%. An example of such a meningioma, and the calculation of its volume, is presented.


Giant intracranial aneurysms simulating brain neoplasms on computed tomography. Giant intracranial aneurysms (GIA) may simulate brain neoplasms on computed tomography (CT) scans. We present three cases in which a GIA was mistakenly diagnosed as a brain neoplasm on the basis of CT findings. The correct diagnosis was made in each case by cerebral angiography. The possibility of GIA must be considered when a nonenhanced CT study shows a well circumscribed mass without edema at the base of the brain and contrast infusion reveals homogeneous or inhomogeneous enhancement.


The use of coronal sections in evaluating lesions of the sellar and parasellar regions. Nine cases from a series of 12 are presented to illustrate the value of coronal sections in delineating the borders and origins of extraaxial sellar and parasellar masses. In this projection, the presence or absence of suprasellar extension is demonstrated, and two important signs are discussed. A rim of cisternal cerebrospinal fluid termed the "cap" is seen over the superior border of masses extending into the suprasellar region defining their extraaxial location. The broad base of a lesion will define its origin. The limitations of the method are also discussed.


Contrast enhancement: diagnostic significance from a statistical viewpoint. Contrast enhancement attenuation units were calculated from 13 tissues and organs of 20 rats at five different times after bolus 125I-diatrizoate administration. Percent distribution volume of diatrizoate was calculated from these results. The statistical significance of differences in contrast enhancement between each of 72 tissue pairs was determined at each of the five times. A similar treatment of percent distribution volume for 60 tissue pairs was determined. The time elapsed after contrast medium injection appears to be of pivotal importance in contrast enhancement diagnosis. Calculation of percent contrast distribution volume is of potential diagnostic importance, since it reveals contrast medium behavior not evident from a visual perusal of scans. The above methods can be readily adapted to computed tomography scanning.


Comparative efficacy of contrast agents in computed tomography scanning of the brain. Various contrast agents with either sodium or meglumine cations and iothalamate and diatrizoate anions are compared in a series of patients with malignant gliomas. There is no difference in the ability of these agents to enhance tumors in cranial computed tomography.


Peripheral contrast enhancement in chronic epidural hematomas. Three cases of chronic epidural hematomas with contrast enhanced margins on computed tomography (CT) are presented. The CT findings in epidural hematoma are discussed, and two possible mechanisms for the enhancing margin of the chronic epidural hematoma are suggested.


Image quality in cranial computed tomography. Image quality in cranial computed tomography (CT) was evaluated with phantom and patient studies on both a first (single beam) and a second (multiple beam) generation scanner. When comparable radiation doses were used, there were only minor differences in resolution, low contrast detectability, and noise level. The pattern of noise relative to the size of the area in which it was measured was somewhat different. On patient studies, no differences were found when contrast-material-filled vessel visibility and gray--white matter distinction were analyzed. A lesion was obscured by streak artifacts in one scanner in one of 22 patients scanned on both machines. The major factor in image quality as seen in the two scanners seemed to be in the production of artifacts. This was apparent in artifacts from motion, high contrast discontinuities, beam hardening, and edge enhancement. Multiple factors must be considered in assessing CT image quality. In particular, further studies to quantitatively evaluate noise quality and artifact production are needed.


Transsphenoidal encephalocele associated with agenesis of corpus callosum: value of metrizamide computed cisternography. Transsphenoidal encephaloceles are rare congenital malformations that are classified among the medial dysraphias and that are therefore associated with an agenesis of the corpus callosum. Clinically, the diagnosis is difficult, but hypertelorism and weakening eyesight should be of suggestive value. Diagnosis is basically radiological. In the past, it was founded on roentgenography, tomography of the base of the skull, pneumoencephalography, and angiography when necessary. Today, metrizamide computed cisternography using axial transverse and coronal sections, supplemented by sagittal reconstructions, allows for a complete examination of bony, meningeal, and cerebral abnormalities.


A device to indicate anatomical level in computed tomography. A device was designed that makes possible direct anatomical correlation between the computed tomography scan and radiographic scout films. The acrylic-air groove approach used here eliminates the possibility of producing image degrading artifacts as is common with catheter type markers.


An inexpensive color display for computed tomography scanners and other imaging systems. The use of color pictures and displays for interpreting images obtained from computed tomography scanners, scintillation cameras, and ultrasound equipment is an interesting possibility. As currently supplied, color television monitors may add significantly to the cost of a system. A relatively simple way of converting an entertainment grade color television receiver to color monitor operation is described. The display system is significantly lower in cost than vendor supplied monitors and produces images of similar quality.


Anomalies of the systemic venous return. Anomalies in the course and drainage of systemic veins, in particular the inferior vena cava, markedly complicate or even prevent cardiac catheterization and some surgical procedures. Such anomalies have been observed in 32 out of 1,266 children subjected to catheterization and angiocardiography, i.e. 2.5 per cent. Severe anomalies of a superior vena cava were observed in six children, one of them having an associated anomaly of an inferior vena cava. Anomalies of the inferior vena cava were observed in 27 children. The latter included persistent paired development of the inferior vena cava, aplasia of suprarenal portion with azygos or hemiazygos continuation, its persistence at the side of the cardiac apex and combination of these findings. In 19 of the children with an anomaly of the inferior vena cava there was a visceral situs indeterminatus associated, often with severe congenital heart disease and with a large intracardiac shunt (e.g. transposition of the great arteries and stenosis or atresia of the pulmonary artery). Suspicious of such combinations of visceral situs indeterminatus with anomalies of the inferior vena cava and severe congenital heart disease can be suspected on plain chest films, but the diagnosis can be definitely determined only by angiocardiography.


The relationship between chest radiographic scores and respiratory function tests in children with cystic fibrosis. Chest radiographic scores and respiratory function on 80 sets of results from 50 patients with Cystic Fibrosis were analyzed. Chest radiographic scores were assessed independently using the method of Chrispin and Norman. Respiratory function tests were found to correlate well with the chest radiographic score, the best correlation being with the forced expiratory volume in 0.75 sec. to forced vital capacity ratio F.E.V. 0.75/ F.V.C. (r = -0.674 n = 80 p less than 0.001).


Cervical neurogenic tumors presenting as thoracic apical masses in infants and children. Seven cases of cervical neurogenic tumor presented in an almost identical manner roentgenographically; a polypoid extrapleural mass at the lung apex. The association of neuroblastoma with Horner syndrome and heterochromia of the irides is mentioned. Characteristic roentgen appearance should be appreciated due to good prognosis of cervical neuroblastoma with prompt therapy.


The telltale triangle: use of the supine cross table lateral radiograph of the abdomen in early detection of pneumoperitoneum. The most sensitive method for detecting a small pneumoperitoneum depends upon directing a horizontal x-ray beam tangential to the collection of free air. We have observed in the detection of small amounts of free intraabdominal air that the supine cross table lateral abdominal view is most valuable. Such small amounts of free intraperitoneal air collect between loops of bowel at the highest points in the peritoneal space forming typical small triangular lucencies with their bases at the peritoneal reflection.


The incidence of pelvic phleboliths in pediatric patients. During a seven year period in a pediatric x-ray department 15 patients with pelvic phleboliths were encountered in a total of an estimated 12,000 pelvic roentgenograms, an incidence of 1 case per 800. The age range was from 9 to 17 years (average age 13 years), there were 10 girls and 5 boys, and 6 patients had more than 1 phlebolith.