Decreased training volume and increased carbohydrate intake increases oxidized LDL levels.

We studied effects of probiotics and training volume on oxidized LDL lipids (ox-LDL), serum antioxidant potential (s-TRAP) and serum antioxidants (s-α-tocopherol, s-γ-tocopherol, s-retinol, s-ß-carotene and s-ubiquinone-10) in marathon runners during 3-months training period, 6-days preparation period and marathon run. Runners (n=127) were recruited for a randomized, double-blind intervention during which they received either Lactobacillus rhamnosus GG (LGG, probiotic group) or placebo drink (placebo group) during whole study. During the preparation period, subjects decreased training and increased carbohydrate intake. Blood samples were taken at baseline, before 6-days preparation, before and immediately after the marathon. Probiotics did not have any effect on ox-LDL, s-TRAP or serum antioxidants levels during the study. Interestingly, ox-LDL increased by 28% and 33% during the preparation period and decreased by 16% and 19% during the marathon run in the placebo and probiotic groups, respectively (in all, P<0.001). No changes were seen in s-TRAP before marathon, but during run s-TRAP raised by 16% in both groups (both, P<0.001). The increase of ox-LDL level during the preparative period after several months' training suggests that aerobic training may reduce the concentration of ox-LDL and that decrease of training together with increased energy intake, mainly carbohydrate, before marathon is capable of increasing the level of ox-LDL.

Lactobacillus rhamnosus GG and Streptococcus thermophilus induce suppressor of cytokine signalling 3 (SOCS3) gene expression directly and indirectly via interleukin-10 in human primary macrophages.

In the present study we have characterized T helper type 2 (Th2) [interleukin (IL)-10]/Th1 (IL-12) cytokine expression balance in human primary macrophages stimulated with multiple non-pathogenic Gram-positive bacteria used in the food industry and as probiotic substances. Bacteria representing Lactobacillus, Bifidobacterium, Lactococcus, Leuconostoc, Propionibacterium and Streptococcus species induced anti-inflammatory IL-10 production, although quantitative differences between the bacteria were observed. S. thermophilus was able to induce IL-12 production, while the production of IL-12 induced by other bacteria remained at a low level. The highest anti-inflammatory potential was seen with bifidobacteria, as evidenced by high IL-10/IL-12 induction ratios. All studied non-pathogenic bacteria were able to stimulate the expression of suppressor of cytokine signalling (SOCS) 3 that controls the expression of proinflammatory cytokine genes. Lactobacillus and Streptococcus species induced SOCS3 mRNA expression directly in the absence of protein synthesis and indirectly via bacteria-induced IL-10 production, as demonstrated by experiments with cycloheximide (CHX) and anti-IL-10 antibodies, respectively. The mitogen-activated protein kinase (MAPK) p38 signalling pathway played a key role in bacteria-induced SOCS3 gene expression. Enhanced IL-10 production and SOCS3 gene expression induced by live non-pathogenic Lactobacillus and Streptococcus is also likely to contribute to their immunoregulatory effects in vivo.

Nutritional modulation of exercise-induced immunodepression in athletes: a systematic review and meta-analysis.

BACKGROUND: Heavy exercise induces marked immunodepression that is multifactorial in origin. Nutrition can modulate normal immune function. OBJECTIVE: To assess the efficacy of nutritional supplements in exercise-induced immunodepression in athletes. DESIGN: Systematic review. REVIEW METHODS: Randomised and/or controlled trials of athletes undertaking nutritional supplements to minimise the immunodepression after exercise were retrieved. The primary outcome measure was incidence of upper respiratory tract (URT) illness symptoms after exercise, and secondary outcomes included cortisol, cell counts, plasma cytokine concentration, cell proliferative response, oxidative burst, natural killer cell activity and immunoglobulins. When data were available for a pooled estimate of the effect of intervention, meta-analyses were conducted for direct comparisons. RESULTS: Forty-five studies were included (1603 subjects). The studies were heterogeneous in terms of exercise interventions, selection of athletes, settings and outcomes. The overall methodological quality of most of the trials was poor. Twenty studies addressed carbohydrate supplementation, eight glutamine, 13 vitamin C and four others interventions. Three trials assessed the effect of intervention on prevention of URT infections. The pooled rate ratio for URT infections after vitamin C supplementation against placebo was 0.49 (0.34-0.71). Carbohydrate supplementation attenuated the increase in cortisol and neutrophils after exercise; vitamin C attenuated the decrease in lymphocytes after exercise. No other interventions had significant or consistent effect on any of the studied outcomes. CONCLUSIONS: Although the prevention of URT infections by vitamin C was supported by two trials, further studies are needed. The available evidence failed to support a role for other nutritional supplements in preventing exercise-induced immune suppression. Larger trials with clinically relevant and uniform end points are necessary to clarify the role of these nutritional interventions.

