Contractile effects of 15-E2t-isoprostane and 15-F2t-isoprostane on chicken embryo ductus arteriosus

Isoprostanes (IsoPs) are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonate. Cyclooxygenase-derived PGs play a major role in ductus arteriosus (DA) homeostasis but the putative role of IsoPs has not been studied so far. We investigated, using wire myography, the vasoactive effects of 15-E(2t)-IsoP and 15-F(2t)-IsoP in the chicken embryo DA, pulmonary artery (PA) and femoral artery (FA). 15-E(2t)-IsoP and 15-F(2t)-IsoP contracted DA, PA, and FA rings in a concentration-dependent manner. 15-E(2t)-IsoP was equally efficacious (mean±SE E(max)=1.25±0.06 mN/mm) as and more potent (-log of molar concentration producing 50% of E(max)=pEC(50)=7.00±0.04) than the thromboxane-prostanoid (TP) receptor agonist U46619 (E(max)=1.49±0.11 mN/mm; pEC(50)=6.48±0.05) in contracting chicken DA (pulmonary side). 15-F(2t)-IsoP was less potent (pEC(50)=5.74±0.11) and less efficacious (E(max)=0.96±0.11) than U46619. Concentration-dependent contractions to 15-E(2t)-IsoP and U46619 in DA rings were competitively inhibited by the TP receptor antagonist SQ29548 (0.1 μM to 10 μM) with no decrease in the E(max) values. SQ29548 also inhibited concentration-dependent contraction to 15-F(2t)-IsoP but this inhibition was associated with a decrease in E(max). Pre-incubation of DA rings with 15-F(2t)-IsoP inhibited responses to U46619 and, in vessels contracted with U46619 (1 μM), 15-F(2t)-IsoP (>1 μM) evoked a relaxant response. Enzyme immunoassay did not show a measurable release of 15-F(2t)-IsoP by DA rings. In conclusion, 15-E(2t)-IsoP is a potent and efficacious constrictor of chicken DA, acting through TP receptors. In contrast, 15-F(2t)-IsoP is probably acting as a partial agonist at TP receptors. We speculate that IsoPs play a role in the control of chicken DA tone and could participate in its closure.     

The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats

The mechanism by which valproic acid (VPA) induces liver injury remains unknown, but it is hypothesized to involve the generation of toxic metabolites and/or reactive oxygen species. This study's objectives were to determine the effect of VPA on plasma and hepatic levels of the F(2)-isoprostane, 15-F(2t)-IsoP, a marker for oxidative stress, and to investigate the influence of cytochrome P450- (P450-) mediated VPA biotransformation on 15-F(2t)-IsoP levels in rats. In rats treated with VPA (500 mg/kg), plasma 15-F(2t)-IsoP was increased 2.5-fold at t(max) = 0.5 h. Phenobarbital pretreatment (80 mg/kg/d for 4 d) in VPA-treated rats increased plasma and liver levels of free 15-F(2t)-IsoP by 5-fold and 3-fold, respectively, when compared to control groups. This was accompanied by an elevation in plasma and liver levels of P450-mediated VPA metabolites. Pretreatment with SKF-525A (80 mg/kg) or 1-aminobenzotriazole (100 mg/kg), which inhibited P450-mediated VPA metabolism, did not attenuate the increased levels of plasma 15-F(2t)-IsoP in VPA-treated groups. Plasma and hepatic levels of 15-F(2t)-IsoP were further elevated after 14 d of VPA treatment compared to single-dose treatment. Our data indicate that VPA increases plasma and hepatic levels of 15-F(2t)-IsoP and this effect can be enhanced by phenobarbital by a mechanism not involving P450-catalyzed VPA biotransformation.     

