Relative bioavailability of ethinyl estradiol from two different oral contraceptive formulations after single oral administration to 18 women in an intraindividual cross-over design

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE2. After single-dose administration of both formulations to 18 women in an intraindividual cross-over design, there was no difference in the target variables for EE2 (Cmax, tmax and AUC). With respect to EE2, both formulations were bioequivalent. The observation of others, reporting higher EE2 levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation, was not confirmed.     

Comparison of serum ethinyl estradiol, sex-hormone-binding globulin, corticoid-binding globulin and cortisol levels in women using two low-dose combined oral contraceptives

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (alpha = 0.05, beta = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE2) levels were analyzed in single and pooled samples using anti-EE2-6 beta-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and Cmax and tmax were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226 nmol/l, 89-93 mg/l and 280-281 micrograms/l, respectively. Mean maximum EE2 levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg.h.ml-1. The recently reported differences in serum EE2 and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.     

Intrasubject variability in the pharmacokinetics of ethynyloestradiol

Intrasubject and intersubject variability in the metabolism of ethynyloestradiol (EE) was assessed in a cross-over randomized study of 6 women who each received 3 months treatment with 50 μg EE and 50 μg EE with 250 μg levonorgestrel (LNG). Blood samples were collected at the end of each treatment month, assayed for EE and the half-life of elimination (T_el and bioavailability (area under the serum concentration-time curve, AUC) calculated. Intrasubject variability for T_el and AUC varied markedly; the variability was random and not correlated with the formulation administered. The intrasubject variability for T_el and AUC was 31 and 17%, respectively, and intersubject variability 66 and 95%. The intersubject range of values was more than 3-fold for both T_el and AUC and the intrasubject range about 2-fold. The pharmacokinetics of EE were not influenced by LNG; mean values for T_el and AUC were 17.3 ± 5.5 h and 11.1 ± 3.8 ng/ml/h, respectively, when EE was administered alone compared with 16.4 ± 4.8 h and 12.5 ± 3.9 ng/ml/h when given with LNG. However, EE influenced the metabolism of LNG; T_el for LNG was 19.3 ± 4.2 h when administered alone and significantly higher (30.0 ± 11.2 h) when given with EE. There was no correlation between the rate of metabolism of EE and that of LNG. The intrasubject variability shown in this and other studies suggests that genetic factors are less important in intersubject variability than previously thought. Some implications of intrasubject variability are discussed.     

Oral contraceptives containing 20 or 30 micrograms ethinylestradiol and 150 micrograms desogestrel: pharmacokinetics and pharmacodynamic parameters

The serum concentrations of ethinylestradiol (EE) and 3-keto-desogestrel (KDG) were compared during treatment with a combination of 20 micrograms EE + 150 micrograms DG (20EE/DG) or of 30 micrograms EE + 150 micrograms DG (30EE/DG). During intake of both preparations, the peak levels and the areas under the curve (AUC) of EE increased significantly by approximately 100% between days 1 and 10. In the steady state, the maximal EE levels were 75 +/- 34 pg/ml (20EE/DG) and 136 +/- 55 pg/ml (30EE/DG), and the AUC were 464 +/- 236 pg.h/ml and 840 +/- 492 pg.h/ml. The KDG levels, which were identical with both preparations, increased between days 1 and 21 by approximately 300% up to values of 4.5 +/- 1.6 ng/ml. There were large interindividual variations in the AUC of EE and KDG and no correlation between the levels of EE and KDG. On day 21 of intake of 30EE/DG, the serum concentrations of sex-hormone- and corticosteroid-binding globulin were higher by 16% and 12%, respectively than with 20EE/DG. Although the morning peak levels of cortisol did not differ, the decrease which occurred thereafter, according to the circadian rhythm, was slower with 30EE/DG. There was no relationship between the serum concentrations of EE and/or KDG and the occurrence of irregular bleedings, which was similar during treatment with both preparations. As most of the women who bled had bleedings both with 20EE/DG and 30EE/DG, an influence of predisposition can be assumed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the role of intestinal bacteria in metabolism of synthetic and natural steroid hormones