Effect of live and inactivated Lactobacillus rhamnosus GG on experimentally induced rhinovirus colds: randomised, double blind, placebo-controlled pilot trial.

The aim of this work was to investigate the usability of an experimental rhinovirus model in probiotic trials aiming to assess effectiveness in viral infections, and to provide preliminary data of live and inactivated probiotic Lactobacillus rhamnosus GG for larger-scale trials utilising the model. 59 subjects were randomised to receive 100 ml of fruit juice supplemented with 10(9) cfu of live or heat-inactivated (by spray-drying) L. rhamnosus GG or control juice daily for six weeks. After three weeks subjects were intranasally inoculated with experimental rhinovirus. Infection rate (at least one positive culture for challenge virus on five days following inoculation or at least four-fold rise in antibody response to challenge virus) was 14/19 in the group receiving live probiotic strain and 18/20 both in the group receiving heat-inactivated probiotic strain and in the control group (P=0.36). The occurrence and severity of cold symptoms on the five days following the inoculation was lowest in the group receiving live probiotic strain (P=0.45). This trial was the first one dedicated to the investigation of the effect of probiotics using the experimental rhinovirus model. The model showed potential for demonstration of efficacy of probiotics in controlled respiratory viral infections. Occurrence and severity of cold symptoms and number of subjects with rhinovirus infection was lowest in the group receiving live L. rhamnosus GG, but differences were not statistically significant. Further large-scale studies are needed to demonstrate the efficacy of L. rhamnosus GG in respiratory infections.

Sequential regimen of the antiprogesterone RU486 and synthetic progestin for contraception.

OBJECTIVE: To examine the effect of sequential use of the antiprogesterone RU486 and synthetic progestin on ovarian function of healthy women. DESIGN: Healthy women were given a sequential antiprogesterone-progestin treatment. Blood samples were taken twice a week during one control cycle and one to three treatment cycles; prospective analysis. SETTING: The outpatient clinic of the Helsinki City Maternity Hospital, Helsinki, Finland, and Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Helsinki, Finland. PATIENTS: Eleven healthy women, volunteers, 20 to 34 years of age. INTERVENTIONS: A dose of 25 mg/d of RU486 was given during cycle days 1 to 21, and synthetic progestin (5 mg of norethisterone to six and 5 mg of medroxyprogesterone acetate to five women) during cycle days 22 to 31. MAIN OUTCOME MEASURES: Serum P, E2, FSH, and LH were measured from serum samples. RESULTS: In 20 of the 24 treatment cycles analyzed the serum concentrations of P were anovulatory. In the remaining 4 cycles, P levels rose above 3 ng/mL, suggestive of ovulation. Folliculogenesis was not completely inhibited, but serum E2 profiles were subnormal and delayed. Bleeding control was satisfactory. CONCLUSIONS: Antiprogesterone RU486 hampers or delays follicular development, suggesting a possible use as an estrogen-free oral contraceptive. However, the synthetic progestins used in this regimen induced serum P rises in some cycles. The synthetic progestin provides the cycle control, but its possible effect on the reliability of the method remains to be evaluated.