The effects of oxidation products of arachidonic acid and n3 fatty acids on vascular and platelet function

15-F?(t)-isoprostane (15-F?(t)-IsoP), an oxidation product of arachidonic acid (AA), affects vascular and platelet function; however, the bioactivity of other fatty acids oxidation products is unknown. This paper studied rat aortic vascular reactivity and human platelet aggregation in response to 14 oxidation products of AA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and α-linolenic acid (ALA) compared with 15-F?(t)-IsoP. It also compared the F?(t)-IsoPs profile in human platelets. EPA-derived 15-F?(t)-IsoP constricted rat aorta less than 15-F?(t)-IsoP, but none of the other oxidation products affected vascular reactivity. Only 15-F?(t)-IsoP (10?? M) directly affected platelet aggregation. 15-F?(t)-IsoP, ent-16-F?-phytoprostane (from ALA) and isofurans A and B (from AA) inhibited reversible aggregation to U46619. Unlike plasma, the platelet profile of F?-IsoP showed that 8-F(2t)-IsoP were higher than 15-F?(t)-IsoP. Unlike 15-F?(t)-IsoP, the test compounds derived from fatty acids oxidation did not affect vascular or platelet function. Elevated platelet 8-F?(t)-IsoP could limit 15-F?(t)-IsoP-induced aggregation under conditions of oxidant stress.     

15-F(2t)-isoprostane exacerbates myocardial ischemia-reperfusion injury of isolated rat hearts

Reactive oxygen species induce formation of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a specific marker of in vivo lipid peroxidation, which is increased after myocardial ischemia and during the subsequent reperfusion. 15-F(2t)-IsoP possesses potent bioactivity under pathophysiological conditions. However, it remains unknown whether 15-F(2t)-IsoP, by itself, can influence myocardial ischemia-reperfusion injury (IRI). Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit (KH) solution at a constant flow rate of 10 ml/min. 15-F(2t)-IsoP (100 nM), SQ-29548 (1 microM, SQ), a thromboxane receptor antagonist that can abolish the vasoconstrictor effect of 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ in KH, or KH alone (vehicle control) was applied for 10 min before induction of 40 min of global ischemia followed by 60 min of reperfusion. During ischemia, saline (control), 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ, or SQ in saline was perfused through the aorta at 60 microl/min. 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ, or SQ in KH was infused during the first 15 min of reperfusion. Coronary effluent endothelin-1 concentrations were significantly higher in the group treated with 15-F(2t)-IsoP than in the control group during ischemia and also in the later phase of reperfusion (P < 0.05). Infusion of 15-F(2t)-IsoP increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size relative to the control group. SQ abolished the deleterious effects of 15-F(2t)-IsoP. 15-F(2t)-IsoP exacerbates myocardial IRI and may, therefore, act as a mediator of IRI. 15-F(2t)-IsoP-induced endothelin-1 production during cardiac reperfusion may represent a mechanism underlying the deleterious actions of 15-F(2t)-IsoP.     

Isomer-specific contractile effects of a series of synthetic f2-isoprostanes on retinal and cerebral microvasculature

F2-isoprostanes (F2-IsoP's) are biologically active prostanoids formed by free radical-mediated peroxidation of arachidonic acid. Four different F2-IsoP regioisomers (5-, 8-, 12-, and 15-series), each comprising eight racemic diastereomers, total 64 compounds. Information regarding the biological activity of IsoP's is largely limited to 15-F2t-IsoP (8-iso-PGF2alpha). We recently demonstrated that 15-F2t-IsoP and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, evoked vasoconstriction and TXA2 generation in retina and brain microvasculature. We have now examined and compared the biological activities of a series of recently synthesized new 5-, 12-, and 15-series F2-IsoP isomers in pig retinal and brain microvasculature. We hereby show that other 15-series F2-IsoP isomers, 15-epi-15-F2t-IsoP, ent-15-F2t-IsoP, and ent-15-epi-15-F2t-IsoP, are also potent vasoconstrictors. The 12-series isomers tested, 12-F2t-IsoP and 12-epi-12-F2t-IsoP, also caused marked vasoconstriction. Of the 5-series isomers tested, 5-F2t-IsoP and 5-epi-5-F2t-IsoP possessed no vasomotor properties, whereas ent-5-F2t-IsoP caused modest vasoconstriction. The vasoconstriction of ent-5-F2t-IsoP, 12-F2t-IsoP, and 12-epi-12-F2t-IsoP was abolished by removal of the endothelium, by TXA2 synthase and receptor inhibitor (CGS12970, L670,596), and by receptor-mediated Ca2+ channel blockade (SK & F96365); correspondingly, these isomers increased TXB2 formation by activating Ca2+ influx (detected with fura 2-AM) through non-voltage-dependent receptor-mediated Ca2+ entry (SK & F96365 sensitive) in endothelial cells. In conclusion, as seen with 15-F2t-IsoP, ent-5-F2t-IsoP, 12-F2t-IsoP, and 12-epi-12-F2t-IsoP constricted both retinal and brain microvessels by inducing endothelium-dependent TXA2 synthesis. These new findings broaden the scope of our understanding regarding the potential involvement of F2-IsoP's as mediators of oxidant injury.     