Administration of antimicrobial agents to subjects taking oral contraceptives has been reported to lead to contraceptive failure and subsequent pregnancy. In women taking oral contraceptives antimicrobial agents could have an effect on both endogenous hormone levels and on the metabolism of the exogenously administered steroids. To investigate these possibilities, antimicrobial agents were administered for short periods to normal women taking various steroid drugs: Megestrol acetate (MA), medroxyprogesterone acetate (MPA), norethisterone (NET), a combination of NET and ethinylestradiol (EE) or a combination of lynestrenol and EE. During ampicillin administration the 24-h morning plasma concentrations of MA, MPA and NET were increased compared to the control values. In the MA and MPA experiments the afternoon values were determined and also found to be increased. In the subjects taking oral contraceptives plasma EE concentration showed a tendency to decrease during ampicillin administration on the third, fourth or fifth morning of ampicillin administration, but was never lower than the pretreatment values. In other experiments plasma estrone (E1) and estradiol (E2), urinary total E1, E2 and estriol (E3) and fecal unconjugated and conjugated E1, E2 or E3 were determined by RIA before, during and after administration of oxytetracycline (2 X 500 mg/day for 5 days) to 5 young male subjects. Furthermore urinary and fecal estrogens were determined in 1 male subject after administration of erythromycin for 6 days and in 2 normally menstruating women after tetracycline and trimethoprim administration, respectively. During treatment with antimicrobial drugs an increase in the excretion of fecal conjugated and, with the exception of the oxytetracycline experiments, also of unconjugated estrogens paralleled a decrease in urinary estrogen excretion, especially for E2 and E3. In both urine and feces the E1/E2 and E1 + E2/E3 ratios increased due to diminished reductive metabolism of estrogens in the gut. No significant effects on plasma unconjugated estrogen concentrations were observed. The results suggest that the intestinal bacterial flora plays a significant role in estrogen metabolism. However, further studies are necessary, because our results do not explain why administration of antibiotics may cause contraceptive failure.     

Development of a monoclonal antibody for use in radioimmunoassay of ethynylestradiol

Production of monoclonal antibodies (MABs) to a 17 alpha-ethynyl-1,3,5 (10)-estratriene-3,17 beta-diol (ethynylestradiol, EE2) hapten is described. Culture antibodies generated by hybridized cells tested in enzyme-linked immunosorbent assay (ELISA) bound the 6-oxoethynyl-estradiol-6-(0-carboxymethyl) oxime-bovine serum albumin conjugate (EE2-6-0 CMO-BSA) but not BSA. On radioimmunoassay (RIA) with tritiated ethynylestradiol (3H-EE2), some of the antibodies demonstrated high binding affinity (Ka = 2.8 X 10(10) M-1) to EE2. Estradiol-17 beta, estrone and estriol did not show any displacement of 3H-EE2 from the MABs even at high concentration (1 X 10(4) ng/mL). Among the widely used progestins, norethynodrel and norethisterone exhibited considerable cross-reactivity (25.7-100% and 0.3-54.1%, respectively) but not levonor-gestrel with the MABs. The high affinity demonstrated by the MABs to EE2 3-sulfate but not to EE2 17-sulfate and EE2 3,17-disulfate suggests the dominant role of the 17 beta-hydroxyl group in immunogenicity.     

Contribution of diet to the dosing time-dependent change of vitamin D3-induced hypercalcemia in rats

We have recently reported that the degree of hypercalcemia as an adverse effect induced by a single large-dose of active vitamin D3 varied with its dosing time without alteration in therapeutic effect for secondary hyperparathyroidism in patients with chronic renal failure. The present study was conducted to elucidate an effect of intestinal calcium (Ca) absorption on the chronopharmacological profiles of vitamin D3. 1, 25-dihydroxy-cholecalciferol (D3, 2 microg/kg) or vehicle alone was orally administered at two different times (2 and 14 hours after lights on; HALO) to male Wistar rats (n= 10) kept in rooms with a 12 h light-dark cycle. Blood samples for serum Ca concentration were taken before and 3, 6, 9, and 12 hours after the administration. Urine was collected for 6 hours after dosing. An identical protocol was repeated using the same animals after 16 hours fasting by a cross-over fashion. Under free-fed condition, basal concentration of serum Ca was higher at a resting period (lights on) than during an active period (lights off). Serum Ca reached its peak at 6 hours after dosing in both timings, while the value was significantly higher in the 2 HALO trial than in the 14 HALO trial. Area under the serum Ca concentration-time curve from 0 to 12 hours (AUC0-12h) and urinary excretion of Ca for 6 hours were also significantly higher in the 2 HALO trial than in the 14 HALO trial. When fasted, basal Ca concentration was reduced compared with the free-fed condition, while the daily variation was maintained. Serum Ca concentration profiles from 3 to 12 hours after dosing were not significantly different between the 2 HALO and 14 HALO trials. The AUC0-12h of serum Ca or its urinary excretion was not different between both trials. Serum concentrations of parathyroid hormone and total protein, measured before and 6 hours after the dosing were not affected by the dosing schedule. We have concluded that intestinal Ca absorption is a major factor for the chronopharmacological phenomenon of D3-induced hypercalcemia in intact rats, while intestinal and renal involvement may be relatively small in the mechanism of the intrinsic diurnal variation of serum Ca.     

Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: The effect of water and timing of meal intake on oral delivery of Salmon Calcitonin

Background

To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT).

Methods

The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic^® NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration

Results

Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (C_max and AUC_0–4) of plasma sCT but comparable time to reach maximum concentration (T_max). The sCT AUC_0–4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing.

Conclusion

0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.     

Semen traits and metabolic and gonadotropic hormone profiles in ram lambs treated with glucose

Two experiments were conducted to examine reproductive and endocrine responses of ram lambs to exogenous glucose. In Experiment 1, three ram lambs (6 mo of age) received 100 ml ip of saline (0.9%) daily and three animals received 50 g glucose (100 ml 50% dextrose) daily for 18 d. In Experiment 2, ten lambs (5 per group) were treated similarly for 10 d. Serum samples were collected intensively before and after GnRH treatment on the last day of both experiments. After 15 d of glucose treatment in Experiment 1, treated rams weighed 58 kg compared with 68 kg for the controls (P = 0.08). A similar numerical trend was observed in Experiment 2, suggesting that intraperitoneal glucose decreases feed intake. In both experiments, 50 g of glucose induced a rapid elevation in serum glucose to greater than 120 mg/dl compared with 70 to 80 mg/dl for the controls (P < 0.05). Serum insulin rose to over 6 ng/ml in both trials in lambs receiving glucose compared with values of about 2 ng/ml for the controls (P < 0.01). Serum growth hormone was not altered (P > 0.10) by glucose in either experiment and IGF-1 was similar (P > 0.20) between groups in Experiment 2. Although serum concentrations of prolactin tended (P = 0.14) to be reduced by glucose treatment (64 +/- 21 ng/ml) compared with that of the controls (120 +/- 21 ng/ml) in Experiment 1, the opposite trend (P = 0.20) was observed in Experiment 2. Serum thyroxine was elevated (P = 0.08) in glucose-treated rams compared with that in controls in Experiment 2 but triiodothyronine concentrations were similar (P > 0.80) between groups. In Experiment 1, area under the curve (AUC) for LH after a GnRH challenge tended (P = 0.14) to be greater in glucose-treated (1,351 units) than in control (999 +/- 139 units) animals. The AUC for FSH (Experiment 1) did not differ (P = 0.30) between groups. The LH AUC in Experiment 2 was about 2,500 units for both groups (P = 0.80). The AUC for testosterone in Experiment 1, was 5,452 and 2,597 (+/- 1051) units for rams treated with 0 and 50 g glucose/d (P = 0.13), but testosterone AUC in Experiment 2 was similar between groups (P > 0.70). No effect of exogenous glucose was evident in either experiment for semen traits. Results suggest that 50 g ip glucose daily for 10 or 18 d induced large increases in serum insulin but other metabolic and reproductive hormones were not greatly influenced.     

Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women

ObjectiveTo investigate the pharmacokinetics of 17β-estradiol (E2) administered orally versus those of 17β-E2 administered sublingually in transgender women.MethodsSingle doses of 17β-E2 were administered orally (1 mg) to 10 transgender women and then sublingually (1 mg) after a 1-week washout period. Blood samples were collected at baseline (0 hour) and at 1, 2, 3, 4, 6, and 8 hours after dosing. The samples were frozen and analyzed using liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay.ResultsThe results demonstrated that sublingual E2 had a significantly higher peak serum E2 concentration of 144 pg/mL, measured using LC-MS/MS, compared with an oral E2 concentration of 35 pg/mL, measured using LC-MS/MS (P = .003). Sublingual E2 peaked at 1 hour and oral E2 peaked at 8 hours, as measured using LC-MS/MS. The area under the curve (AUC) (0-8 hours) for sublingual E2, measured using LC-MS/MS, was 1.8-fold higher than the AUC (0-8 hours) for oral E2, measured using LC-MS/MS. Additionally, sublingual E2 was found to have an increased E2-to-estrone ratio at all time points (1.1 ± 1.0 vs 0.7 ± 0.4, P ≤ .0001), the clinical significance of which is unclear.ConclusionOral E2 administered sublingually has a different pharmacokinetic profile, with higher serum E2 levels and AUC (0-8 hours) than traditionally administered oral E2. Multidaily dosing may be necessary to suppress testosterone levels with sublingual E2. The appropriate dosing, efficacy, and safety of sublingual E2, compared with those of other E2 preparations, are unknown.     

