African Americans and Caucasian Americans: differences in glucocorticoid-induced insulin resistance.

African Americans are more insulin resistant than Caucasian Americans and this discrepancy cannot be explained by measures of body weight or body composition. The aim of the study was to compare the sensitivity of African Americans and Caucasian Americans to glucocorticoids by measuring glucose and insulin responses to a meal challenge under conditions of placebo and glucocorticoid. A total of 160 healthy or overweight/obese African American and Caucasian American participants completed exercise testing and a liquid meal challenge during separate laboratory visits. Participants were evaluated following treatments with placebo and dexamethasone (4 mg). Main outcome measures were correlation between body composition measures (body mass index, percent body fat, waist circumference) and insulin responses; insulin and glucose responses after a liquid meal challenge; and calculated HOMA. After dexamethasone treatment African Americans were significantly more hyperinsulinemic after a meal as indicated by higher peak insulin (p=0.02) and postprandial insulin areas under the curve (p=0.006) than Caucasians. Additionally, African Americans were more insulin resistant than Caucasian Americans under both placebo and dexamethasone as determined by fasting insulin and HOMA (p=0.05). Waist circumference correlated with post-dexamethasone insulin AUC and HOMA in Caucasian Americans (p<0.05), but none of the body composition measures were predictive of IR for African Americans. African Americans are more sensitive to glucocorticoids (dexamethasone) than Caucasian Americans, as indicated by significantly greater peak insulin and postprandial insulin areas under the curve. The glucocorticoid receptor and its potential interactions with stress may contribute to this ethnic disparity.

Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation.

Administration of dehydroepiandrosterone (DHEA) appears to have physiological effects opposing those of glucocorticoids in several animal models. Recently, immunomodulatory effects of treatment with DHEA have been described. This paper reports the effects of DHEA treatment on splenocyte blastogenic responses as well as thymic and spleen weights in C3H/HeN mice. Pretreatment of mice with sc DHEA (60 mg/kg.day) for 3 days in vivo antagonized the profound suppression of in vitro blastogenic responses seen in T- and B-lymphocytes after a single injection of dexamethasone (DEX; 60 mg/kg). Pretreatment with DHEA also significantly reduced dexamethasone-induced thymic and splenic atrophy. Splenic lymphocytes from DHEA-treated mice were markedly more resistant to in in vitro suppression of blastogenesis by DEX at 10(-6)-10(-8) M compared to lymphocytes from control mice. However, DHEA added to lymphocyte cultures in vitro over a concentration range from 10(-7)-10(-8) M failed to protect against suppression of mitogenic responses caused by addition of DEX to cultures. In summary, DHEA given in vivo antagonizes the suppressive actions of DEX on lymphoid target tissues in mice.

Melatonin metabolite excretion during childhood and puberty.

Daily urinary excretion of conjugated 6-hydroxymelatonin, the major metabolite of the pineal hormone melatonin, has been determined in 54 boys and 47 girls (aged 3-16 yr) and 20 normal adults to determine whether a change in melatonin production is seen during the maturation of reproductive function in humans. There was no correlation between daily excretion rates and age in children, and the excretion rates were similar to those in adults. In addition, children of all ages had normal circadian patterns of 6-hydroxymelatonin excretion from the earliest age tested. A significant increase in 6-hydroxymelatonin excretion was observed at the time of the onset of breast development (Tanner stage II) in girls. No similar difference was seen during puberty in males. The significance of this difference in Tanner II girls is not known.

Endocrine response to high-intensity exercise: dose-dependent effects of dexamethasone.

