Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases.

Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, beta-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted beta-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrP(Sc) deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas.

Expression of AMPA receptor subunits (GluR1-GluR4) in gonadotrophin-releasing hormone neurones of young and middle-aged persistently oestrous rats during the steroid-induced luteinising hormone surge.

Glutamate provides excitatory input to gonadotrophin-releasing hormone (GnRH) neurones and elicits a response indicative of AMPA receptors. To determine if and which AMPA subunits are expressed by GnRH neurones, we conducted triple-label immunohistochemistry and confocal analyses on tissue obtained at 08.00, 12.00, 16.00 and 20.00 h from young and middle-aged, persistently oestrous (MA-PE) rats that were ovariectomised and primed with oestrogen and progesterone to induce a luteinising hormone (LH) surge. Each AMPA subunit was found in GnRH neurones, but in different patterns across the diurnal cycle, which were influenced by age. GluR1 expression increased earlier in young rats and the percentage of Fos-positive GnRH neurones expressing GluR1 rose significantly and was sustained from 12.00-16.00 h. GluR1 expression was delayed in MA-PE rats and the percentage of Fos-positive GnRH neurones expressing GluR1 peaked at 20.00 h. GluR2 expression in GnRH neurones did not change over time and was not affected by age; however, the percentage of Fos-positive GnRH neurones expressing GluR2 increased earlier and was sustained from 08.00-16.00 h in young rats whereas, in MA-PE rats, this percentage peaked at 20.00 h. GluR3 expression also increased earlier in young rats and peaked at 12.00 h but was delayed in MA-PE rats and peaked at 20.00 h. The number of Fos-positive GnRH neurones that coexpressed GluR3 peaked at 12.00 h in young rats but showed little change from 12.00-20.00 h in MA-PE rats. GluR4 expression was maintained at higher levels at 08.00 and 12.00 h in young rats; although the percentage of Fos-positive GnRH neurones expressing GluR4 peaked at 12.00 h in young rats, it showed little change in MA-PE rats. In summary, our data show that a higher proportion of Fos-positive GnRH neurones coexpressed AMPA receptor subunits in young rats and the expression, particularly of GluR1 and GluR2, was increased and sustained throughout the surge, whereas GluR3 and GluR4 expression peaked just before. In MA-PE rats, the rate of expression of GluR subunits and Fos in GnRH neurones was altered in a manner that may explain the delay and attenuation of the LH surge.

Effects of sequential or group exposure to unrestrained estrual females on expression of sexual behavior in sexually experienced beef bulls.

We tested the hypothesis that expression of sexual behavior in bulls is affected by the manner in which they are exposed to unrestrained, sexually receptive females. Twelve Angus bulls were used in a crossover design involving two treatments, each tested four times for a total of eight tests for each bull. Sexual interactions were quantified for each of four, 30-min periods under the following treatments: 1) exposure to each of four estrual females in sequence (SEQ); or 2) exposure to four estrual females as a group (GRP). Bulls were blocked into three testing groups, the order of which was stratified across eight test days. The order in which bulls were tested on a particular day had no effect on bulls' expression of mount interactions, or flehmen responses, suggesting that each group of bulls had similar sexual motivation at the beginning of each test. However, the bull testing order x treatment x time interaction influenced mounting interval (P = 0.08), copulation frequency (P <0.05), and copulation success ratio (P <0.05). When bulls were in GRP and tested first on test days, more (P <0.05) copulations were distributed to the first three females encountered compared with either the fourth female (P <0.05) or to each of the other females in SEQ (P <0.05). During later tests, other bulls in GRP were not able to copulate as frequently (P <0.05) with each female, displayed lower (P <0.05) copulation success ratios, and were allowed copulations by fewer (P <0.05) females during each 30-min test. When bulls were in SEQ, they displayed similar numbers of copulations regardless of the order in which they were tested, and had stable mounting intervals; however, copulation success ratio decreased (P <0.05) more rapidly during subsequent tests. Flehmen responses were initially displayed more frequently (P <0.05) when bulls were in GRP, but this effect diminished during subsequent 30-min tests. In conclusion, exposure of bulls to GRP induced greater sexual responsiveness than SEQ; however, this effect was due to enhanced sexual activity during the early stages of sexual encounters and with females that were not recently mated. Interestingly, bulls seem to repeatedly copulate with each individual female until, apparently, female sexual receptivity became attenuated. Thereafter, recently mated females allowed fewer episodes of repeated copulations, but they did not completely cease copulating with novel bulls.

Effects of novel females and stage of the estrous cycle on sexual behavior in mature beef bulls.