高龄患者腹腔镜结直肠癌根治术围手术期对机体应激及内脏蛋白的影响

目的:研究高龄病人(75岁以上)腹腔镜与开腹结直肠癌根治术围手术期白介素6(IL-6)、IL-10和C反应蛋白(CRP)及内脏蛋白的差异.方法:将41例行结直肠癌根治术的高龄患者按患者意愿分为腹腔镜组(n=20)和开腹组(n=21),两组患者的一般资料如年龄、性别、体重指数(BMI)等有可比性,检测两组患者术前、术后的应激指标:血清IL-6、IL-10和CRP及营养蛋白:前白蛋白(prealbumin,PRE)、转铁蛋白(transferrin,TRF)、视黄醇结合蛋(retinal-binding protein,RbP)的变化.结果:两组患者CRP在术后1、2、3d均较术前明显升高(P<0.01),术后2d达到峰值,腹腔镜组术后CRP明显低于开腹组(P<0.01);两组患者血清IL-6、IL-10术后也明显升高,腹腔镜组明显低于开腹组(P<0.01),但IL-10升高持续时间短.PRE、TRF、RbP术后两组均较术前有明显下降(P<0.01),术后1 d、2 d两组各指标无显著性差异(P>0.05),术后3 d腹腔镜组4种蛋白指标均明显高于开腹组(P<0.01).结论:对高龄病人两种不同手术方式应激水平及内脏蛋白指标的研究提示,腹腔镜结直肠癌根治术较开腹手术创伤小,应激水平低,有利于机体内脏蛋白的恢复,这对微创外科的实施是一个有力支持.     

Levels of serum creatine kinase and myoglobin in women after two isometric exercise conditions

The purpose of this study was to measure serum creatine kinase (CK) activity and serum myoglobin (MG) concentrations in women after two unilateral isometric knee extension exercises. Forty maximal voluntary contractions (MVC) were held for 10 s, with either a 5 s (10:5) or 20 s 10:20 exercise (349.4 +/- 66.1 mU . ml-1) and 6 h and MG values were measured pre, 0, 3, 6, and 18 h post exercise. For CK, the highest post exercise values were observed at 6 h following the 10:20 exercise (349.4 +/- 66.1 mU . ml-1) and 6 h following the 10:5 exercise (194.1 +/- 18.6 mU . ml-1). For MG, the highest values were found 3 h after the 10:20 exercise (148.9 +/- 61.7 ng . ml-1) and 6 h after the 10:5 exercise (67.3 +/- 10.9 ng . ml-1). Serum CK and MG levels were significantly greater (p less than 0.01) after the 10:20 exercise bout. The data demonstrate that CK and MG values for women increase significantly after isometric exercise. Since greater tension levels were maintained during the 10:20 exercise it is hypothesized that increased serum CK and MG values after isometric exercise may be related to the tension generated by the contracting muscle.     

Immunological and cardiometabolic risk factors in the prediction of type 2 diabetes and coronary events: MONICA/KORA Augsburg case-cohort study

Background

This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort.

Methods and Findings

Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike''s information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092–0.149] and 0.113 [0.093–0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028–0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013–0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028–0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003–0.021] compared to the cardiometabolic risk model), respectively.

Conclusions

Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint.     

Cytokine production by peripheral blood mononuclear cells in recurrent miscarriage

It has been postulated that a proportion of recurrent miscarriage (RM) might be due to immune causes. The objective was to determine whether cytokine expression in peripheral blood mononuclear cell is altered in patients with a history of RM. We compared the levels of IL-2, IL-4, IL-10, IL-13, TGFbeta1 and IFNgamma in the supernatant of Phytohemagglutinin stimulated mononuclear cells in 21 women with RM at the time of 3rd or higher abortion (group I), 32 women who were at least 3 months past their 3rd or higher abortion (group II) and 32 pregnant women with no history of abortion (group III). Gestational age was matched between groups I and III. Group I had higher level of IL-2 than group III (P=0.001). Group II showed higher level of IL-2 (P=0.001) and IFNgamma (P=0.015) than group III. The production of IL-10 by mononuclear cells of group III was higher than both group I (P=0.002) and group II (P=0.001). There was no difference in the levels of IL-2, IL-10 and IFNgamma between groups I and II. Also, the levels of IL-4, IL-13, and TGFbeta1 were similar among the groups. The data indicate an elevation of Th1 cytokines in women with RM as compared to normal pregnant women, and IL-10 is an important cytokine in the maintenance of pregnancy.     