Regulation of [3H]D-Aspartate Release by the 5-F2t-Isoprostane and Its 5-Epimer in Isolated Bovine Retina

We have evidence that 15-F?-isoprostanes (15-F?-IsoPs) regulate excitatory neurotransmitter release in ocular tissues. Although 5-F?-IsoPs are abundantly produced in mammals, their pharmacological actions on neurotransmitter release remain unknown. In the present study, we compared the effect of the 5-F?-IsoP epimer pair, 5-F(2t)-IsoP (C5-OH in β-position) and 5-epi-5-F(2t)-IsoP (C5-OH in α-position), on K?-evoked [3H]D-aspartate release in isolated bovine retina. We further examined the role of prostanoid receptors on the inhibitory action of 5-epi-5-F(2t)-IsoP on [3H]D-aspartate overflow. Isolated bovine retina were prepared for studies of K?-evoked release of [3H]D-aspartate using the superfusion method. 5-epi-5-F(2t)-IsoP (0.01 nM to 1 μM), attenuated K?-evoked [3H]D-aspartate release in a concentration-dependent manner, with the inhibitory effect of 26.9% (P < 0.001; IC?? = 0.2 μM) being achieved at 1 μM concentration. Its 5-(S)-OH-epimer, 5-F(2t)-IsoP (0.1 nM-1 μM), exhibited an inhibitory biphasic action, yielding a maximal response of 35.7% (P < 0.001) at 10 nM concentration of the drug (IC?? value of 3 nM). Although the prostanoid-receptor antagonists, AH 6809 (10 μM; EP???/DP) and BAY-u3405 (10 μM; DP/Tx) exhibited no effect on 5-epi-5-F(2t)-IsoP (10 nM-1 μM)-mediated inhibition, SC-19220 (1 μM; EP?) completely reversed 5-epi-5-F(2t)-IsoP (0.1 μM and 1 μM)-induced attenuation of K?-evoked [3H]D-aspartate release. Similarly, both SC-51322 (10 μM; EP? and AH 23848 (1 μM; EP?) reversed the inhibitory action elicited by 5-epi-5-F(2t)-IsoP (0.1 μM) on the neurotransmitter release. We conclude that the 5-F?-IsoP epimer pair, 5-F(2t)-IsoP and 5-epi-5-F(2t)-IsoP, attenuate K?-induced [3H]D-aspartate release in isolated bovine retina presumably via prostanoid receptor dependent mechanisms. The trans-orientation of the allylic hydroxyl group at position C5 accounts for the apparent biphasic response exhibited by 5-F(2t)-IsoP on excitatory neurotransmitter release.     