PIP: To assess the effectiveness of an estrogen-free oral contraceptive (OC) involving the sequential administration of an antiprogesterone and synthetic progestin, 11 healthy Finnish women 20-34 years of age were enrolled in a prospective investigation for 1-3 cycles. 25 mg of RU-486 was administered for the first 21 days of the cycle, followed by 5 mg of norethisterone or medroxyprogesterone acetate for the next 10 days. It was hypothesized that prolonged RU-486 administration would prevent the follicle from surviving for ovulation. During the RU-486 phase, P increases above 3 ng/ml (suggestive of ovulation) were recorded in only four of the 24 treatment cycles analyzed. Mean serum estradiol concentrations were 147 pg/ml in ovulatory women and 72 pg/ml in anovulatory women, indicating that follicle development was subnormal and delayed, but not completely inhibited. Baseline secretion of luteinizing hormone (LH) increased during RU-486 administration, while an LH surge greater than 100% over baseline was recorded in the majority of cycles during progestin administration. No significant changes occurred in follicle-stimulating hormone levels. Menstrual bleeding began 1-5 days after progestin discontinuation; women who took norethisterone experienced no breakthrough bleeding or spotting during treatment. It is concluded that the main antiovulatory effect of RU-486 is attributable to its antiprogestational effect on the preovulatory P rise.

Interference with ovulation by sequential treatment with the antiprogesterone RU486 and synthetic progestin.

Seven healthy women were treated with the antiprogesterone RU486, 25 mg/d, on days 1 to 14 of the follicular phase of the menstrual cycle, followed by the synthetic progestin NET in the luteal phase of the cycle. Venous blood samples were collected twice per week. Serum E2, P, and RU486 concentrations were determined by RIAs, and FSH and LH by immunofluorometric assays. Ultrasonography was used to measure the sizes of the follicles. Serum concentrations of FSH and LH were not suppressed during the treatment. Ovulation was apparently suppressed during RU486 treatment according to E2 and P concentrations and ultrasonography findings. During NET treatment, some evidence of ovulation and follicle growth were found during the first treatment periods. During the third treatment cycle, there was no evidence of ovulation (n = 2). Estradiol concentrations were sufficient to stimulate normal proliferative growth of the endometrium during the treatment. Control of bleeding was good. The exact mechanism of action of RU486 on steroid synthesis and ovulation is not clear, but it appears to act at the ovarian level. The evidence indicates that sequential RU486/progestin treatment could be developed to result in suppression of follicular growth and ovulation.

PIP: In Finland, physicians at the outpatient clinic at the Helsinki City Maternity Hospital followed 7 26-38 year old women who took 25 mg RU-486/day during days 1-14 (follicular phase) and 5 mg of norethindrone/day (NET) during days 15-24 (luteal phase) for 1 menstrual cycle or for 3 menstrual cycles to investigate the possibility of sequential use of an antiprogesterone and progestin as an oral contraceptive. They used ultrasonography to monitor follicular growth and obtained blood samples 2 times/week to do radioimmunoassays and immunofluorometric assays to measure estradiol, progesterone, RU-486, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels. They took endometrial biopsies at the end of RU-486 treatment (days 12- 13) and during NET treatment (days 21-22). Before RU-486/NET treatment the physicians performed various tests during a control cycle. RU-486 treatment did not alter FSH or LH levels. Progesterone and estradiol levels and ultrasonography indicated, however, that RU-486 did suppress ovulation. Ovulation and follicle growth did occur during NET treatment, yet during the third cycle no one ovulated. Bleeding control was adequate. It appeared that the mechanism of action of RU-486 on steroid synthesis and ovulation occurred at the ovarian level. Even though RU-486 at least partially inhibited estradiol synthesis, sufficient estradiol remained to stimulate normal proliferative growth of the endometrium. None of the women experienced steroidal side effects from the treatment. These findings indicated that further development of sequential RU-486/progestin treatment could suppress follicular growth and ovulation.

Cyclic progestin administration brings about luteinization during continuous antiprogestin treatment.

