Gastroenteritis caused by Campylobacter concisus.

We describe a case of gastroenteritis caused by Campylobacter concisus. The pathogenic potential of C. concisus has yet to be elucidated. Recent studies indicate an association with enteric disease in immunocompromised patients and inflammatory bowel disease in children. Molecular identification methods may be necessary for identifying certain Campylobacter species because of phenotypic similarity.

Fetectomy alters maternal pituitary-adrenal function in pregnant rhesus macaques.

The interplay between the fetus and mother may play a key role in the regulation of primate pregnancy and parturition. This study was designed to test the hypothesis that fetectomy alters maternal pituitary-adrenal function. Between 117 and 122 days of gestation (term = 167 days), six rhesus macaques underwent surgery for catheter implantation. At surgery the fetuses were removed while the membranes and placenta were left in situ. Six additional intact catheterized pregnant animals served as controls. Animals were maintained under a 12L:12D cycle with lights-on from 0700 to 1900 h. Beginning at least 1 wk after surgery, maternal arterial blood samples were collected at 3-h intervals for 24 h for hormone and catecholamine analysis. This sampling protocol was repeated at weekly intervals until cesarean delivery at 151-157 days of gestation. Following fetectomy, plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were significantly lower (36%, 35%, and 44%, respectively) compared with control animals (P;lt 0.05). Despite a significant reduction in overall levels, the rhythm in maternal plasma cortisol was maintained following fetectomy. Plasma dopamine and norepinephrine were also depressed (P;lt 0.05), whereas epinephrine remained unaffected. Our data clearly demonstrate the role of the fetus in the regulation of the maternal pituitary-adrenal axis during gestation. This interaction plays a significant role in the regulation of maternal endocrine function that may influence the initiation of labor.

Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes.

Mice lacking steroid 5 alpha-reductase 1 and 2 were produced by gene targeting and breeding. Male mice without 5 alpha-reductase 2 or without both enzymes had fully formed internal and external genitalia and were fertile, but had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administration increased seminal vesicle and coagulating gland weights in mice deficient in 5 alpha-reductase 2 and increased the weights of the prostate, seminal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5 alpha-reductases (GI 208335X) decreased prostate and coagulating gland weights of control mice, but had no effect in those lacking 5 alpha-reductase 1 and 2. Castration reduced the sizes of these tissues in animals of all genotypes. Androgen-dependent gene expression was decreased in the seminal vesicles of mice lacking one or more 5 alpha-reductases and was restored by administration of T or DHT. Female mice missing both enzymes exhibited parturition and fecundity defects similar to those of animals without 5 alpha-reductase 1. We conclude that T is the only androgen required for differentiation of the male urogenital tract in mice and that the synthesis of DHT serves largely as a signal amplification mechanism.

Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens.

OBJECTIVES: To determine the effects of a saw palmetto herbal blend (SPHB) compared with finasteride on prostatic tissue androgen levels and to evaluate needle biopsies as a source of tissue for such determinations. METHODS: Prostate levels of testosterone and dihydrotestosterone (DHT) were measured on 5 to 10-mg biopsy specimens (18-gauge needle cores) in three groups of men with symptomatic benign prostatic hyperplasia: 15 men receiving chronic finasteride therapy versus 7 untreated controls; 4 men undergoing prostate adenomectomy to determine sampling variability (10 specimens each); and 40 men participating in a 6-month randomized trial of SPHB versus placebo, before and after treatment. RESULTS: Prostatic tissue DHT levels were found to be several times higher than the levels of testosterone (5.01 versus 1.51 ng/g), that ratio becoming reversed (1.05 versus 3.63 ng/g) with chronic finasteride therapy. The finasteride effect was statistically significant for both androgens (P <0.01), and little overlap of individual values between finasteride-treated and control patients was seen. In the randomized trial, tissue DHT levels were reduced by 32% from 6.49 to 4.40 ng/g in the SPHB group (P <0.005), with no significant change in the placebo group. CONCLUSIONS: For control versus finasteride-treated men, the tissue androgen values obtained with needle biopsy specimens were similar-both for absolute values and the percentage of change-to those previously reported using surgically excised volumes of prostatic tissue. The quantification of prostatic androgens by assay of needle biopsies is thus feasible and offers the possibility of serial studies in individual patients. The SPHB-induced suppression of prostatic DHT levels, modest but significant in a randomized trial, lends an element of support to the hypothesis that inhibition of the enzyme 5-alpha reductase is a mechanism of action of this substance.

