Decreasing resistance in the maternal uterine and peripheral arterial system is apparently unrelated to plasma and urinary levels of nitrite/nitrate and cyclic-guanosinmonophosohate during the course of normal pregnancies

Aims: The aim of the presented study was to clarify the relationship between the pulsatility index of the uterine arteries and the maternal cubital artery and peripheral concentrations of the metabolites of nitric oxide (NO) and its second messenger cyclic guanosinmonophophate (cGMP) during the normal course of pregnancy and postpartum. Methods: 49 uncomplicated pregnancies were investigated every 46 weeks until delivery, 29 of them were additionally investigated postpartum. Paralleling each Doppler sonografic investigation maternal blood and urine samples were taken. The measurements of nitrite/ nitrate and cGMP were performed with a colorimetric and radio immuno assay. We demonstrate a significant decrease of the PI of the uterine arteries and of the cubital artery with inverse correlation to advancing gestational age. Results: The concentrations of nitrite/nitrate and cGMP remain stable during gestation and do not correlate to the PI of the uterine and cubital artery. Postpartum a reincrease in the uterine and peripheral resistance can be shown. The concentrations of urinary cGMP and nitrite/ nitrate as well as plasma cGMP remain unchanged, whereas plasma nitrite/nitrate decreases postpartum. Conclusions: The status of NO biosyntheses in normal pregnancy remains controversial. We hypothesize further systemically acting mediators which contribute to the decreasing vascular resistance

Estrone and estradiol concentrations in human ovaries, testes, and adrenals during the first two years of life

To determine the origin of estrogens in infant blood, we measured estrone (E1) and estradiol (E2) in the gonads of 50 girls and 64 boys who died suddenly between birth and 2 yr of age as well as in the adrenals of 18 of these infant girls and 16 of the boys. In the adrenals, E1 [median, 2.8 ng/g (10.4 pmol/g); range, 1.1-4.8 ng/g (4.1- 17.8 pmol/g)] and E2 [median, 3.0 ng/g (10.9 pmol/g); range, 1.2-5.3 ng/g (4.4-19.5 pmol/g)] were found in similar concentrations and were independent of age and sex. In the gonads, E2 was the major estrogen, but the concentrations differed markedly between the sexes; E2 exceeded E1 almost 10-fold in the ovaries and 2-fold in the testes. On the average, the gonads of the infant girls had 5 times more E2 and 2 times more E1 than those of the boys. As in plasma, E2 concentrations were highest in the ovaries of 1- to 6-month-old girls [median, 10.5 ng/g (38.5 pmol/g); range, 1.1-55.1 ng/g (4.0-202.0 pmol/g)] and in testes of 1- to 3-month-old boys [median, 1.8 ng/g (6.6 pmol/g); range, 0.6- 6.4 ng/g (2.3-23.5 pmol/g)]. Ovarian E2 concentrations declined to less than 3.0 ng/g (11.0 pmol/g) by the end of the first year of life, and testicular E2 declined to less than 1.0 ng/g (3.7 pmol/g) after only 6 months of age. Gonadal estrogen concentrations paralleled changes in gonadal morphology. Ovarian weights varied in a pattern of rise and fall similar to that of ovarian E2 concentrations; the biggest ovaries contained multiple macroscopic cysts. Testicular E2 closely correlated with Leydig cell development and testicular testosterone concentrations. We infer, therefore, that the surge of plasma E2 in infant girls originates from ovarian follicles and that of boys from testicular Leydig cells, and that these both occur as a result of the postnatal surge in gonadotropin secretion. The basal plasma E1 and E2 pool, however, is derived from the adrenals and remains at a comparatively constant level in both sexe

Obstructive Sleep Apnea Syndrome Is Less Frequent in Patients With Well-Controlled Acromegaly Treated With Somatostatin Analogues, Pegvisomant or in Combination

Background: Obstructive sleep apnea (OSA) often occurs in patients with active acromegaly and improves after treatment. Less is known about the development of OSA in patients after a longer period of control treated with somatostatin analogues (SSA) and pegvisomant. Methods: Seventy-nine patients (12 females, 17 males; age 49 +/- 14 years; body mass index 29.9 +/- 5.4 kg/m(2); IGF-1 184 +/- 73 mu g/L; disease duration 13 +/- 8 years (mean +/- standard deviation)) with wellcontrolled acromegaly treated with SSA (38%), pegvisomant (38%) or in combination (24%) who underwent ambulatory polygraphy were included in a prospective multicenter cross-sectional study. Results: Fourteen percent had OSA (range of apnea-hypopnea index (AHI) 5 -15). Patients with OSA (AHI >= 5 vs. < 5) had a longer disease duration (16 +/- 1 vs. 12 +/- 8 years; P = 0.01) and were older (61 +/- 9 vs. 47 +/- 13 years; P = 0.037). The AHI of all patients correlated with age (P = 0.01; r = 0.44). No differences were seen in terms of BMI and Epworth sleepiness scale score. Previous transsphenoidal surgery and radiation had no impact of the detection of OSA. The duration of well-controlled acromegaly was 7 +/- 3 years. Conclusion: OSA in patients with well-controlled acromegaly treated with SSA, pegvisomant or in combination is less frequent (14%) than previously described. Early treatment to reduce the active disease period should be aimed to prevent OSA

Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance

The roles of GH and its receptor (GHR) in metabolic control are not yet fully understood. We studied the roles of GH and the GHR using the GHR antagonist pegvisomant for metabolic control of healthy nonobese men in fasting and nonfasting conditions. Ten healthy subjects were enrolled in a double blind, placebo-controlled study on the effects of pegvisomant on GHRH and GH-releasing peptide-6 (GHRP-6)-induced GH secretion before and after 3 days of fasting and under nonfasting conditions (n = 5). Under the condition of GHR blockade by pegvisomant in the nonfasting state, GHRP-6 (1 microg/kg) caused a increase in serum insulin (10.3 +/- 2.1 vs. 81.3 +/- 25.4 mU/L; P < 0.001) and glucose (4.2 +/- 0.3 vs. 6.0 +/- 0.6 mmol/L; P < 0.05) concentrations. In this group, a rapid decrease in serum free fatty acids levels was also observed. These changes were not observed under GHR blockade during fasting or in the absence of pegvisomant. We conclude that although these results were obtained from an acute study, and long-term administration of pegvisomant could render different results, blockade of the GHR in the nonfasting state induces tissue-specific changes in insulin sensitivity, resulting in an increase in glucose and insulin levels (indicating insulin resistance of liver/muscle), but probably also in an increase in lipogenesis (indicating normal insulin sensitivity of adipose tissue). These GHRP-6-mediated changes indicate that low GH bioactivity on the tissue level can induce changes in metabolic control, which are characterized by an increase in fat mass and a decrease in lean body mass. As a mechanism of these GHRP-6-mediated metabolic changes in the nonfasting state, direct nonpituitary-mediated GHRP-6 effects on the gastroentero-hepatic axis seem probable

Ghrelin drives GH secretion during fasting in man

OBJECTIVES: In humans, fasting leads to elevated serum GH concentrations. Traditionally, changes in hypothalamic GH-releasing hormone and somatostatin release are considered as the main mechanisms that induce this elevated GH secretion during fasting. Ghrelin is an endogenous ligand of the GH secretagogue receptor and is synthesized in the stomach. As ghrelin administration in man stimulates GH release, while serum ghrelin concentrations are elevated during fasting in man, this increase in ghrelin levels might be another mechanism whereby fasting results in stimulation of GH release. DESIGN AND SUBJECTS: In ten healthy non-obese males we performed a double-blind placebo-controlled crossover study comparing fasting with and fasting without GH receptor blockade. GH, ghrelin, insulin, glucose and free fatty acids were assessed. RESULTS: While ghrelin levels do not vary considerably in the fed state, fasting rapidly induced a diurnal rhythm in ghrelin concentrations. These changes in serum ghrelin concentrations during fasting were followed by similar, profound changes in serum GH levels. The rapid development of a diurnal ghrelin rhythm could not be explained by changes in insulin, glucos

Phenotype Selection Reveals Coevolution of Muscle Glycogen and Protein and PTEN as a Gate Keeper for the Accretion of Muscle Mass in Adult Female Mice

We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice) characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold) if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK), were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α) and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß) and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice

The diagnostic accuracy of integrated positron emission tomography/computed tomography in the evaluation of pulmonary mass lesions in a tuberculosis-endemic area

Background. Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing pulmonary mass lesions and specifically for estimating risk of malignancy. Tuberculosis (TB) is known to cause false-positive PET-CT findings.Objective. To investigate the utility of PET-CT in the evaluation of pulmonary mass lesions and nodules in a high TB prevalence setting.Methods. All patients referred for the evaluation of a solitary pulmonary nodule or mass and who underwent PET-CT scanning over a 3-year period were included. The PET-CT findings, including maximum standardised uptake value (SUVmax), were compared with the gold standard (tissue or microbiological diagnosis). The sensitivity, specificity, positive and negative predictive values and diagnostic accuracy for malignant disease were calculated according to the SUVmax cut-off of 2.5 and a proposed cut-off obtained from a receiver operating characteristic (ROC) curve.Results. Forty-nine patients (mean (standard deviation) age 60.1 (10.2) years; 29 males) were included, of whom 30 had malignancy. Using an SUVmax cut-off of 2.5, PET-CT had a sensitivity, specificity, positive and negative predictive value and diagnostic accuracy for malignancy of 93.3%, 36.8%, 70.0%, 77.8% and 71.4%, respectively. After a ROC curve analysis, a suggested SUVmax cut-off of 5.0 improved the specificity to 78.9% and the diagnostic accuracy to 86.7%, with a small reduction in sensitivity to 90.0%.Conclusions. The diagnostic accuracy of PET-CT in the evaluation of pulmonary mass lesions using the conventional SUVmax cut-off of 2.5 was reduced in a TB-endemic area. An SUVmax cut-off of 5.0 has a higher specificity and diagnostic accuracy for malignancy, with a comparable sensitivity