The antiprogestin RU 486 has been proposed for use as a contraceptive because it disturbs folliculogenesis and inhibits ovulation when given continuously. In order to achieve regular and predictable withdrawal bleeding and to counteract the continuous influence of estrogen on the endometrium, a sequential, cyclic progestin regimen has been added. The drawback has been the frequent rise in the concentration of serum P, suggesting ovulation. The present pilot study with three subjects was carried out to test whether simultaneous administration of RU 486 and progestin during the second half of the cycle would eliminate the rise in serum P concentrations. Based on elevated serum P values, five of the seven cycles were apparently ovulatory. RU 486 alone, when given throughout the cycle at a dose of 8 mg per day without added progestin, resulted in anovulatory cycles, but the lengths of these cycles were prolonged. We conclude that both simultaneous and sequential cyclic co-administration of progestin with RU 486 abolishes the antiovulatory action of RU 486. This decreases the possibility of using antiprogestins in non-estrogenic contraceptive regimens (unless contraceptive effects of RU 486 exist at the endometrial level).

Pharmacokinetics of mifepristone after low oral doses.

Relatively low doses of the antiprogestin mifepristone (RU 486) have recently proven to be efficient for a variety of possible clinical uses of the drug. However, the pharmacokinetics after low single oral doses have not been characterized. We evaluated the pharmacokinetics of mifepristone following single ingestion of 2 and 25 mg in five women as well as repeated ingestion of 8 mg in two women. Maximal serum concentrations were reached rapidly (within 0.5-2 h) with all doses used. Serum mifepristone concentrations were proportional to the oral doses taken. The mean (+/- SD) areas under the concentration curves (AUCs) (0-24 h) were 1134 (+/- 144), 4846 (+/- 64), and 17,015 (+/- 4,421) h x ng/mL following 2, 8, and 25 mg doses, respectively. No cumulative increases in serum concentrations were detected with prolonged daily administration of 8 mg of mifepristone. The study subjects appeared to vary in their ability to metabolize mifepristone, as two different half-lives (t1/2) emerged after both 2 and 25 mg single doses (24.2 +/- 0.6 [SD] h for three subjects; and 44.4 +/- 1.8 [SD] h for two subjects). We conclude that within the dose range of 2-25 mg/day, the pharmacokinetics of mifepristone are linear, unlike those seen following ingestion of higher daily doses. Keeping in mind previously published data on the biological effects of low dose mifepristone administration, these data infer that certain effects of the drug, such as inhibition of ovulation, might be achieved at serum concentrations of approximately 100 ng/mL.

PIP: At the outpatient clinic of Lohja District Hospital in Lohja, Finland, clinical researchers examined the pharmacokinetics of mifepristone in 5 healthy women, 29-37 years old, receiving a single dose of 2 mg mifepristone and of 25 mg mifepristone and in 2 other women receiving 8 mg mifepristone each day for 30 days. Regardless of the dose, serum concentrations of mifepristone peaked within 1.2-1.4 hours. These concentrations were proportional to the oral doses: 104-227 ng/ml after 2 mg dose; 474-561 ng/ml after 8 mg dose; and 1285-4851 ng/ml after 25 mg dose. The areas under the concentration curves (0-24 hours) were also proportional to the oral doses: 1134.4, 4846, and 17,015.2, respectively. Daily doses of 8 mg mifepristone over 30 days did not effect cumulative increases in serum concentrations. The women taking the 2 mg and 25 mg single oral doses exhibited different half-lives (24.2 [3 women] vs. 44.4 [2 women] hours; p = 0.001), suggesting that they varied in their ability to metabolize mifepristone. These findings show that, at daily ingestion of 2-25 mg mifepristone, the pharmacokinetics of mifepristone are linear. Based on these findings, the authors think that inhibition of ovulation might be achieved at serum concentrations of about 100 ng/ml.