We recently reported that in 30-50% of healthy men and women the release of ACTH and cortisol stimulated by exercise is not suppressed by prior administration of a 4-mg dose of dexamethasone (DEX). We now explore other potential differences between these subjects and those whose exercise response was suppressed by examining the effect of a smaller, 1-mg, dose of DEX on exercise-stimulated ACTH and cortisol. Men (n = 15) and women (n = 9) were studied during three high intensity exercise tests: one after taking placebo, one after taking 1 mg DEX, and one after taking 4 mg DEX. Before participation, subjects underwent a test for classification as either a high (HR; n = 10) or low (LR; n = 14) reactor and a maximal exercise test to assess maximal aerobic capacity. Distinct dose-related reductions in plasma concentrations of ACTH, cortisol, and dehydroepiandrosterone (DHEA) were noted for HR under the treatment conditions, whereas both doses of DEX blocked ACTH, cortisol, and DHEA release in LR. Furthermore, basal plasma cortisol, DHEA, and DHEA sulfate were significantly higher in HR compared to LR. Thus, there are inherent basal and stress-reactive differences in HR and LR, and these differences may be useful in constructing a model for the mechanisms and physiological regulation of hypothalamic-pituitary-adrenal axis activation. The question of whether these differences in reactivity of the ACTH-cortisol axis between the HR and LR groups have implications for individual short term function or long term health remains to be answered.

True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog.

Congenital adrenal hyperplasia (CAH) is a recognized cause of precocious pseudopuberty. Some children with CAH also develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen four such children (three boys and one girl) who had the diagnosis of CAH made between the ages of 3 and 6 yr. These patients were treated with standard doses of hydrocortisone and fludrocortisone. A diagnosis of true precocious puberty was made because of testicular enlargement in the boys, breast development in the girl, progressive pubic hair development, rapid growth, and rapid bone age maturation. Plasma steroid levels were elevated for age, and gonadotropin levels were within the normal pubertal range, both basally and in response to LHRH stimulation. We treated these children with daily sc injections of a LHRH analog (LHRHa) for 6-18 months in addition to the standard hydrocortisone and fludrocortisone therapy for CAH. LHRHa significantly decreased basal plasma LH and FSH, peak LH and FSH responses to native LHRH, and testosterone levels. Testis size decreased in the males, and breast development regressed in the female. LHRHa therapy led to significant decreases in linear growth rate, ulnar growth rate, and rate of bone age advancement. These results suggest that LHRHa is an effective adjunct to hydrocortisone and fludrocortisone in the treatment of true precocious puberty complicating CAH.

Partial anomalous pulmonary venous drainage associated with 45,X Turner's syndrome.

Turner's syndrome has well-described associations with congenital heart disease. Up to one third of patients with karyotype 45,X may have coarctation of the aorta. In addition, patients with hypertrophic cardiomyopathy, septal defects, dextrocardia, and anomalous pulmonary venous drainage have been reported anecdotally. Twenty-one consecutive patients with Turner's syndrome were prospectively evaluated. All patients underwent examination by a pediatric cardiologist, electrocardiogram, chest radiograph, and echocardiogram. Three patients with evidence of right ventricular volume overload had cardiac catheterization. Of 12 patients with karyotype 45,X 3 had partial anomalous pulmonary venous drainage with intact atrial septum. One of the 3 also had moderate aortic stenosis. Two additional patients with 45,X had coarctation of the aorta and bicuspid aortic valve, and 4 other patients had minor cardiac defects. Of 9 patients with mosaic karyotype, 1 had a minor cardiac defect. The observations suggest that there may be a significant association of 45,X Turner's syndrome and partial anomalous pulmonary venous drainage.

Evidence to suggest nitric oxide is an interstitial regulator of Leydig cell steroidogenesis.

Recent studies have suggested that nitric oxide (NO) may function as both an intracellular and intercellular signal that affects neural and immunological activity, vascular tone, platelet adhesion, and production of some hormones. Arginine analogs such as NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine methyl ester (L-NAME) act to inhibit the intracellular formation of NO and have been used to study the effects of decreased NO formation on physiological systems. A single in vivo study has suggested that a similar analog, NG-nitro-L-arginine, increases serum testosterone (T), but the organ site and mechanism of action were not investigated. The present study was performed to investigate the effects of NO synthase inhibitors on Leydig cell function. L-NMMA and L-NAME, but not the inactive enantiomer (D-NMMA), increased both basal and human chorionic gonadotropin (hCG)-stimulated T production while decreasing guanosine 3':5'-cyclic monophosphate (cGMP). There was no effect on either adenosine 3':5'-cyclic monophosphate (cAMP) accumulation or specific hCG binding. These results suggest that NO formation, which is inhibited by L-NMMA and L-NAME, is important in the regulation of Leydig cell T production by interstitial cells of the testis, and that changes in cGMP levels might be involved in this process.