Biocultural aspects of gender differences in body composition and obesity during childhood and adolescence

Gender differences in body composition, the prevalence in overweight and obesity as well as in physical activity patterns were tested among 3003 children and adolescents aging between 6 and 18 years (x = 12.1 +/- 3.6) in Vienna and rural parts of Eastern Austria. As to be expected, the absolute and relative amount of body fat was significantly higher among girls of nearly all age groups, while boys exhibited a significantly higher amount of lean or fat free body mass. The prevalence of overweight and obesity was markedly higher among prepubertal girls, however significantly lower among younger and older adolescent girls aging 11 years and older in comparison to their male counterparts. This was however only true of adolescents originating from Austria. Considering adolescents with a background of migration originating from Turkey or the Near East, a significantly higher amount of overweight and/or obesity was found among girls. Therefore, biocultural factors have to be considered to explain gender differences in obesity during childhood and adolescence.     

Pharmacological actions of isoprostane metabolites and phytoprostanes in human and bovine pulmonary smooth muscles

We examined the responses to various isoprostane derivatives in bovine/human airway and pulmonary arteries. All biological activity of 15-F(2t)-IsoP was lost in its two major metabolites (15-keto-15-F(2t)-IsoP and 13,14-dihydro-15-keto-15-F(2t)-IsoP). We also examined the effects of several metabolites of 15-F(2t)-IsoP synthesized within our own laboratory-both epimers of 2,3-dinor-15-F(2t)-IsoP and of 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP, as well as 20-carboxy-2,3,4,5-tetranor-15 oxo-5,6,13,14-tetrahydro-15-F(2t)-isoP)-finding none of these to have any substantial excitatory effect. Finally, several plant-derived isoprostanes ("phytoprostanes") synthesized within our laboratory elicited little or no excitatory response in these three pulmonary smooth muscle preparations. We conclude that, although isoprostane exhibit powerful constrictor effects on airway and pulmonary vascular smooth muscles, metabolic processing of those isoprostanes essentially abolishes those biological actions; also, the phytoprostanes lack any appreciable pharmacological activity on those smooth muscle preparations.     

Quantification of dinor, dihydro metabolites of F2-isoprostanes in urine by liquid chromatography/tandem mass spectrometry

The F2-isoprostanes (F2-IsoP) are a series of prostaglandin (PG)-F2-like compounds that are produced by free-radical-mediated oxidation of arachidonic acid. One F2-IsoP with potent biological activity is 15-F2t-IsoP and increased levels of 15-F(2t)-IsoP have been measured in several diseases. The major urinary metabolite of 15-F2t-IsoP (8-iso-PGF(2alpha)) is 2,3-dinor-5,6-dihydro-15-F2t-IsoP (15-F2t-IsoP-M). Previously, we developed a stable isotope dilution gas chromatography/negative chemical ionization/mass spectrometry (MS) assay for 15-F2t-IsoP-M, which, while highly sensitive, required time-consuming derivatization and thin-layer chromatography purification. We now report the development of a more rapid high-performance liquid chromatography method coupled to electrospray ionization-tandem mass spectrometry (LC/MS/MS) to analyze all of the dinor,dihydro metabolites of the F2-IsoP isomers (F2-IsoP-M). The precision of this assay was +/-5.0% and the accuracy 80%. The assay remained linear over a range of 1-100 ng injected onto the LC column. Levels of F2-IsoP-M determined by the LC/MS/MS assay method significantly correlated with levels of 15-F2t-IsoP-M determined by the GC/MS assay (R = 0.77y = 67.2x-0.5). The levels of F2-IsoP-M detected in spot urines from 40 normal subjects were 38.1+/-19.1 ng/mg creatinine (mean+/-SD). This method provides an accurate and rapid assay to assess oxidative status in vivo.     