Glucocorticoids, androgens, testis mass, and the energetics of vocalization in breeding male frogs.

Male advertisement vocalization in frogs is known to be one of the energetically most expensive activities of ectothermic vertebrates. Glucocorticoids have marked effects on energy metabolism, and, generally, plasma concentrations of glucocorticoids increase during the course of prolonged exercise bouts. Androgen concentrations are also known to vary considerably among breeding male frogs. Intraspecific and interspecific comparisons were used to test for a relationship among androgen concentration, corticosterone concentration, testis mass, and the energetics of vocalization in natural populations of calling male frogs. The results of this study indicate that: (1) intraspecific variation in androgen and corticosteroid concentrations in breeding male frogs is positively correlated as a result of both interindividual variation in the amount of performed vocalization and the relationship between calling effort of an individual male and the level of calling in other males, (2) interspecific variation in corticosteroid concentration of calling male frogs is correlated with the relative energy expended in the species-specific vocalization, and (3) when differences in testis mass are controlled for, vocalization effort is correlated with androgen concentration among species of breeding male frogs. These findings are in contrast to some recent work reported from laboratory experiments on calling frogs.

Short-term folic acid supplementation induces variable and paradoxical changes in plasma homocyst(e)ine concentrations.

Folic acid is presently the mainstay of treatment for most subjects with elevated plasma homocyst(e)ine concentrations [Plasma or serum homocyst(e)ine, or total homocysteine, refers to the sum of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocystein-cysteine, whether free or bound to plasma proteins.] Changes in homocyst(e)ine in response to folic acid supplementation are characterized by considerable interindividual variation. The purpose of this study was to identify factors that contribute to heterogeneity in short-term responses to folic acid supplementation. The effects of folic acid supplementation (1 or 2 mg per day) for 3 wk on plasma homocyst(e)ine concentrations were assessed in 304 men and women. Overall, folic acid supplementation increased mean plasma folate 31.5 +/- 98.0 nmol/L and decreased mean plasma homocyst(e)ine concentrations 1.2 +/- 2.4 micromol/L. There was evidence of substantial interindividual variation in the homocyst(e)ine response from -18.5 to +7.1 micromol/L, including an increase in homocyst(e)ine in 20% of subjects (mean increase 1.5 +/- 1.4 micromol/L). Basal homocyst(e)ine, age, male gender, cigarette smoking, use of multivitamins, methylene tetrahydrofolate reductase, and cystathionine beta-synthase polymorphisms accounted for 47.6% of the interindividual variability in the change in homocyst(e)ine after folic acid supplementation, but about 50% of variability in response to folic acid was not explained by the variables we studied.

Oestrogen upregulates noradrenaline release in the mediobasal hypothalamus and tyrosine hydroxylase gene expression in the brainstem of ovariectomized rhesus macaques.

Noradrenaline plays a key role in the initiation of ovulation in nonprimate species. A similar noradrenaline role in the primate has not been established experimentally. We utilized the ovariectomized-oestrogen-supplemented (OVX + E) rhesus macaque to examine the effects of intravenous (i.v.) infusion of oestradiol-17beta (E2) on the activity of the brain noradrenaline system. Experiment 1 established the induction of a preovulatory surge-like release of luteinizing hormone in OVX + E monkeys by i.v. infusion of E2 (OVX + E + E2). In experiment 2, a marked increase in hypothalamic microdialysate noradrenaline concentrations occurred after identical E2 infusion into the OVX + E monkeys that were used in experiment 1. In experiment 3, tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus of the brainstem increased at various times after E2 infusion as determined by semiquantitative in situ hybridization. The amount of TH mRNA in OVX + E + E2 animals was higher (P < 0.05) than that in either the OVX + E or OVX monkeys; no difference was found in the latter two groups. Moreover, selected locus coeruleus sections from E2-infused monkeys were examined for the localization of oestrogen receptors (ER) by in situ hybridization. Both ER-alpha and ER-beta mRNAs were expressed in the locus coeruleus, although the expression was greater for ER-alpha than for ER-beta. We conclude that i.v. infusion of E2, which induces a preovulatory surge-like release of LH, stimulates brain noradrenaline activity; this enhanced activity likely involves an ER-mediated process and is reflected by hypothalamic noradrenaline release and locus coeruleus TH mRNA expression. The results support the concept that noradrenaline can influence the E2-stimulated ovulation in nonhuman primates and that the brainstem is one of the components in this neuroendocrine process.

Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis.

OBJECTIVE: We studied pregnant women in preterm labor with and without intrauterine infection to determine whether fetal hypothalamic-pituitary-adrenal axis activation occurs in the setting of infection-induced preterm parturition. STUDY DESIGN: Amniotic fluid collected by amniocentesis and maternal blood from patients in preterm labor with intact membranes at 24 to 34 weeks' gestation were analyzed by radioimmunoassay for the steroid hormones estrone, estradiol, progesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol. Amniotic fluid was also obtained for microbial culture and for interleukin 6 measurements by enzyme immunoassay. RESULTS: Patients with intrauterine infection (n = 11) had significantly higher amniotic fluid concentrations of dehydroepiandrosterone (539 +/- 79 pg/mL) and of cortisol (5.28 +/- 1.0 microg/dL) than did patients with preterm labor and preterm delivery without infection (n = 11; 273 +/- 82 pg/mL and 1.61 +/- 1.05 microg/dL, respectively) or patients with preterm labor and subsequent term delivery (n = 11; 202 +/- 79 pg/mL and 1.82 +/- 1.0 microg/dL, respectively). Furthermore those patients who were delivered within 7 days after enrollment (who were also more likely to have intrauterine infection) had higher amniotic fluid concentrations than did those who were not delivered within 7 days of both estrone (586 +/- 101 pg/mL vs 314 +/- 98 pg/mL) and estradiol (238 +/- 44 pg/mL vs 91 +/- 43 pg/mL). CONCLUSION: Intrauterine infection was associated with increased fetal adrenal androgen and cortisol biosynthesis, and delivery within 7 days after the onset of preterm labor was associated with increased placental estrogen synthesis. These data are consistent with fetal hypothalamic-pituitary-adrenal axis activation in the setting of infection-associated preterm delivery.

Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid.

Elevated total plasma homocysteine (tHcy) is an established risk factor for the development of vascular disease and neural tube defects. Total homocysteine levels can be lowered by folic acid supplements but individual response is highly variable. In this case-control study, involving 142 coronary artery disease (CAD) patients and 102 controls, we have typed six genetic polymorphisms in three homocysteine metabolizing genes and examined their relationship to the incidence of CAD, tHcy levels, and lowering of tHcy levels in response to folic acid supplementation. We found that two single nucleotide polymorphisms in the cystathionine beta synthase (CBS) gene, 699C --> T and 1080T --> C, are associated with decreased risk of CAD and increased responsiveness to the tHcy lowering effects of folic acid. Individuals homozygous for 699T were significantly underrepresented in CAD patients as compared to controls (4.9% vs 17.3%, P = 0.0015), as were individuals homozygous for the 1080C (29.6% vs 44.2%, P = 0.018). Additionally, 699T and 1080C homozygous individuals were the most responsive to folate supplementation. 699T homozygotes lowered tHcy levels 13.6% on average, compared to 4.8% lowering in 699C homozygotes (P = 0.009), while 1080C homozygotes lowered 12.9% compared to just 2.7% for 1080T homozygotes (P = 0.005). The two polymorphisms in CBS are third codon changes and would not be predicted to affect the underlying protein. However, there is strong linkage disequilibrium between these two positions, suggesting that they may also be linked to other as yet unidentified polymorphisms within the CBS gene. These observations suggest that specific CBS alleles are a risk factor for the development of vascular disease and that genetic information could be predictive of individual response to folic acid supplementation.

Temporary ovarian inactivity in elephants: relationship to status and time outside.

The captive elephant population in North America is in reproductive decline and, without importation from the wild, may cease to be viable within the next several decades. The estrous cycle of three captive, reproductive-age African elephants was monitored for 3 years by measuring serum progesterone concentrations. Each elephant experienced one or more episodes of extended low progesterone (>12 weeks), analogous to supposed terminal cessation of estrous cyclicity or 'flatlining' that has been described in some captive Asian and African elephants. Other studies have reported lengthy non-luteal (follicular) phases that indicate extended episodes of ovarian inactivity; however, this phenomenon has not been examined in detail. In this study, total duration of temporary ovarian inactivity or acyclicity followed a social rank pattern, with the most subordinate female having the longest and the dominant female the shortest duration. During periods of acyclicity, the number of hours the elephants spent outside was significantly less than during non-luteal or luteal phases of the cycle. Except in one instance, behavioral data recorded by elephant keepers during their interactions with the elephants showed no change in handling during periods of ovarian inactivity. Further study is necessary to distinguish the causative agent for temporary cessation of estrous cyclicity. Understanding this phenomenon is imperative for the future reproductive viability of captive elephant populations.