Milk containing probiotic Lactobacillus rhamnosus GG and respiratory illness in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: To determine whether long-term daily consumption of milk containing probiotic Lactobacillus rhamnosus GG (GG) decreases respiratory illness in children. SUBJECTS/METHODS: A randomized, double-blind, placebo-controlled trial was conducted with 523 children aged 2-6 years attending day care centers in Finland. Subjects received either normal milk or the same milk with GG on three daily meals for 28 weeks. Daily recording of children' symptoms was done by parents. Primary outcome data from 501 subjects were available for analysis, and data from 128 subjects were analyzed as completed cases in terms of recovery of GG in fecal samples. RESULTS: Number of days with at least one respiratory symptom in all subjects was 5.03/month (95% confidence interval (CI): 4.92-5.15) in the GG group and 5.17/month (95% CI: 5.05-5.29) in the placebo group incidence rate ratio (IRR) 0.97; 95% CI: 0.94-1.00; P=0.098). In the completed cases, the figures were 4.71 days/month (95% CI: 4.52-4.90) in the GG group and 5.67 days/month (95% CI: 5.40-5.94) in the placebo group (IRR 0.83; 95% CI: 0.78-0.88; P<0.001). CONCLUSIONS: Consumption of GG reduced the occurrence of respiratory illness in children attending day care centers in the completed cases subgroup, but not in the total population. Thus, future clinical trials are warranted to clarify the association between fecal recovery of a probiotic and the symptom prevalence.

Similar effects of leucine rich and regular dairy products on muscle mass and functions of older polymyalgia rheumatica patients: a randomized crossover trial.

OBJECTIVES: Leucine-rich milk and whey proteins have been suggested for prevention of age related loss of muscle mass and strength i.e. sarcopenia. The effects of milk protein supplementation and low intensity home based physical exercise on body composition and muscle functions were investigated. DESIGN: A randomized double blind crossover trial. SETTING: Community dwelling members of Helsinki rheumatoid association. PARTICIPANTS: Older people (N=47, mean age 69.5 years) suffering from polymyalgia rheumatica. INTERVENTION: Patients performed as many stand ups as possible twice a day after which they ingested a regular (Control) or a whey protein enriched dairy product with high leucine content (Test). The 8-week intervention periods were separated by a 4-week wash-out. MEASUREMENTS: Body composition was measured by dual x-ray absorptiometry and muscle functions by hand grip strength, force platform countermovement jump performance, chair stand test, and walking speed. RESULTS: The 16-week home-based post-exercise supplementation resulted in a 1.8% increase (p = 0.052) in lower limb muscle mass. Walking speed (+5.3%, p = 0.007) and chair stand test performance (-12.2 %, p < 0.001) were also improved. Furthermore, a tendency for increased jump power (+3.0%, p = 0.084) was observed. However, significant and consistent differences were not found in the changes of muscle mass indices or muscle functions between supplements, but the test supplement tended to prevent accumulation of body fat. CONCLUSION: A low intensity home based exercise program combined with post-exercise milk protein supplementation is feasible despite some gastrointestinal complaints and seems effective in improving the muscle mass and functions of older persons with a inflammatory disease. Further studies are needed to establish, whether and to what extent the use of leucine-enriched whey products prevent or treat age-associated sarcopenia and whether they are superior to the present commercial milk products.

Dose-response relationships of RU 486.

Clinical experience has indicated that the effects of RU 486 can be divided into dose-dependent and dose-independent effects. Examples of the dose-dependent effects include the antiglucocorticoid effects of RU 486, whereas pregnancy termination or dilatation of the cervix can be considered dose-independent with the various regimens tested so far. Following oral intake in man, the serum levels of RU 486 are in the micromolar range, and the half-life is approximately 30 hours. The concentrations of RU 486 in myometrial tissue are approximately one-third of those measured in serum. However, due to saturation of alpha 1-acid glycoprotein (AAG), the serum binding protein for RU 486, the serum levels remain similar within the dose range of 100-800 mg of RU 486. The unbound RU 486 is metabolized by two-step demethylation or by hydroxylation. The demethylated and hydroxylated metabolites of RU 486 retain considerable affinities of 9-21% towards the human progesterone receptor, and 45-61% towards the human glucocorticoid receptor (RU 486 = 100%), suggesting a biological role for the metabolites. Rat serum lacks a specific binding protein for RU 486. Even though the levels of RU 486 in rat adipose tissue are 40 times as high as those seen in serum, the concentrations of RU 486 in rat brain are only 28% of the serum levels. This indicates that diffusion of RU 486 into the central nervous system is restricted by the blood-brain barrier. Hence, the dose-dependency of certain centrally mediated effects of RU 486 might be explained by the limited diffusion of RU 486 into hypothalamic/hypophyseal sites, which seem to be reached only after ingestion of high doses of RU 486. However, the peripheral effects of RU 486, such as termination of pregnancy, are mediated via steroid receptors in target tissues. This suggests that similar biological effects can be attained at considerably lower doses than the ones currently in use.