The role of physical activity and fitness on the metabolic syndrome in adolescents: effect of different scores. The AFINOS Study

The aim of this study was to examine the associations of objectively measured physical activity (PA) and cardiorespiratory fitness (CRF) with different continuous metabolic syndrome (MetS) scores in adolescents. A cross-sectional sub-sample of 202 adolescents (99 girls), aged 13–17 years, were selected from the AFINOS Study. Body mass index, sum of 6 skindfold, waist circumference, systolic and diastolic blood pressure, insulin, glucose, triacylglycerol, and HDL-cholesterol levels were determined. Moderate PA (MPA), vigorous PA (VPA) and moderate to vigorous PA (MVPA) were assessed by the ActiGraph accelerometer for 7 consecutive days and CRF was estimated by the 20-m shuttle run test. Three continuous MetS scores were calculated according to the methodology of the Corpus Christi Child Heart Study (CCCHS), the Aerobic Center Longitudinal Study (ACLS), and the European Youth Heart Study (EYHS). VPA and MVPA were significantly related with CRF. Only CRF, and not patterns of PA, was inversely and independently associated with the three MetS scores although with different magnitudes (ranged: β = 0.22 to 0.36, p < 0.05). A significant VPA x CRF interaction (p = 0.011) was found using the ACLS MetS score. Trends across VPA-CRF groups were significantly different with ACLS and EYHS (p = 0.002 and p = 0.006, respectively), but not with CCCHS (p = 0.313) continuous MetS scores. These findings support the key role of CRF on the MetS and the relevance of PA, especially VPA, to provide CRF in adolescents. A unified pediatric definition of MetS might minimize the discrepancies among studies.     

Correlation between two markers of inflammation, serum C-reactive protein and interleukin 6, and indices of oxidative stress in patients with high risk of cardiovascular disease.

As evidence of the involvement of inflammation and oxidative damage in pathogenesis of age-related chronic diseases is growing, epidemiologists need to develop measures of both conditions to study their relationships in human populations. One way of searching for appropriate biomarkers is to examine correlations between different inflammatory markers and oxidative indices. We examined cross-sectional correlations between two inflammatory markers, serum C-reactive protein (CRP) and interleukin (IL)-6, and three oxidative indices, plasma levels of alpha-tocopherol and beta-carotene, and urinary levels of 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoP), in 60 individuals at high risk of cardiovascular disease. Correlations between the biomarkers were examined graphically and using the Pearson correlation coefficient. No correlation was found between plasma levels of alpha-tocopherol and either of the inflammatory markers. Plasma beta-carotene inversely correlated with IL-6 (r = -0.46, p=0.0002) and CRP (r = -0.41, p = 0.001). Although urinary F2-IsoP did not correlate with IL-6, this biomarker positively correlated with CRP (r = 0.31, p = 0.002). As only urinary F2-IsoP levels have been validated against known oxidative assaults, their positive association with CRP levels is interpreted as evidence of an interconnection between low-level inflammation and oxidative status. Urinary levels of F2-IsoP and serum levels of CRP represent appropriate biomarkers for future studies of inflammation and oxidative status in humans.     

Age at Puberty and the Emerging Obesity Epidemic

Background

Recent studies have shown that puberty starts at younger ages than previously. It has been hypothesized that the increasing prevalence of childhood obesity is contributing to this trend. The purpose of this study was to analyze the association between prepubertal body mass index (BMI) and pubertal timing, as assessed by age at onset of pubertal growth spurt (OGS) and at peak height velocity (PHV), and the secular trend of pubertal timing given the prepubertal BMI.

Methodology/Principal Findings

Annual measurements of height and weight were available in all children born from 1930 to 1969 who attended primary school in the Copenhagen municipality; 156,835 children fulfilled the criteria for determining age at OGS and PHV. The effect of prepubertal BMI at age seven on these markers of pubertal development within and between birth cohorts was analyzed. BMI at seven years was significantly inversely associated with age at OGS and PHV. Dividing the children into five levels of prepubertal BMI, we found a similar secular trend toward earlier maturation in all BMI groups.

Conclusion/Significance

The heavier both boys and girls were at age seven, the earlier they entered puberty. Irrespective of level of BMI at age seven, there was a downward trend in the age at attaining puberty in both boys and girls, which suggests that the obesity epidemic is not solely responsible for the trend.     

Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors

Obesity and premature adrenarche (PA) are both associated with bone age (BA) advancement of unclear etiology, which may lead to earlier puberty, suboptimal final height and obesity in adulthood. Our objective was to understand the hormonal and anthropometric characteristics of BA advancement in a spectrum of prepubertal children with and without obesity and PA. In this cross-sectional study of 66 prepubertal children (35 PA, 31 control, 5-9 years), BMI z-score, hormonal values and response to an oral glucose tolerance test were the main outcome measures. Subjects were divided into tertiles by BA divided by chronological age (BA/CA), an index of BA advancement. Subjects in the top tertile for BA/CA had the highest dehydroepiandrosterone sulfate (DHEAS), free testosterone (%), hemoglobin A(1C), BMI z-score, and weight (P < 0.05). BMI z-score (r = 0.47), weight (r = 0.40), free testosterone (%) (r = 0.34), and DHEAS (r = 0.30) correlated with BA/CA (P < 0.02). Regression analysis showed greater BA/CA in PA compared to controls after controlling for weight (0.21 ± 0.56, P < 0.004). An exploratory stepwise regression model showed that weight, estradiol, and DHEAS were the strongest predictors of BA/CA accounting for 24% of its variance. Obesity was highly associated with BA advancement in this study of prepubertal children. In addition, children with PA had greater BA/CA at any given weight when compared to controls. These findings suggest a possible hormonal factor, which potentiates the effect of obesity on BA advancement in children with obesity and/or PA.     

Oxidative and nitrosative stress markers in bus drivers

Exposure to ambient air pollution is associated with many diseases. Oxidative and nitrosative stress are believed to be two of the major sources of particulate matter (PM)-mediated adverse health effects. PM in ambient air arises from industry, local heating, and vehicle emissions and poses a serious problem mainly in large cities. In the present study we analyzed the level of oxidative and nitrosative stress among 50 bus drivers from Prague, Czech Republic, and 50 matching controls. We assessed simultaneously the levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and 8-oxodeoxyguanosine (8-oxodG) in urine and protein carbonyl groups and 3-nitrotyrosine (NT) in blood plasma. For the analysis of all four markers we used ELISA techniques. We observed significantly increased levels of oxidative and nitrosative stress markers in bus drivers. The median levels (min, max) of individual markers in bus drivers versus controls were as follows: 8-oxodG: 7.79 (2.64-12.34)nmol/mmol versus 6.12 (0.70-11.38)nmol/mmol creatinine (p<0.01); 15-F(2t)-IsoP: 0.81 (0.38-1.55)nmol/mmol versus 0.68 (0.39-1.79)nmol/mmol creatinine (p<0.01); carbonyl levels: 14.1 (11.8-19.0)nmol/ml versus 12.9 (9.8-16.6)nmol/ml plasma (p<0.001); NT: 694 (471-3228)nmol/l versus 537 (268-13833)nmol/l plasma (p<0.001). 15-F(2t)-IsoP levels correlated with vitamin E (R=0.23, p<0.05), vitamin C (R=-0.33, p<0.01) and cotinine (R=0.47, p<0.001) levels. Vitamin E levels also positively correlated with 8-oxodG (R=0.27, p=0.01) and protein carbonyl levels (R=0.32, p<0.001). Both oxidative and nitrosative stress markers positively correlated with PM2.5 and PM10 exposure. In conclusion, our study indicates that exposure to PM2.5 and PM10 results in increased oxidative and nitrosative stress.     