Alterations in serum steroid concentrations in the clearnose skate, Raja eglanteria: correlations with season and reproductive status.

Serum steroid hormones in the peripheral circulation of the clearnose skate, Raja eglanteria, were measured at the time of capture and at various times throughout the year while the animals were maintained as a captive breeding population. These analyses demonstrate interesting correlations between changes in hormone concentrations and annual reproductive events. Animals were sampled once (78 females, 20 males) or multiple times (15 females). For both groups of females, 17beta-estradiol was detected throughout the year with significant elevations occurring during October and November when ovarian follicles begin to mature (as determined through necropsy examinations), and January and February when maximum mating activity is observed and egg laying begins. Testosterone and dihydrotestosterone concentrations were significantly elevated in females only during January and February. Testosterone elevations were synchronous with longer-term elevations in 17beta-estradiol in females sampled either once or repetitively. Testosterone concentrations in males were significantly elevated during times of maximum breeding activity compared to periods of sexual inactivity. Data from females sampled during five stages of the egg laying process, as defined by the position of palpable egg capsules within the reproductive tract, revealed that 17beta-estradiol was highest when egg capsules were forming in the nidamental gland (stage 2) or uterus (stage 3); testosterone and dihydrotestosterone were maximal when eggs were in the uterus (stage 3) or cloaca (stage 4); and progesterone was significantly elevated immediately after oviposition (stage 5), suggesting a possible role for progesterone in the regulation of sequential laying of egg pairs. J. Exp. Zool. 284:575-585, 1999.

Dynamics of periovulatory steroidogenesis in the rhesus monkey follicle after ovarian stimulation.

The temporal relationships and regulation of events in the primate follicle during the periovulatory interval are poorly understood. This study was designed to elucidate the dynamics of steroid synthesis in the macaque follicle during ovarian stimulation cycles in which serum/follicular fluid aspirates were collected at precise intervals before (0 h) and after (up to 36 h) administration of the ovulatory human chorionic gonadotrophin (HCG) bolus. Serum concentrations of progesterone increased (P < 0.05) within 30 min, and follicular fluid progesterone concentrations were elevated 180-fold within 12 h, of HCG injection, and remained elevated until the time of ovulation. In contrast, 17beta-oestradiol concentrations increased initially, but then declined (P < 0.05) by 36 h post-HCG. Acute incubation of granulosa cells with and without steroidogenic substrates demonstrated that: (i) 3beta-hydroxysteroid dehydrogenase and aromatase activities were present in equivalent amounts before and after HCG; whereas (ii) P450 side-chain cleavage activity increased (P < 0.05) within 12 h of HCG; and (iii) exogenous low-density lipoprotein and cholesterol were not utilized for steroidogenesis. This model should be useful for further studies on ovulation and luteinization in primates, and enable elucidation of the local actions of progesterone and other steroids at specific time points during the periovulatory interval.

Serum prolactin concentrations in the captive female African elephant (Loxodonta africana): potential effects of season and steroid hormone interactions.

Research was conducted to determine whether seasonal changes in prolactin secretion occur in nonpregnant female African elephants and to examine potential functional interrelationships between secretion of prolactin, cortisol, and progesterone. Weekly blood samples were taken for 18 months from four female African elephants and the sera were analyzed by RIA for progesterone, cortisol, and prolactin concentrations. There was no significant effect of season on serum concentrations of prolactin. Estrous cycles averaged 14 weeks in length and were composed of a 9-week luteal phase and a 5-week follicular phase (based on progesterone concentrations consistently >200 and <200 pg/ml, respectively). Estrous cycle synchronicity was evident between pairs of elephants. Serum concentrations of prolactin (3.91 +/- 0.69 ng/ml; range: 0.84-15.8 ng/ml) were significantly lower during the luteal, compared with the follicular, phase (P < 0.0001; t test) and were positively correlated with serum concentrations of cortisol (r = 0.14; P < 0.05). Mean (+/-SE) serum concentration of cortisol was 5.7 +/- 1.3 ng/ml (range: 1.4-19.3 ng/ml), and concentrations of this adrenal steroid were negatively correlated with progesterone concentrations (r = -0.15; P < 0.01). Increased serum concentrations of prolactin detected during the follicular phase suggest that this hormone may be regulated by ovarian estrogens and may play a role in modulating ovarian function in the elephant.