Postprandial endothelial function does not differ in women by race: an insulin resistance paradox?

Insulin resistance is associated with endothelial dysfunction. Because African-American women are more insulin-resistant than white women, it is assumed that African-American women have impaired endothelial function. However, racial differences in postprandial endothelial function have not been examined. In this study, we test the hypothesis that African-American women have impaired postprandial endothelial function compared with white women. Postprandial endothelial function following a breakfast (20% protein, 40% fat, and 40% carbohydrate) was evaluated in 36 (18 African-American women, 18 white women) age- and body mass index (BMI)-matched (age: 37 ± 11 yr; BMI: 30 ± 6 kg/m(2)) women. Endothelial function, defined by percent change in brachial artery flow-mediated dilation (FMD), was measured at 0, 2, 4, and 6 h following a meal. There were no significant differences between the groups in baseline FMD, total body fat, abdominal visceral fat, and fasting levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, or serum estradiol. Although African-American women were less insulin-sensitive [insulin sensitivity index (mean ± SD): 3.6 ± 1.5 vs. 5.2 ± 2.6, P = 0.02], both fasting triglyceride (TG: 56 ± 37 vs. 97 ± 49 mg/dl, P = 0.007) and incremental TG area under the curve (AUC(0-6hr): 279 ± 190 vs. 492 ± 255 mg·dl(-1)·min(-1)·10(-2), P = 0.008) were lower in African-American than white women. Breakfast was associated with a significant increase in FMD in whites and African-Americans, and there was no significant difference in postprandial FMD between the groups (P > 0.1 for group × time interactions). Despite being insulin-resistant, postprandial endothelial function in African-American women was comparable to white women. These results imply that insulin sensitivity may not be an important determinant of racial differences in endothelial function.     

Effect of resistance exercise on postprandial lipemia.

The purpose of this study was to examine the effect of resistance exercise on postprandial lipemia. Fourteen young men and women participated in each of three treatments: 1) control (Con), 2) resistance exercise (RE), and 3) aerobic exercise (AE) estimated to have an energy expenditure (EE) equal that for RE. Each trial consisted of performing a treatment on day 1 and ingesting a fat-tolerance test meal 16 h later (day 2). Resting metabolic rate and fat oxidation were measured at baseline and at 3 and 6 h postprandial on day 2. Blood was collected at baseline and at 0.5, 1, 2, 3, 4, 5, and 6 h after meal ingestion. RE and AE were similar in EE [1.7 +/- 0.1 vs. 1.6 +/- 0.1 (SE) MJ, respectively], as measured by using the Cosmed K4b(2). Baseline triglycerides (TG) were significantly lower after RE than after Con (19%) and AE (21%). Furthermore, the area under the postprandial response curve for TG, adjusted for baseline differences, was significantly lower after RE than after Con (14%) and AE (18%). Resting fat oxidation was significantly greater after RE than after Con (21%) and AE (28%). These results indicate that resistance exercise lowers baseline and postprandial TG, and increases resting fat oxidation, 16 h after exercise.     

Role of gonadotropins and insulin in controlling steroidogenesis and growth of antral bovine follicles in perifusion culture

Bovine follicles (2 to 4 mm in diameter) were isolated from the ovaries of 4-to 6-mo-old Holstein calves and placed in perifusion culture. Groups of 6 to 8 follicles/flask were cultured for 4 or 21 h with 1) no hormones; 2) tonic follicle-stimulating hormone (FSH) (10 ng/ml) and luteinizing hormone (LH) pulses (4 ng/ml) once every 4 h; 3) insulin (200 I.U./l); or 4) tonic FSH, LH pulses and insulin. After 0, 4 and 21 h of perifusion culture, each follicle was incubated in 1 ml of medium containing 3(H)-thymidine for 1 h. The 3(H)-thymidine incorporated into DNA of the follicle as well as the amount of estradiol-17 (E2) and testosterone (T) secreted into the medium were determined. Follicles treated with or without gonadotropins secreted higher levels of E2 and T after 4 h of perifusion compared to the 0 h controls. This elevated secretion rate was not maintained and 3(H)-thymidine incorporation was not increased over 0 h control values after 21 h of culture. Insulin suppressed the T secretion after 4 h in culture and increased 3(H)-thymidine incorporation at both 4 and 21 h of culture. After 21 h of culture, the gonadotropin and insulin treatment also enhanced 3(H)-thymidine incorporation. These results demonstrate that insulin is more mitogenic than the gonadotropin treatment tested, suggesting that insulin or insulin-like factors may play a physiological role in the growth of bovine follicles in vivo.     