Urinary F₂-isoprostanes, obesity, and weight gain in the IRAS cohort

Obesity has been associated with increased F(2)-isoprostane (F(2)-IsoP) levels cross-sectionally. However, the prospective association may be inverse, based on our earlier finding that elevated urinary F(2)-IsoP levels predict lower risk of diabetes. This earlier finding led us to hypothesize that urinary F(2)-IsoPs reflect the intensity of oxidative metabolism and as such predict lower risk of both diabetes and weight gain. We examined cross-sectional relationships with obesity and prospective relationships with weight gain using the data from 299 participants of the Insulin Resistance Atherosclerosis Study (IRAS), all of whom were free of diabetes at baseline. Four urinary F(2)-IsoPs were assayed in stored baseline urine samples using liquid chromatography with tandem mass spectrometry: iPF(2α)-III, 2,3-dinor-iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI (F(2)-IsoP 1-4, respectively). Baseline F(2)-IsoPs were positively associated with baseline measures of obesity; the strongest associations were found with two F(2)-IsoPs: odds ratios (95% confidence intervals) for overall and abdominal obesity were 1.74 (1.26-2.40) and 1.63 (1.18-2.24) for F(2)-IsoP2 and 1.47 (1.12-1.94) and 1.64 (1.22-2.20) for F(2)-IsoP4. F(2)-IsoP2 showed the strongest and significant inverse association with weight gain during the 5-year follow-up period: increase in F(2)-IsoP2 equal to 1 s.d. was associated with 0.90 kg lower weight gain (P = 0.02) and the odds ratios for relative (≥5%) and absolute (≥5 kg) weight gain were 0.67 (0.47-0.96) and 0.57 (0.37-0.87), respectively. The other three F(2)-IsoPs were consistently inversely associated with weight gain, although not significantly, suggesting that different F(2)-IsoPs vary in their ability to detect the association with weight gain.     

Gonadotropin pulsatile secretion in girls with premature menarche

Five prepubertal girls (2.3-8.1 years old) were studied for isolated or recurrent vaginal bleeding in the absence of other signs of precocious puberty (premature menarche). Four of these girls with recurrent vaginal bleeding were studied for pulsatile gonadotropin secretory patterns. During sleep 3 girls showed luteinizing hormone (LH) pulses with low amplitude and a pubertal pattern of frequency whereas follicle-stimulating hormone (FSH) increased without demonstrable episodic secretion. Luteinizing hormone-releasing hormone (LHRH) tests demonstrated that FSH responses are greater than the LH responses, as in prepuberty. In 3 cases estradiol levels had augmented above normal prepubertal range. The menses spontaneously stopped during the follow-up. A reevaluation of the gonadotropin pattern, having the menses stopped for 6 months, in one of the girls with pulsatile LH secretion showed an apulsatile prepubertal LH pattern. Also estradiol levels returned to prepubertal range. A follow-up of 10-66 months of these patients did not show any growth and bone acceleration or signs of precocious puberty. Our data suggest that in premature menarche a partial and transient activation of hypothalamo-pituitary axis could be present. Premature menarche seems to be a benign and self-limiting condition and one of the girls had a normal onset of puberty during follow-up.     

Evaluation of Metabolic Risk in Prepubertal Girls Versus Boys in Relation to Fitness and Physical Activity

BackgroundLow levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a risk of the development of metabolic syndrome. Contradictory findings are reported in the literature regarding the influence of sex and CRF and PA on metabolic changes.ObjectiveThe aim of this study was to analyze the effects of CRF and PA on lipid and carbohydrate metabolism biomarkers in boys and girls.MethodsA total of 82 prepubertal boys and 55 girls (7–12 years of age) were classified according to sex, low or high CRF, and performance or nonperformance of PA. Anthropometric and blood pressure (BP) measurements, plasma lipid profile values, glucose and insulin levels, and homeostasis model assessment for insulin resistance were analyzed.ResultsThe percentage of boys with high CRF and performance of PA was higher than that of girls (P < 0.05). When children of the same sex were compared, higher values for body mass index and waist circumference z-scores were found for boys with low CRF compared with boys with high CRF (P < 0.001) without differences between girls, and in all groups classified by PA. Systolic and diastolic BPs were higher in boys than in girls, in both CRF and PA groups (P < 0.05). In the low CRF and no PA groups, girls had higher plasma glucose, total cholesterol, and low-density lipoprotein cholesterol levels than boys, with higher high-density lipoprotein cholesterol and apolipoprotein A levels (P < 0.05).ConclusionsSex in relation to CRF and PA could affect the plasma lipid profile. These changes in girls are associated with low CRF and low levels of PA. Considering these results, we suggest the need to improve CRF and promote PA, especially in girls, to reduce metabolic risk.     