Identification, characterization and distribution of motilin immunoreactivity in the rat central nervous system.

Motilin-immunoreactivity was evaluated in rat brain using 15 different antisera and by combining gel filtration, high pressure gel filtration and reverse phase high pressure liquid chromatography with radioimmunoassay. Gel filtration chromatography demonstrated a high molecular weight and low molecular weight form of immunoreactive motilin. The high molecular weight form predominated in brain while the low molecular weight peptide was the predominant form of duodenum. The low molecular weight immunoreactive motilin was indistinguishable from synthetic porcine motilin by gel filtration and high molecular weight gel filtration. Low molecular weight rat motilin could, however, be distinguished from synthetic porcine motilin by high pressure liquid chromatography and certain antisera. Immunological results suggest that the slight structural difference may be in the N-terminal portion of the molecule. Immunoreactivity was measured in grossly and microdissected regions of the rat brain. The peptide had quite a unique distribution as highest concentrations are observed in the cerebellum. High concentrations were also observed in hypothalamic nuclei. Particularly high concentrations were noted in the organum vasculosum lamina terminalis. Lowest motilin concentrations in the rat brain were in the pons and the medulla. The distribution of motilin in rat brain suggests that it may have roles in regulating both neuroendocrine and neurological processes.

The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino)tetralin on resident intruder aggression in the rat.

Various serotonergic agents may reduce aggression in rats, but how they act in different parts of the brain is unknown. This study attempted to unravel part of this question by application of different serotonergic ligands into the lateral ventricle (i.c.v.) of male rats (resident-intruder aggression). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin; 1 and 10 micrograms), a specific 5-HT1A agonist, affected neither aggression nor any other behaviour. The mixed 5-HT1A,B,C agonist, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride), and the 5-HT1A/1B agonist, eltoprazine ((1-(2,3)-dihydro-1,4-benzodioxin-5-yl)piperazine hydrochloride), suppressed aggression at i.c.v. doses of 10 and 30 micrograms. This reduction was not caused by sedation. These data suggest a role of postsynaptic 5-HT1B receptors in mediating the anti-aggressive effects of mixed 5-HT1 agonists.

The effects of dorsal raphe administration of eltoprazine, TFMPP and 8-OH-DPAT on resident intruder aggression in the rat.

To evaluate the role of somatodendritic 5-HT1A receptors in the mediation of aggressive behaviour, eltoprazine, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride) and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) were administered locally into the dorsal raphe nucleus of rats. 8-OH-DPAT (1 and 10 micrograms) and eltoprazine (10 and 30 micrograms) reduced aggression, but concomitantly reduced social interest and increased inactivity. TFMPP (1 and 10 micrograms) did not reduce aggression. As 8-OH-DPAT and to a lesser extent eltoprazine affect 5-HT1A receptors, it is proposed that a general reduction of serotonergic neurotransmission by activation of somatodendritic serotonergic autoreceptor leads to a non-specific reduction of aggression. As TFMPP has a significantly lower affinity for 5-HT1A receptors than 8-OH-DPAT or eltoprazine, the lack of effect of TFMPP supports this view.

Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness?

Thyroidal economy in systemic nonthyroidal illness (the sick euthyroid syndrome) is marked by reductions in both thyroid function and peripheral T4 to T3 conversion, presumed to reflect a homeostatic mechanism to conserve energy. TSH levels tend to be normal in these patients, and the mechanism underlying reduced thyroidal secretion is unknown. Since increased blood levels of tumor necrosis factor (TNF) are found in many of the conditions associated with the sick euthyroid syndrome, we hypothesized that TNF might affect the function of the thyroid gland. We, therefore, explored the effects of TNF on TSH stimulation of the thyroid, employing a human thyrocyte cell culture model. Cells were incubated with various concentrations (0-1000 pg/mL) of recombinant human TNF-alpha and bTSH (1 mU/mL), with measurement of secreted thyroglobulin (Tg) and cyclic AMP (cAMP) as the end points of stimulation. TNF had no effect on either basal or TSH-stimulated cAMP generation, but significantly blunted TSH-stimulated Tg secretion. No loss of cell viability and growth was observed based on trypan blue exclusion and thymidine incorporation by cells. These studies demonstrated an inhibitory effect on TNF on human thyrocytes in concentrations comparable to blood levels seen in humans during systemic illness. We conclude that increases in serum TNF may be responsible for reduced thyroid function in patients with the sick euthyroid syndrome.

Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA), the most abundantly secreted human adrenal steroid, has no known specific function. In spite of this fact there is an abundance of data associating DHEA with "health" in both man and experimental animals. Research in our laboratory has demonstrated evidence for an antagonistic interaction between DHEA and glucocorticoids (GC) in liver and brown adipose tissue. We hypothesized that DHEA also antagonized effects of GC on the immune system and that this "immune protective effect" might explain the diffuse positive effects of DHEA reported in the literature. Effects of GC on the immune system include involution of the thymus when given in animals in vivo and death of thymic lymphocytes in vivo with exposure to these steroids. We hypothesized that DHEA would block this GC mediated thymocyte destruction in vivo and in vitro. Pretreatment with DHEA for three days blocked approximately 50% of the thymic involution seen with dexamethasone. Results of in vitro experiments confirmed protective effects of DHEA in pretreated animals. (less than 50% of cell death in lymphocytes from pretreated mice compared with lymphocytes from control mice.) We conclude from these studies that DHEA protects against at least one GC anti-immune effect, thymic lymphocyte lysis.

Effect of chronic growth hormone administration on diabetic nephropathy in the rat.

Indirect data exist which implicate elevated growth hormone (GH) as a factor in the development of diabetic nephropathy. The administration of somatostatin (SRIH) has been shown to reverse many of the changes found in early diabetic nephropathy; however, it is unknown whether SRIH causes these effects by the suppression of GH or by other unspecified factors. To study directly the possible effect of excess GH in the development of diabetic nephropathy, either ovine growth hormone (0.2 mg oGH) or diluent buffer was administered IM daily for 19 weeks to diabetic rats and to controls. Severity of nephropathy was assessed by 24 hour urine albumin excretion (UAE), relative kidney weight, and kidney histology. Results showed that diabetic rats overall had elevated UAE and kidney weight vs non-diabetic rats (46.2 +/- 8.6 vs 5.4 +/- 1.3 mg per day and 5.7 +/- 0.2 vs 2.7 +/- 0.1 mg per g of body weight, respectively, p < 0.001). However, no differences were detected between diabetic rats treated with GH compared to control diabetic rats. Additionally, diabetic rats had histopathologic changes consistent with early diabetic nephropathy, but no difference in severity scores was found between diabetic groups. These data provide evidence against GH as an etiologic factor in the development of diabetic nephropathy and it is speculated by the authors that SRIH exerts its protective renal effects in diabetes by mechanisms other than GH suppression.

Effects of photochemical smog and mineral nutrition on ponderosa pine seedlings.

Two-year-old seedlings of ponderosa pine (Pinus ponderosa Dougl. ex Laws) were exposed to ambient concentrations of photochemical smog (AA) and clean air (CA) during a single field season at Tanbark Flat of the San Gabriel Mountains in the Los Angeles Basin. The seedlings were grown in a perlite-vermiculite medium with full supply of nutrients (based on modified Hoagland solution); reduced to 50% supply of N; reduced to 50% supply of Mg; and reduced to 50% supply of N+Mg. No significant effects of air pollution exposures on injury development, stem growth and concentrations of plant pigments were determined. The seedlings in the AA treatment had decreased N concentration in current year needles compared with CA seedlings; however, the needle concentrations of other elements did not change. Reduction of N supply in the growing medium caused decreased N, P, Ca, K and chlorophyll a concentrations in needles. Stem growth of the seedlings with reduced N supply was significantly decreased as well. No changes in stem growth or chemical composition of plants with reduced Mg supply were noted. Reduction of supply of nutrients did not change responses of trees to the air pollution exposures.

Growth response of bigcone Douglas fir (Pseudotsuga macrocarpa) to long-term ozone exposure in southern California.