The objective of this experiment was to determine the effects of unrestrained females on sexual behavior of bulls. Twelve Angus bulls were used in three Latin square replicates where sexual interactions between one bull and one female were quantified for each of four 60-min tests (T1, T2, T3, and T4, respectively). All bulls received the following treatments: 1) exposure to four estrual females in sequence (A-B-C-D); 2) exposure to two estrual females in alternating sequence (E-F-E-F); 3) exposure repeatedly to one estrual female (G-G-G-G); and 4) exposure repeatedly to one diestrous female (CON). During T1, mount interactions, mounts with intromission and mounting intervals were similar when bulls were in A-B-C-D, E-F-E-F, or G-G-G-G. Fewer mount interactions, no mounts with intromission, and increased mounting intervals (P < 0.05) occurred in CON. During T2, there were more mount interactions, more mounts with intromission, and decreased mounting intervals (P < 0.05) when bulls were in A-B-C-D or E-F-E-F compared with when they were in G-G-G-G or CON. More mount interactions (P < 0.05) occurred in G-G-G-G compared with CON, but mounts with intromission and mounting intervals did not differ. During T3, more mount interactions (P < 0.05) occurred in G-G-G-G than in CON; otherwise, sexual behaviors were similar among treatments. Mounting intervals during T3 were similar among A-B-C-D, E-F-E-F, and G-G-G-G, but were all decreased (P < 0.05) compared with CON. During T4, more mount interactions, more mounts with intromission, and decreased mounting intervals (P < 0.05) occurred when bulls were in A-B-C-D compared with other treatments. Mount interactions were similar when bulls were in E-F-E-F, G-G-G-G, or CON; however, more (P < 0.05) mounts with intromission occurred when bulls were in E-F-E-F compared with G-G-G-G or CON. Mounting intervals during T4 were decreased (P < 0.05) in E-F-E-F compared with the CON treatment, whereas in G-G-G-G, they were intermediate. Mounts without intromission were not affected by female novelty or receptivity, but novel females induced more flehmen responses. In conclusion, novel, females, overall, enhanced sexual activity of bulls; however, bull sexual responses diminished after 2 h, even when a novel female was presented. Estrual females that were repeatedly paired with bulls displayed diminished sexual receptivity, but if mated females were rested for 60 min, they allowed further copulation from familiar bulls that were not sexually sated.

Effects of supplementing combinations of inorganic and complexed copper on performance and liver mineral status of beef heifers consuming antagonists.

Performance, immune response, and liver trace mineral status were measured in growing heifers supplemented with different copper (Cu) concentrations and sources when diets contained the Cu antagonists Mo, S, and Fe. Sixty Angus x Hereford heifers were managed in two groups for 112 d and were either individually fed diets and mineral treatments using individual feeding stalls (Stall) or pen-fed grass hay and individually supplemented mineral treatments (Pen). The basal diet of grass hay, rolled barley, and soybean meal was analyzed to contain 6 mg Cu/kg DM. The treatments consisted of 1) no supplemental Cu (Control); 2) 49 mg Cu/kg DM from Cu sulfate (i.e. approximately five times NRC recommendation for Cu from CuSO4) (5X-SO4); 3). 22 mg Cu/kg DM from CuSO4 (2X-SO4); 4). 22 mg Cu/kg DM from a combination of 50% CuSO4 and 50% Cu-amino acid complex (50-50); and 5). 22 mg Cu/kg DM from a combination of 25% CuSO4, 50% Cu-amino acid complex, and 25% Cu oxide (CuG) (25-50-25). All heifers were supplemented with the Cu antagonists Mo (10 mg/kg DM), S (2,900 mg/kg DM), and Fe (500 mg/kg DM). These diets resulted in dietary Cu:Mo ratios that averaged 0.5:1 for Control, 4.5:1 for the 5X-SO4, and 2.4:1 for 2X-SO4, 50-50, and 25-50-25. Rate and efficiencies of gain and cell-mediated immune function were not different (P > 0.10) among treatments. Data suggest supplements containing combinations of inorganic and complexed Cu interacted differently in the presence of Mo, S, and Fe. Heifers consuming the 25-50-25 supplement in the Stall group initially lost hepatic Cu rapidly but this loss slowed from d 50 to d 100 compared to the Control (P = 0.07), 50-50 (P < 0.05), and 2X-SO4 (P < 0.05) heifers and was similar (P > 0.10) to that in the 5X-SO4 heifers. In the Pen group, total hepatic Cu loss tended to be greater for 25-50-25 and 2X-SO4 compared to 5X-SO4 heifers (P = 0.09 and P = 0.06, respectively); Cu loss in the 50-50 heifers was similar (P > 0.10) to that in the 5X-SO4 heifers. This suggests that supplementing combinations of inorganic and amino acid-complexed Cu was as effective in limiting hepatic Cu loss during antagonism as was increasing dietary Cu levels to five times the NRC recommendation. A combination of 25% CuSO4 , 50% Cu-amino acid complex, and 25% CuO limited liver accumulation of Mo compared to supplements without CuO and could provide a strategic supplementation tool in limiting the systemic effects of Cu antagonism in beef cattle.