PIP: RU-486 has both dose-dependent effects and dose-independent effects. Acute treatment of single doses of at least 400 mg RU-486 increase secretion of adrenocorticotropic hormone. 50-100 mg RU-486 activate the hypothalamo-pituitary-adrenal (HPA) axis. Pregnancy termination and dilatation of the cervix are dose-independent effects. Oral ingestion in humans results in RU-486 serum concentrations in the micromolar range with a half-life of about 30 hours. RU-486 levels in myometrial tissue are about 33% lower than those in the serum. 2-step demethylation or hydroxylation metabolizes unbound R-486. The resulting RU-486 metabolites are able to bond strongly to the human progesterone receptor and to the human glucocorticoid receptor (9-21% and 45-61%, respectively, vs. 100% for RU-486), indicating that the metabolites have a biological role. Research in rats suggests that the blood-brain barrier prevents the diffusion of RU-486 into the central nervous system. Limited diffusion of RU-486 into hypothalamic/hypophyseal sites may account for the dose-dependency of certain centrally mediated effects of RU-486. Oral intake of high doses of RU-486 appears to be the only route to hypothalamic/hypophyseal sites. Steroid receptors in target tissues, e.g., endometrium, mediate RU-486's indirect effects, e.g., pregnancy termination, indicating much lower doses of RU-486 than are now being used can have the same effects.

Twin pregnancy with a fetus in each half of a uterus didelphys.

A rare case of a twin pregnancy with a fetus in each half of a uterus didelphys (double uterus, double cervix and septate vagina) is reported. A longitudinal vaginal septum and two portios were detected during the first labor of this patient. During her second pregnancy ultrasonography was performed in the 16th week, and pregnancy was detected in each half of the double uterus. Both fetuses were of similar size and corresponded to the gestational age. A completely separated double uterus was confirmed by ultrasonography. In the 38th week a female and a male infant were delivered by cesarean section. The follow-up of this pregnancy and the management of the labor are reported.

Effects of intermittent antiprogestin RU486 combined with cyclic medroxyprogesterone acetate on folliculogenesis and ovulation.

The results of several studies have suggested an inhibitory effect of the antiprogestin RU486 on late stages of folliculogenesis and ovulation. To assess the feasibility of using this property to inhibit ovulation without losing cycle control, an intermittent administration of RU486 alternated with medroxyprogesterone acetate (MPA) was tested in a phase I study. RU486 at a dose of 50 mg/day was given on menstrual cycle days 9-11 and 27-29, and 10 mg/day of MPA was given on cycle days 17-26 for three consecutive cycles to six Finnish and five Chilean women. Blood samples were collected two to three times a week for serum progesterone and oestradiol assays in three treatment cycles. One control cycle and one post-treatment recovery cycle were also monitored by serum samplings. Ultrasonography was carried out to measure follicular diameters in the treatment cycles. In 29 of 32 cycles, bleeding commenced within 3 days after the last MPA pill intake. Out of 32 treatment cycles, 20 were without luteal activity (serum progesterone < 9 nmol/l). Although 12 treatment cycles showed luteal activity (serum progesterone > or = 9 nmol/l), a clear rupture of a pre-ovulatory follicle > 15 mm, verified by ultrasonography, was seen in only one treatment cycle. During the treatment cycles with luteal activity (serum progesterone levels > or = 9 nmol/l), serum oestradiol concentrations were significantly higher on cycle days 9-18 and significantly lower at the end of the cycle compared with the cycles without luteal activity.(ABSTRACT TRUNCATED AT 250 WORDS)