Long-term radial growth of bigcone Douglas fir (Pseudotsuga macrocarpa) was studied throughout its range in the San Bernardino Mountains of southern California, where ambient ozone has been high for approximately the past 40 years. A gradient of both ozone concentration and precipitation exists from west (high) to east (low). Growth rates of bigcone Douglas fir are considerably lower since 1950 throughout the San Bernardino Mountains, with the largest growth reductions in the western part of the range where ozone exposure is highest. Needle retention is also somewhat lower at high ozone sites. Lower annual precipitation since 1950 may have some impact on long-term growth reductions, and short-term growth reductions induced by drought are an important component of long-term growth reductions at sites with high ozone exposure. An ozone-climate stress complex may be responsible for recent reductions in the growth of bigcone Douglas fir.

A case study of nitrogen saturation in western U.S. forests.

Virtually complete nitrification of the available ammonium in soil and nitrification activity in the forest floor are important factors predisposing forests in the San Bernardino Mountains of southern California to nitrogen (N) saturation. As a result, inorganic N in the soil solution is dominated by nitrate. High nitrification rates also generate elevated nitric oxide (NO) emissions from soil. High-base cation saturation of these soils means that soil calcium depletion or effects associated with soil acidification are not an immediate risk for forest health as has been postulated for mesic forests in the eastern U.S. Physiological disturbance (e.g., altered carbon [C] cycling, reduced fine root biomass, premature needle abscission) of ozone-sensitive ponderosa pine trees exposed to high N deposition and high ozone levels appear to be the greater threat to forest sustainability. However, N deposition appears to offset the aboveground growth depression effects of ozone exposure. High nitrification activity reported for many western ecosystems suggests that with chronic N inputs these systems are prone to N saturation and hydrologic and gaseous losses of N. High runoff during the winter wet season in California forests under a Mediterranean climate may further predispose these watersheds to high nitrate leachate losses. After 4 years of N fertilization at a severely N saturated site in the San Bernardino Mountains, bole growth unexpectedly increased. Reduced C allocation below- ground at this site, presumably in response to ozone or N or both pollutants, may enhance the bole growth response to added N.

Nitrate in polluted mountainous catchments with Mediterranean climates.

The mountains of southern California receive some of the highest rates of nitrogen (N) deposition in the world (approximately 40 kg ha(-1) year(-1)). These high rates of deposition have translated into consistently high levels of nitrate (NO3-) in some streams of the San Bernardino Mountains. However, not all streams are exhibiting these high levels of NO3-. Perennial streams have high NO3- concentrations (approximately 200 micromoles l(-1)) while ephemeral streams do not (approximately 20 micromoles l(-1)). This difference points to groundwater as the source of the NO3- observed in streams. Furthermore, the evidence indicates a differential impact of N deposition on terrestrial and aquatic systems in Mediterranean climates, with aquatic systems being impacted more quickly. The primary reason for this difference involves the asynchrony between the time that atmospheric deposition occurs (summer), the time period of maximum soil NO3- availability and leaching (winter), and the time of maximum plant N demand (spring). Our results indicate that semiarid Mediterranean climate systems behave differently from more humid systems in that, because of this asynchrony, aquatic systems may not be indicative of changes in terrestrial ecosystem response. These differences lead us to the conclusion that the extrapolation of impacts from humid to Mediterranean climates is problematic and the concept of N saturation may need to be revisited for semiarid and seasonally dry systems.

Hormone-containing cosmetics may cause signs of early sexual development.

Exogenous hormone exposure can cause early sexual development, but only one report suggests that this may occur secondary to the use of hair-care products. This study evaluated the usage frequency and biological effects of hormone-containing hair-care products. We reviewed the records of 102 consecutive dependent children referred for evaluation of sexual precocity. Eight children (7.8%) were using these products. All eight were black (100%), compared to 57 (61%) of the 94 patients not using such products (p < 0.05). There was no significant difference between these two groups in mean age, sex distribution, height, height standard deviation score, bone age:chronologic age ratio, or serum estradiol level. We conclude that exposure to hormones in hair-care products may be more frequent than expected and should be considered in the differential diagnosis of early sexual development in children.