Acute heat stress prior to downhill running may enhance skeletal muscle remodeling

Heat shock proteins (HSPs) are chaperones that are known to have important roles in facilitating protein synthesis, protein assembly and cellular protection. While HSPs are known to be induced by damaging exercise, little is known about how HSPs actually mediate skeletal muscle adaption to exercise. The purpose of this study was to determine the effects of a heat shock pretreatment and the ensuing increase in HSP expression on early remodeling and signaling (2 and 48 h) events of the soleus (Sol) muscle following a bout of downhill running. Male Wistar rats (10 weeks old) were randomly assigned to control, eccentric exercise (EE; downhill running) or heat shock + eccentric exercise (HS; 41°C for 20 min, 48 h prior to exercise) groups. Markers of muscle damage, muscle regeneration and intracellular signaling were assessed. The phosphorylation (p) of HSP25, Akt, p70s6k, ERK1/2 and JNK proteins was also performed. As expected, following exercise the EE group had increased creatine kinase (CK; 2 h) and mononuclear cell infiltration (48 h) compared to controls. The EE group had an increase in p-HSP25, but there was no change in HSP72 expression, total protein concentration, or neonatal MHC content. Additionally, the EE group had increased p-p70s6k, p-ERK1/2, and p-JNK (2 h) compared to controls; however no changes in p-Akt were seen. In contrast, the HS group had reduced CK (2 h) and mononuclear cell infiltration (48 h) compared to EE. Moreover, the HS group had increased HSP72 content (2 and 48 h), total protein concentration (48 h), neonatal MHC content (2 and 48 h), p-HSP25 and p-p70s6k (2 h). Lastly, the HS group had reduced p-Akt (48 h) and p-ERK1/2 (2 h). These data suggest that heat shock pretreatment and/or the ensuing HSP72 response may protect against muscle damage, and enhance increases in total protein and neonatal MHC content following exercise. These changes appear to be independent of Akt and MAPK signaling pathways.     

First-Trimester Maternal Serum Levels of sFLT1, PGF and ADMA Predict Preeclampsia

Background

Placental growth factor (PGF), soluble fms-like tyrosine kinase 1 (sFLT1) and asymmetric dimethylarginine (ADMA) are involved in the pathogenesis of preeclampsia. Abnormal maternal sFLT1, PGF and ADMA levels are detectable weeks before the onset of preeclampsia.

Objective

To investigate sFLT1, PGF and ADMA in the first trimester of pregnancy as predictors of preeclampsia.

Methods

In this prospective nested case-control study, 740 pregnant women enrolled at 12–16 weeks of gestation and followed up until 6 weeks after delivery at the Shanghai First Maternity and Infant Health Hospital of Tongji University between January 2010 and December 2012. Forty-four women developed preeclampsia. Urinary proteins were measured using 24-hour collection or dipsticks. sFLT1, PGF and ADMA were measured by ELISA in the first trimester. Pulsatility index (PI) was measured by Doppler ultrasound in the second trimester.

Results

First-trimester serum sFLT1 and ADMA levels of women who developed preeclampsia were significantly higher compared with women with normal pregnancies (sFLT1: 0.321±0.023 vs. 0.308±0.019 ng/ml, P = 0.001; ADMA: 0.86±0.16 vs. 0.68±0.20 μM, P<0.001). First-trimester serum PGF levels of women who developed preeclampsia were significantly lower than in women with normal pregnancies (115.72±32.55 vs. 217.30±74.48 pg/ml, P<0.001). Multiple logistic regression and receiver-operating characteristic curves identified first-trimester PGF and ADMA to be sensitive and selective predictors of preeclampsia (area under the curve [AUC]: 0.902), as well as second-trimester uterine artery pulse index (AUC: 0.836).

Conclusion

In the first trimester, maternal serum sFLT1, PGF and ADMA levels, as well as second-trimester uterine artery PI, could predict preeclampsia.