Changes in urinary dinor dihydro F(2)-isoprostane metabolite concentrations, a marker of oxidative stress, during and following asthma exacerbations

To investigate changes in oxidant stress during and following acute asthma exacerbations, this study measured 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), the major urinary metabolite of 15-F(2t)-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F(2)-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89-7.8; follow-up: 2.47 ng/Cr mg (1.56-6.86); discharge: 1.42 ng/Cr mg (0.7-4.44); both p<0.01), but not significantly different between admission and follow-up. F(2)-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31-1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F(2)-IsoP-M concentrations compared to stable asthmatics. F(2)-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F(2)-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.     

Low serum allopregnanolone levels in girls with precocious pubarche

Allopregnanolone, a neuroactive steroid, increases during pubertal development and high concentrations are present in subjects with precocious puberty. The aim of the present study was to evaluate serum allopregnanolone levels in girls with precocious pubarche (PP). Basal gonadotropins and steroid hormones were assessed in 17 girls with PP, 22 girls with central precocious puberty (CPP), 25 girls with normal puberty at the same pubertal stage of CPP ones, and 17 prepubertal girls. Adrenocorticotropin hormone (ACTH) and gonadotropin-releasing hormone (GnRH) stimulation tests were performed in all subjects with PP, and in 12 out of 22 with CPP. All girls with normal puberty underwent to GnRH test, while ACTH test was performed in 17 out of 25. Basal dehydroepiandrosterone sulfate (DHEAS) concentrations resulted significantly higher in PP and normal pubertal girls than in prepubertal ones. Allopregnanolone, gonadotropins and estradiol levels were significantly lower in PP group with respect to CPP (P<0.05), while they were comparable among PP, normal pubertal and prepubertal groups. After ACTH administration, allopregnanolone concentrations significantly increased in all groups (P<0.05). After GnRH stimulation, its levels significantly increased in CPP and normal pubertal controls (P<0.05), while no incremental rise was found in PP girls. In conclusion, our study shows that in girls with PP basal and GnRH-stimulated levels of allopregnanolone are significantly lower than in CPP girls. These data suggest that this neurosteroid may be considered a new marker of pubertal development.     

Racial Differences in the Tracking of Childhood BMI to Adulthood

Objective: The possibility that there are racial differences in the patterns of BMI (kilograms per meter squared) change throughout life has not been examined. For example, the high prevalence of obesity among black women could result from a higher prevalence of obesity among black girls or because normal‐weight black girls experience larger BMI increases in adolescence or adulthood than do their white counterparts. Therefore, we examined the tracking of childhood BMI into adulthood in a biracial (36% black) sample. Research Methods and Procedures: Five‐ to 14‐year‐old children (2392) were followed for (mean) 17 years. Childhood overweight was defined as BMI ≥ 95th percentile, and adult obesity was defined as BMI ≥ 30 kg/m². Results: The tracking of childhood BMI differed between whites and blacks. Among overweight children, 65% of white girls vs. 84% of black girls became obese adults, and predictive values among boys were 71% (whites) vs. 82% (blacks). These racial differences reflected contrasting patterns in the rate of BMI change. Although the initial BMI of black children was not higher than that of white children, BMI increases with age were larger among black girls and overweight black boys than among their white counterparts. In contrast, relatively thin (BMI < 50th percentile) white boys were more likely to become overweight adults than were their black counterparts. Discussion: These findings emphasize the black/white differences in BMI changes with age. Because of the adult health consequences of childhood‐onset obesity, early prevention should be given additional emphasis.