Growth hormone deficiency in autoimmune polyglandular disease type 1.

This is a case report of 2 patients who were diagnosed to have autoimmune polyglandular disease type 1. Both developed mucocutaneous candidiasis, hypoparathyroidism, vitiligo, and adrenocortical insufficiency. Both were noticed to have subnormal linear growth velocity and delayed bone age. Both showed subnormal stimulated serum growth hormone values indicating growth hormone deficiency. The first case showed favorable response to growth hormone therapy.

Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism.

The observation of severe behavioral reactions or learning problems in three teenagers treated with L-thyroxine for juvenile acquired hypothyroidism prompted us to conduct a prospective study of achievement and behavioral characteristics of patients with newly diagnosed juvenile acquired hypothyroidism. On diagnosis of juvenile acquired hypothyroidism and before treatment with L-thyroxine, 23 children and adolescents underwent a comprehensive battery of psychoeducational tests, which was repeated after 3, 12, and 24 months of replacement therapy. Results revealed that adverse behavioral reactions and learning problems were relatively rare in these children, although symptoms of juvenile acquired hypothyroidism were associated with increased distractibility, hyperactivity, and poorer achievement. The least gain in achievement was made by children with more severe hypothyroidism at diagnosis; children with the best psychologic outcome were those who achieved euthyroidism more slowly. We conclude that severe behavioral manifestations of L-thyroxine therapy for juvenile acquired hypothyroidism are uncommon, but mild behavioral symptoms and poorer school achievement may occur in about 25% of patients, who represent the most severe cases at diagnosis.

Brain tumors in children and adolescents--III. Effects of radiation and hormone status on intelligence and on working, associative and serial-order memory.

The effects on intelligence and memory of two post-surgical conditions (radiation treatment, hormone deficiency and supplementation) were explored in 46 children and adolescents with tumors in a variety of brain sites. Verbal intelligence, but not non-verbal intelligence, varied positively with age at radiation treatment. Memory for word meanings was unrelated to either radiation history or to hormone status. Severe deficits in serial position memory occurred with impaired hormone function and an older age at tumor onset. Severe deficits in working memory were associated with a history of radiation and a principal tumor site that involved thalamic/epithalamic brain regions. Radiation treatment and hormone status affect later cognitive function in children and adolescents with brain tumors. Although the greater vulnerability of the verbal intelligence of the younger radiated child and the serial order memory of the child with later tumor onset and hormone disturbances remain to be explained, and although the form of the relationship between radiation and tumor site is not fully understood, the data highlight the need to consider the cognitive consequences of pediatric brain tumors according to a set of markers that include maturational rate, hormone status, radiation history, and principal site of the tumor.

Growth failure and bony changes induced by deferoxamine.

We reviewed the linear growth and growth plate morphology in all children with homozygous beta thalassemia followed in Toronto, for whom monthly height percentiles were available before, and for a 36-month period after, the initiation of nightly subcutaneous deferoxamine therapy. All patients were less than 7 years of age when begun on deferoxamine, and had received nightly deferoxamine for a minimum of 36 months. Marked abnormalities of the metaphyseal growth plate were readily observed in the distal ulnar, radial, and tibial metaphyses in 11 of 37 patients in whom a significant decline in mean height percentile was also noted. (In 10 of these 11 patients, height was less than the 15th percentile after 36 months.) These 11 patients had received a significantly greater (p less than 0.025) initial and average daily dose of deferoxamine, and had maintained a significantly lower (p less than 0.025) mean serum ferritin concentration over the 36 months, than the remainder of the cohort. To determine whether deferoxamine played a causative role in growth failure, growth in patients who began deferoxamine before the age 2 years was compared to that of patients who began after age 5 years, for the period between 2 and 5 years of age. Only patients begun on deferoxamine prior to age 2 years demonstrated a significant (p less than 0.01) decline in height percentile by the third year, implicating deferoxamine therapy as the cause of growth failure. We conclude that both the decline in height percentile and the bony changes observed in well-chelated patients are directly related to deferoxamine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth in children with congenital hypothyroidism detected by neonatal screening.

A prospective analysis of physical growth in 56 children with congenital hypothyroidism compared the children's height, weight, and head circumference with population percentiles. Two measures of skeletal maturation and predictions of adult height were also compared with population standards. The mean percentiles for the children's height and head circumference were higher than population means. Although mean bone age scores were slightly higher, predictions of adult height did not differ significantly from midparental height (arithmetic mean of sum of parental heights) and population means. The duration of intrauterine hypothyroidism as measured by gestational bone age and the duration of postnatal hypothyroidism were inversely correlated with heights attained up to 9 years. This association suggests a possible long-term influence of early hypothyroidism on growth. In children with congenital hypothyroidism, maintenance of serum thyroxine levels in the upper half of the normal range results in normal growth patterns.

Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy.

Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.

External genital abnormalities associated with Wilms tumor.

The records of 170 patients with unilateral and 18 patients with bilateral Wilms tumor and 6 patients with congenital mesoblastic nephroma were reviewed for abnormalities of the external genitalia. There were 4 patients with cryptorchism, 1 with hypospadias, 1 with mixed gonadal dysgenesis, and 3 with male pseudohermaphroditism. Of the group, these 9 patients had earlier symptoms; 6 of them were under two years old. Five patients (27.7%) with bilateral Wilms tumors had external genital anomalies in contrast to only 4 (2.3%) of those with unilateral tumors. One of the 9 children with genital anomalies had unilateral congenital mesoblastic nephroma; the others had Wilms tumor. In all cases the histologic subtypes were unusual. These observations substantiate the previously reported association between external genital abnormalities and Wilms tumor and also represent a somewhat higher than expected incidence. The children with this association are remarkable for the high frequency of a particular histologic type of tumor and for the high incidence of bilaterality. The high incidence of Wilms tumors in the male pseudohermaphrodite population presented suggests that such patients should be monitored for development of renal tumors.

Familial persistent müllerian duct syndrome.

We found persistent müllerian duct structures in 2 phenotypically normal brothers who had undergone an operation for inguinal hernia. The older boy had transverse testicular ectopia and his younger brother had unilateral cryptorchidism. Bilateral orchiopexy was done with excision of the fallopian tubes, uterus and upper vagina. Histological examination showed normal testes in both patients. Since there is a risk of testicular malignancy in such patients, long-term followup is mandatory.

Selective hypoaldosteronism in infancy. Report of a case.

A 10-week-old female infant had anorexia, failure to thrive, and dehydration. Hyponatremia and hyperkalemia were found, along with urinary salt loss and increased plasma renin activity. Plasma deoxycorticosterone, corticosterone, and urinary 18-hydroxycorticosterone levels were increased. The plasma aldosterone levels were inappropriately reduced given the degree of sodium depletion present, while urinary aldosterone concentrations were persistently low. These are characteristic findings of an enzymatic defect in the synthesis of aldosterone involving 18-dehydrogenase, also known as methyl oxidase defect type 2. The infant responded to therapy with fludrocortisone acetate, including catch-up growth in both length and weight. The disease is transmitted by an autosomal recessive gene.

Regulation of the androgen receptor by androgen in normal and androgen-resistant genital skin fibroblasts.

Normal genital skin fibroblast (GSF) monolayers incubated with serum-free medium containing 3 nM [3H]-5 alpha-dihydrotestosterone (DHT) at 37 degrees C for 20 h have about 35% more specific DHT-binding than replicates incubated in serum-free medium with [3H]-DHT for only 1 h to saturate basal specific androgen-receptor activity. If, after 19 h, spent medium is replaced by fresh medium with 3 nM [3H]-DHT for 1 h, specific DHT binding is 85% more than basal. The acquisition of increased binding is temperature dependent (37 greater than 27 degrees C) and cycloheximide (2 microM) suppressible. The increased binding activity is considered to represent an augmentation of androgen receptor concentration because it has the same equilibrium dissociation constant (KD approximately 0.5 nM), rate constant of dissociation (k-1 approximately 6 x 10(-3) min-1) and ligand specificity as basal androgen-receptor activity, and because basal DHT-binding activity is stable in cells preincubated in androgen-free or serum-free medium alone for up to 72 h before assay. Prolonged incubation with methyltrienolone (R1881), a nonmetabolizable synthetic androgen, causes a greater, more persistent increment of androgen receptor activity than does equimolar DHT. The fibroblasts from two subjects with receptor-positive, partial androgen resistance lose their basal receptor activity during prolonged incubation with DHT, but augment it normally with R1881. This suggests that defective DHT metabolism is somehow involved in the pathogenesis of their androgen resistance.