Self-injurious behavior is decreased by cyproterone acetate in adult male rhesus (Macaca mulatta).

Self-injurious behavior (SIB) presents a serious problem in laboratory macaques that cannot be socially housed for scientific reasons and among institutionalized children and adults where it is often associated with different forms of brain dysfunction. We have experienced limited success in reducing SIB in macaques by enhancing their environment with enrichment devices. Psychotropic drugs also help, but problems are associated with their use. Because sexual and aggressive behavioral problems in men have been treated with progestational drugs, we tested the efficacy of cyproterone acetate (CA, 5-10 mg/kg/week) on reducing SIB in 8 singly housed, adult male rhesus macaques. The main findings were: (1) SIB and other atypical behaviors were significantly reduced during CA treatment; (2) serum testosterone was significantly reduced during CA treatment; (3) cerebral spinal fluid (CSF) levels of 5HIAA and HVA, metabolites of serotonin and dopamine, respectively, declined significantly during CA treatment; (4) the duration of SIB positively correlated with levels of 5HIAA in CSF; but (5) sperm counts were not reduced during treatment. Thus, CA was a partially effective treatment (3 months) for adult male macaques whose behavioral problems include SIB. In summary, CA reduced SIB, overall aggression, serum testosterone, CSF 5HIAA, and CSF HVA. We hypothesized that the progestin activity of CA represses the hypothalamic gonadal axis and decreases testosterone, which in turn decreases SIB. In addition, we speculate that the decrease in 5HIAA and HVA in CSF may have been caused by progestins decreasing the activity of MAO. Therefore, the reduction of SIB may also be related to an increase in the availability of active monoamines in the CNS.

Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed. METHODS AND RESULTS: We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5'-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene. CONCLUSIONS: Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B6 offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.

Human chorionic gonadotropin production by the pituitary gland in a premenopausal woman.

OBJECTIVE: Our purpose was to investigate the source of human chorionic gonadotropin production in a nonpregnant, premenopausal woman. STUDY DESIGN: A case of human chorionic gonadotropin production by the pituitary gland in a premenopausal woman is described. RESULTS: Our results confirm that a biologically active human chorionic gonadotropin-like molecule was secreted in a nonpregnant woman. CONCLUSIONS: Our results indicate that the pituitary gland was the most likely source of human chorionic gonadotropin production.

A bolus of recombinant human follicle stimulating hormone at midcycle induces periovulatory events following multiple follicular development in macaques.

The efficacy of follicle stimulating hormone (FSH) as an alternative to luteinizing hormone (LH)/human chorionic gonadotrophin (HCG) for the initiation of periovulatory events in primate follicles is unknown. A single bolus of 2500 IU recombinant (r)-hFSH was compared to 1000 IU r-HCG for its ability to promote oocyte nuclear maturation and fertilization, granulosa cell luteinization and corpus luteum function following r-hFSH (60 IU/day) induction of multiple follicular development in rhesus monkeys. Following the r-hFSH bolus, bioactive luteinizing hormone concentrations were <3 ng/ml. Peak concentrations of serum FSH (1455+/-314 mIU/ml; mean+/-SEM) were attained 2-8 h after r-hFSH, and declined by 96 h. Bioactive HCG concentrations peaked between 2-8 h after r-HCG and remained > or = 100 ng/ml for >48 h, while immunoreactive FSH concentrations were at baseline. The proportion of oocytes resuming meiosis and undergoing in-vitro fertilization (IVF) were comparable for r-hFSH (89%; 47+/-19%) and r-HCG (88%; 50+/-17%). In-vitro progesterone production and expression of progesterone receptors in granulosa cells did not differ between groups. Peak concentrations of serum progesterone in the luteal phase were similar, but were lower 6-9 days post-FSH relative to HCG. Thus, a bolus of r-hFSH was equivalent to r-HCG for the reinitiation of oocyte meiosis, fertilization and granulosa cell luteinization, but a midcycle FSH surge did not sustain normal luteal function in primates.

Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity.

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal-reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.

Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.

BACKGROUND: The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. METHODS: To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. RESULTS: Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 microg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increased plasma folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively. CONCLUSIONS: Cereal fortified with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted.